Competition for publication in Diabetologia continues to grow, and less than 20% of papers are accepted. Of all the high-quality papers I want to draw your attention to articles that I think stand out in some regard and are very interesting. The articles are summarised here. Our publisher, Springer, has kindly made the full text of each of these papers freely available. I hope you enjoy reading them! These will be featured ‘up front’ in the print issue and here on our website. Hindrik Mulder, Editor
Sandra S. Hammer, Cristiano P. Vieira, Delaney McFarland, Maximilian Sandler, Yan Levitsky, Tim F. Dorweiler, Todd A. Lydic, Bright Asare-Bediako, Yvonne Adu-Agyeiwaah, Micheli S. Sielski, Mariana Dupont, Ana Leda Longhini, Sergio Li Calzi, Dibyendu Chakraborty, Gail M. Seigel, Denis A. Proshlyakov, Maria B. Grant, Julia V. Busik
Intermittent fasting has been shown to exert beneficial effects by improving metabolic health. It has also been shown to prevent the development of diabetic retinopathy in mouse models of diabetes. The mechanism(s) responsible for these advantageous effects, however, remains undefined. Sirtuin 1 (SIRT1) is a nutrient-sensing deacetylase that is activated in low-nutrient environments (such as intermittent fasting) and downregulated in diabetes. In this issue, Hammer et al (https://doi.org/10.1007/s00125-021-05431-5) demonstrate that activation of SIRT1/liver X receptor alpha (LXRα) signalling prevents diabetes-induced retinal damage in both cell culture and animal models of diabetes. Specifically, the authors show prevention of inflammation and cell death in neurovascular retinal cells in diabetes, as well as improvement of bone marrow health in diabetic mice via SIRT1 activation. Pharmacological SIRT1 activation also prevented diabetes-induced visual function impairment in mouse models of type 2 diabetes. The authors conclude that these findings suggest that activation of SIRT1 signalling can provide a mechanistic link between the advantageous effects associated with fasting regimens and improvements in metabolic health in diabetes.
Éva Korpos, Nadir Kadri, Sophie Loismann, Clais R. Findeisen, Frank Arfuso, George W. Burke III, Sarah J. Richardson, Noel G. Morgan, Marika Bogdani, Alberto Pugliese, Lydia Sorokin
Tertiary lymphoid organs (TLOs) show structural and functional similarities to secondary lymphoid organs. They form in non-lymphoid tissues to generate local immune responses during chronic infection, autoimmunity and cancer. In this issue, Korpos et al (https://doi.org/10.1007/s00125-021-05453-z) show the presence of TLOs in the pancreas of individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: (1) at risk of diabetes (autoantibody positive); (2) at/after diagnosis; and (3) in the transplanted pancreas with recurrent diabetes. The authors report that pancreatic TLOs in humans with type 1 diabetes and mouse models of type 1 diabetes are structurally and molecularly similar, exhibiting high endothelial venule formation, a biochemically similar reticular fibre network, fibroblastic reticular cells and T and B cells. TLOs were mostly associated with insulin-positive islets containing immune cell aggregates. Based on these findings, the authors suggest that TLOs are potential sites of autoreactive effector T cell generation in islet autoimmunity and may contribute to the progression of disease.
David Nathanson, Ann-Marie Svensson, Mervete Miftaraj, Stefan Franzén, Jan Bolinder, Katarina Eeg-Olofsson
The increasing use of glucose-sensor technologies makes it difficult to design long-term randomised controlled trials with conventional self-monitoring of blood glucose (SMBG) as a comparator. Instead, the evidence regarding the effectiveness of flash glucose monitoring (FM) is largely derived from observational data lacking well-matched non-FM-using control participants. In this issue, Nathanson et al (https://doi.org/10.1007/s00125-021-05437-z) used data from the Swedish National Diabetes Registry (NDR) to investigate long-term changes in glucose control after initiation of FM in comparison with conventional SMBG. The authors also assessed the efficacy of FM in alleviating the incidence of severe hypoglycaemic events. Nathanson and colleagues identified all adults with type 1 diabetes using FM for 2 years, as well as continuous glucose monitoring (CGM)/FM-naive individuals. Propensity scores and inverse probability of treatment weighting were used to balance the groups. The analyses showed a small and lasting decrease in HbA1c in FM users compared with control individuals and a 21% reduction in severe hypoglycaemic events. The authors conclude that FM is associated with improvements in HbA1c and alleviation of severe hypoglycaemia, which supports the use of FM in adults with type 1 diabetes. However, the long-term clinical significance of the modest lowering of HbA1c achieved by FM use remains to be elucidated.
Mugdha V. Joglekar, Wilson K. M. Wong, Fahmida K. Ema, Harry M. Georgiou, Alexis Shub, Anandwardhan A. Hardikar, Martha Lappas
Women with diabetes during pregnancy are at higher risk of developing type 2 diabetes in later life than mothers without any history of gestational diabetes. Although clinical tests enable the identification of mothers at risk of type 2 diabetes, more accurate methodologies for early diabetes prediction are needed. In this issue, Joglekar et al (https://doi.org/10.1007/s00125-021-05429-z) used supervised learning methods to identify circulating microRNAs associated with future type 2 diabetes risk in women with gestational diabetes, post-delivery. They found that levels of specific microRNAs at 12 weeks after delivery predicted diabetes progression over the next 10 years and enhanced current clinical risk-stratification methods. Their results demonstrate the potential of using circulating microRNA biomarkers in the early prediction of future diabetes. The authors conclude that these findings may help to facilitate more accurate identification of mothers at risk of diabetes and make way to interventions that could prevent diabetes in later life.
Amalia Gastaldelli, Norbert Stefan, Hans-Ulrich Häring
The global epidemic of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and the high prevalence of these diseases among individuals with type 2 diabetes have caught the attention of researchers and clinicians treating patients with diabetes affecting the liver. Many drugs are in the pipeline for the treatment of NAFLD/NASH and several glucose-lowering drugs have now been tested specifically for the treatment of liver disease. In this issue, Gastaldelli et al (https://doi.org/10.1007/s00125-021-05442-2) review and appraise the various pharmacological treatment approaches predominantly targeting the liver that have been approved or are in development for the treatment of diabetes and NAFLD/NASH. The authors conclude that the improvement of hyperglycaemia and/or insulin resistance, as well as lipid metabolism, in response to many of these drugs is beneficial for the liver in both type 2 diabetes and NAFLD/NASH. The figure from this review is available as a downloadable slide.
Nima Purvis, Sweta Kumari, Dhananjie Chandrasekera, Jayanthi Bellae Papannarao, Sophie Gandhi, Isabelle van Hout, Sean Coffey, Richard Bunton, Ramanen Sugunesegran, Dominic Parry, Philip Davis, Michael J. A. Williams, Andrew Bahn, Rajesh Katare
Stem cell therapies promise to regenerate the diseased heart by replacing dead cardiac cells and stimulating new blood vessels. However, this approach is limited in individuals with diabetes due to a marked reduction in the number and functional efficacy of cardiac progenitor cells (CPC). In this issue, Purvis et al (https://doi.org/10.1007/s00125-021-05405-7) identified the dysregulation of microRNAs associated with survival, proliferation and self-renewal of CPCs in the diabetic heart. In addition, they demonstrated that therapeutic restoration of microRNA-30c-5p, one of the downregulated microRNAs in diabetic CPCs, activated endogenous stem cells in the diabetic heart and improved their survival by inhibiting pro-apoptotic voltage-dependent anion-selective channel 1 (VDAC1), the direct target of microRNA-30c-5p. The authors conclude that these findings emphasise the need for an understanding of the nature and condition of progenitor/stem cells of diabetic individuals before microRNA-targeted therapy can be used to activate endogenous stem cells in the heart, thereby eliminating the need for stem cell transplantation.
Felicia Gerst, Elisabeth Kemter, Estela Lorza-Gil, Gabriele Kaiser, Ann-Kathrin Fritz, Rita Nano, Lorenzo Piemonti, Marie Gauder, Andreas Dahl, Silvio Nadalin, Alfred Königsrainer, Falko Fend, Andreas L. Birkenfeld, Robert Wagner, Martin Heni, Norbert Stefan, Eckhard Wolf, Hans-Ulrich Häring, Susanne Ullrich
There is accumulating evidence that beta cells acquire a neonatal-like phenotype in type 2 diabetes, i.e. increased basal secretion and reduced glucose responsiveness. The loss of functional maturity occurs early during disease development and hepatic steatosis could be a driver of this process. Fetuin-A is a fetal glycoprotein that is downregulated post-partum, but the secretion of which is increased by hepatocytes of the fatty liver. This glycoprotein is also a marker of insulin resistance and a risk factor for type 2 diabetes. In this issue, Gerst et al (https://doi.org/10.1007/s00125-021-05435-1) report that fetuin-A restrains functional maturity of both neonatal and adult beta cells. They show that fetuin-A impairs TGFβ receptor (TGFBR)–SMAD2/3 signalling, thereby curtailing expression of genes governing beta cell identity. It is also shown to reduce adaptive proliferation via downregulation of forkhead box M1 (FOXM1) targets. By doing so, fetuin-A impairs glucose responsiveness and decreases beta cells mass. Indeed, the authors found a negative correlation between plasma fetuin-A level and beta cell area in individuals without diabetes. The authors conclude that their findings suggest that therapies effectively counteracting hepatic steatosis may also prevent beta cell failure and the onset of type 2 diabetes.
Anita Jeyam, Fraser W. Gibb, John A. McKnight, Brian Kennon, Joseph E. O’Reilly, Thomas M. Caparrotta, Andreas Höhn, Stuart J. McGurnaghan, Luke A. K. Blackbourn, Sara Hatam, Rory J. McCrimmon, Graham Leese, Robert S. Lindsay, John Petrie, John Chalmers, Sam Philip, Sarah H. Wild, Naveed Sattar, Paul M. McKeigue, Helen M. Colhoun, On behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group
As the use of continuous subcutaneous insulin infusion (CSII) to aid diabetes management becomes more widespread, there is still uncertainty regarding its effectiveness and safety. In this issue, Jeyam et al (https://doi.org/10.1007/s00125-021-05413-7) report that, among the Scottish population with type 1 diabetes, CSII initiation is associated with reductions in HbA1c in both adults and children, with the largest improvements being observed in those with the highest starting HbA1c levels. They also report CSII initiation to be associated with an overall reduction in the incidence of severe hospitalised hypoglycaemia and diabetic ketoacidosis, though directions of associations varied across age groups for the latter. Finally, they highlight the existing socioeconomic disparities in CSII usage between least and most deprived areas. The authors conclude that CSII is a promising option for improving glycaemic control, especially for those with high HbA1c levels.
Wolfgang Rathmann, Brenda Bongaerts
Pharmacogenetics is still an emerging field, and there remains a lack of studies on the role of gene variants in treatment responses to novel glucose-lowering drugs (e.g. dipeptidyl peptidase-4 inhibitors [DPP-4i], glucagon-like peptide-1 receptor agonists [GLP-1 RA] and sodium–glucose cotransporter 2 inhibitors [SGLT2i]). In this issue, Rathmann and Bongaerts (https://doi.org/10.1007/s00125-021-05402-w) discuss gene variants related to metabolic responses to these novel agents, including glycaemic effects, diabetes-related metabolic traits and body-weight changes. For example, some studies have indicated a reduced glycaemic response to DPP-4i in individuals carrying GLP1R variants. On the other hand, greater weight reductions with GLP-1 RA were reported in carriers of certain GLP1R variants. For type 2 diabetes risk genes, the authors highlight that the magnitude of HbA1c reductions under DPP-4i therapy is dependent on genotype: HbA1c reductions were larger in those carrying a CDKAL1 variant vs those carrying two copies of the common alleles, whilst it was smaller in individuals carrying a specific TCF7L2 variant (rs7903146 TT genotype). Meanwhile, studies on SGLT2i have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2), but the few pieces of data available indicate no effects. The authors suggest that further identification of type 2 diabetes subtypes will be necessary before pharmacogenetic insights can be used for stratified prescription of novel glucose-lowering drugs.
Bruce A. Perkins, Leif Erik Lovblom, Sebastien O. Lanctôt, Krista Lamb, David Z. I. Cherney
Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. These have led to the discovery that many individuals retain insulin production and, other than for diabetic neuropathy, appear to resist the development of microvascular and macrovascular complications. In this issue, Perkins and colleagues (https://doi.org/10.1007/s00125-021-05403-9) consider the putative mechanisms underlying this phenomenon. They also discuss mechanisms that may result in the maintenance or recovery of beta cells and their function, which include: activation of specific glycolytic enzymes, such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin–angiotensin–aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint pathways. The authors conclude that these mechanisms may, in the future, serve as therapeutic targets. The figures from this review are available as a downloadable slideset.
Andrew P. McGovern, Nick J. Thomas, Sebastian J. Vollmer, Andrew T. Hattersley, Bilal A. Mateen, John M. Dennis
In this issue, McGovern et al (https://doi.org/10.1007/s00125-021-05404-8) investigate the combined effects of age and diabetes on Coronavirus disease-2019 (COVID-19) mortality. Triangulating published data from large UK population-based (OpenSAFELY [n=17,278,392] and QCOVID [n=6,083,102]) and critical care-based (COVID-19 Hospitalisation in England Surveillance System [CHESS] cohort [n=19,256]) studies, the authors describe a disproportionate excess relative mortality risk in younger people with diabetes compared with older people with diabetes. For example, a person aged 40 years with diabetes has the equivalent COVID-19 mortality risk of a 60-year-old person without diabetes: an additional risk of 20 years. This difference reduces significantly with increasing age, so that a person aged 70 with diabetes has the equivalent COVID-19 mortality risk of a 78-year-old person without diabetes: an additional risk of just 8 years. The authors suggest that country-level strategies to define priority groups for vaccination should consider the disproportionate relative risk of COVID-19 mortality in middle-aged people with diabetes.
Mengliu Yang, Sheng Qiu, Yirui He, Ling Li, Tong Wu, Ning Ding, Fanghong Li, Allan Z. Zhao, Gangyi Yang
Besides serving as a traditional inflammatory marker in the clinic, C-reactive protein (CRP) is positively associated with the development of obesity, diabetes and cardiovascular diseases. However, genetic evidence is needed to definitively conclude whether CRP directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker for these. In this issue, Yang, Qiu et al (https://doi.org/10.1007/s00125-021-05384-9) report on a Crp knockout rat model generated to investigate this question. They found that CRP-deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to a high-fat diet. Importantly, it also significantly enhanced the weight-reducing effect of leptin. The authors state that this study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes, but that it also directly regulates adiposity and insulin sensitivity. They conclude that, clinically, elevated blood CRP levels will negate leptin’s actions. Hence, reduction of CRP-induced leptin resistance may be a promising therapeutic strategy for the treatment of obesity and type 2 diabetes.
Mu Zhang, Chunjie Yang, Meng Zhu, Li Qian, Yan Luo, Huimin Cheng, Rong Geng, Xiaojun Xu, Cheng Qian, Yu Liu
Failure of pancreatic and duodenal homeobox factor 1 (PDX1) to localise in the nucleus of islet beta cells under high-fat-diet conditions may contribute to beta cell failure in type 2 diabetes; however, the mechanism of PDX1 intracellular mislocalisation is unclear. Saturated fatty acids (SFAs) are known to be adverse factors in blood glucose regulation, but the underlying mechanisms for this are unknown. Owing to their biochemical features, SFAs are involved in liquid–liquid phase separation, whilst stress granules (SGs) are cytoplasmic structures that form by phase separation and impair nucleocytoplasmic transport. In this issue, Zhang et al (https://doi.org/10.1007/s00125-021-05389-4) investigated whether SG formation contributes to PDX1 mislocalisation and beta cell dysfunction under SFA-induced stress conditions. They found that SGs assembled in cells after they were exposed to SFAs, and that this was dependent on the phosphoinositide 3-kinase (PI3K)/eukaryotic translation initiation factor 2α (eIF2α) axis. They also demonstrated that PDX1 was entrapped in SGs after SFA treatment. The authors suggest that modulation of SG formation may ameliorate the impairment of pancreatic beta cell function and may be a potential therapeutic strategy for obesity and type 2 diabetes.
Rachel B. Forster, Emmanuel Sandoval Garcia, Anniek J. Sluiman, Sheila M. Grecian, Stela McLachlan, Tom J. MacGillivray, Mark W. J. Strachan, Jackie F. Price, on behalf of the Edinburgh Type 2 Diabetes Study (ET2DS) investigators
Diabetic retinopathy is a common complication of diabetes and can have a major impact on quality of life. In this issue, Forster et al (https://doi.org/10.1007/s00125-021-05388-5) report that recent developments have allowed for detailed analysis of the retinal vessels in the back of the eye. This gives hope of identifying early changes that can predetermine local vascular disease. Through follow-up of the Edinburgh Type 2 Diabetes Study, the authors aimed to identify associations between several retinal vessel measurements and the development of diabetic retinopathy. They identified that increased venular tortuosity (curvature of the small veins and how much the vessels twist) and decreased fractal dimension (complexity of the vessel system) were both associated with later development of diabetic retinopathy. Further analysis found venular tortuosity to be a possible biomarker candidate for future risk prediction models, which, according to the authors, could be used to help identify risk of diabetic retinopathy prior to disease onset.
As summarised in an Editorial by our Guest Editor and previous Editor-in-Chief, Sally Marshall (https://doi.org/10.1007/s00125-021-05417-3), our 2021 special issue (https://diabetologia-journal.org/collections/insulin-100/) celebrates 100 years since the discovery of insulin. Fralick and Zinman (https://doi.org/10.1007/s00125-020-05371-6) begin by recounting the story of insulin’s discovery in Toronto, Canada, in 1921/1922. This discovery meant that type 1 diabetes went from being a death sentence to a chronic condition. Despite this, globally, only one in two people currently have access to the insulin they require; Mbanya and colleagues (https://doi.org/10.1007/s00125-020-05375-2) outline the barriers to insulin access and suggest ways to overcome these. For those fortunate enough to have insulin access, hypoglycaemia remains a frequent complication of insulin therapy. Stephanie Amiel (https://doi.org/10.1007/s00125-020-05366-3) describes the immediate and cumulative consequences of hypoglycaemia, whilst Rory McCrimmon (https://doi.org/10.1007/s00125-020-05369-0) summarises the impact of recurrent hypoglycaemia on brain function. Chantal Mathieu (https://doi.org/10.1007/s00125-020-05354-7) suggests options for minimising hypoglycaemia risk, including patient education, insulin analogues, novel technologies and adjunct therapies. To help us understand how insulin therapies work, Yoon and Diano (https://doi.org/10.1007/s00125-021-05395-6) describe the central glucose-sensing mechanisms involved in the regulation of glucose metabolism, whilst Kahn et al (https://doi.org/10.1007/s00125-021-05415-5) outline current and evolving concepts of insulin action/resistance in type 2 diabetes. The authors state that understanding the primary source of metabolic disturbances and drivers of disease will offer important new avenues for the development of novel therapies. Boughton and Hovorka (https://doi.org/10.1007/s00125-021-05391-w) outline an excellent example of a novel therapeutic approach for diabetes, the closed-loop insulin-delivery system, summarising the supporting evidence and limitations of these devices. On a similar note, Weiss and colleagues (https://doi.org/10.1007/s00125-021-05422-6) introduce us to ‘smart’ insulin-delivery devices and molecular technologies designed to exploit feedback regulation. As an alternative approach, Douglas Melton (https://doi.org/10.1007/s00125-020-05367-2) explores the promise of stem cell-derived islet replacement therapy, whilst von Herrath and colleagues (https://doi.org/10.1007/s00125-021-05398-3) give an overview of therapeutics that may help to prevent the destruction of beta cells in the first place. Turning to diabetes complications, David Nathan (https://doi.org/10.1007/s00125-021-05397-4) demonstrates that insulin therapy ameliorates the long-term complications of type 1 diabetes, using findings from the DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) study. To complete this special series, Daniel Drucker (https://doi.org/10.1007/s00125-021-05396-5) looks to the future, highlighting the potential of smart insulins, fully automated insulin delivery, reprogramming of the immune system and stem cell-derived islets to alter the natural history and treatment of type 1 diabetes. This special series is in collaboration with the University of Toronto’s Insulin 100 Scientific Symposium (https://insulin100.com/).
Marie M. Henriksen, Henrik U. Andersen, Birger Thorsteinsson, Ulrik Pedersen-Bjergaard
Symptomatic hypoglycaemia has been reported to reduce quality of life in type 1 diabetes; however, it remains unclear if nocturnal hypoglycaemia (recorded by continuous glucose monitoring [CGM]) affects daily reported quality of life. In this issue, Henriksen et al (https://doi.org/10.1007/s00125-020-05360-9) investigate the impact of CGM-recorded nocturnal hypoglycaemia on quality of life the following day in people with type 1 diabetes. The authors report that, in individuals with hypoglycaemia unawareness, who generally report lower quality of life, unrecognised nocturnal asymptomatic hypoglycaemia was associated with improved self-estimated quality of life the subsequent day (as assessed by the EuroQol-5D visual analogue scale [EQ-5D VAS] but not the WHO Well-Being Index) . The authors suggest that this may be driven by a different biological brain response to hypoglycaemia in people with hypoglycaemia unawareness, in accordance with patterns reported by previous neuroimaging studies. They state that these findings may help to explain differences in perception and attitudes towards hypoglycaemia among people with type 1 diabetes and emphasise the need for reducing the risk of both symptomatic and asymptomatic nocturnal hypoglycaemia.
Charanya Muralidharan, Abass M. Conteh, Michelle R. Marasco, Justin J. Crowder, Jeroen Kuipers, Pascal de Boer, Amelia K. Linnemann
Autophagy is a degradation process in which excessive or damaged cellular materials are degraded and recycled. This degradative process has been shown to promote beta cell homeostasis and proliferation and, also, to protect against apoptosis. Crinophagy is a specialised form of autophagy where secretory granules directly fuse with lysosomes and get degraded. Prior studies have reported impaired autophagy in the context of type 2 diabetes; however, it is unknown if islet autophagy is impaired in type 1 diabetes. In this issue, Muralidharan et al (https://doi.org/10.1007/s00125-021-05387-6) provide evidence of impairment in autophagy in the islets of diabetic NOD mice, as well as impairment of both autophagy and crinophagy in the beta cells of human organ donors with type 1 diabetes. Additionally, the authors report an accumulation of telolysosomes in the beta cells of autoantibody-positive donors, suggesting that lysosomal defects are present prior to the onset of clinical hyperglycaemia. The authors conclude that these findings indicate that the beta cell autophagy and crinophagy impairments observed in type 1 diabetes could be, at least in part, due to defective lysosomes in the prediabetic phase of disease development.
Anita M. Nucci, Suvi M. Virtanen, David Cuthbertson, Johnny Ludvigsson, Ulle Einberg, Celine Huot, Luis Castano, Bärbel Aschemeier, Dorothy J. Becker, Mikael Knip, Jeffrey P. Krischer, The TRIGR Investigators
Accelerated growth during childhood has been considered as a cause for the increasing incidence of type 1 diabetes, either by initiating or accelerating islet autoimmunity (IA). However, the relationship between the occurrence of being overweight and obese during childhood and the development of IA and type 1 diabetes is unknown. In this issue, Nucci, Virtanen et al (https://doi.org/10.1007/s00125-020-05358-3) examined growth measures annually and over time (up to 10 years of age) and the risk of development of IA and type 1 diabetes in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, who have at least one first-degree relative with type 1 diabetes and carry HLA-conferred susceptibility. The authors reported that the occurrence of being overweight at 2–10 years of age was associated with an increased risk of developing type 1 diabetes, but not with the development of IA. This is the first study to examine the relationship between weight status and the development of IA and type 1 diabetes using the standardised definitions of being overweight and obese that guide clinical practice. The authors state that the findings provide further support for existing recommendations to aid with the prevention and treatment of being overweight in childhood.
Alice E. Hughes, Andrew T. Hattersley, Sarah E. Flanagan, Rachel M. Freathy
In 1998, the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. In this issue, Hughes et al (https://doi.org/10.1007/s00125-021-05386-7) review evidence from recent genetics research relevant to the fetal insulin hypothesis. People with monogenic diabetes not only have early-onset diabetes that results from reduced insulin secretion, but also usually have low birthweight. The authors highlight that genome-wide association studies have established overlap between common genetic variants associated with lower birthweight and higher risk of type 2 diabetes. There is strong evidence that certain risk alleles associated with reduced pancreatic beta cell function or metabolically unfavourable patterns of adiposity are associated with lower birthweight when inherited, but fetal risk alleles associated with obesity do not alter birthweight. The authors conclude that it is likely that further advances in genetics research will help us better understand the complex relationship between fetal growth and type 2 diabetes risk, which has both genetic and epigenetic components. The figures from this review are available as a downloadable slideset.
Sergiu-Bogdan Catrina, Xiaowei Zheng
Hypoxia-inducible factors (HIFs) sense oxygen changes and coordinate a multitude of processes that enable cells to cope with hypoxia, such as angiogenesis, mitochondrial respiration, glycolysis, proliferation, differentiation and apoptosis. HIF signalling is tightly controlled and its disturbed activity is involved in several pathologies (such as cancer and ischaemic diseases). In this issue, Catrina and Zheng (https://doi.org/10.1007/s00125-021-05380-z) summarise the role of hypoxia and HIFs in diabetes and its complications. They explain that, while multiple tissues are hypoxic in diabetes, the appropriate reaction of HIF signalling is inhibited by hyperglycaemia and fatty acids. The dysregulated HIF signalling impairs the adaptive responses of tissues to hypoxia and, thus, plays an important pathogenic role in the development of diabetes and its complications. The authors also discuss the potential of specific HIF-targeting therapies for the prevention and treatment of diabetes and its related complications. The figures from this review are available as a downloadable slideset.
Väinö Lithovius, Jonna Saarimäki-Vire, Diego Balboa, Hazem Ibrahim, Hossam Montaser, Tom Barsby, Timo Otonkoski
Congenital hyperinsulinism caused by mutations in the KATP-channel-encoding genes often leads to life-threatening hypoglycaemia. Current treatment options are inadequate and many patients have to undergo radical pancreatic surgery. The development of new pharmacological treatment options is hindered by the lack of disease-specific beta cell models. In this issue, Lithovius et al (https://doi.org/10.1007/s00125-020-05346-7) set out to create a new disease model of congenital hyperinsulinism due to loss-of-function of the KATP channel (KATPHI) to circumvent the issue of limited patient material. They used induced pluripotent stem cells (iPSCs), derived from an individual with KATPHI, as well as CRISPR-Cas9 mutation-corrected iPSCs for control purposes. iPSCs were differentiated into pancreatic islet-like cells, allowing comparison of mutated and corrected cells, which are isogenic, both in vitro and after transplantation into mice. The authors observed insulin hypersecretion in vitro and in vivo, along with increased beta cell proliferation and mass, thus highlighting the relevance of their model for KATPHI research. They concluded that this model could serve as a platform for developing new treatment options for KATPHI.
Louise Cottle, Wan Jun Gan, Ian Gilroy, Jaswinder S. Samra, Anthony J. Gill, Thomas Loudovaris, Helen E. Thomas, Wayne J. Hawthorne, Melkam A. Kebede, Peter Thorn
Accumulating evidence demonstrates that rodent beta cells are structurally and functional polarised. In this issue, Cottle et al (https://doi.org/10.1007/s00125-020-05345-8) investigated whether human beta cells are also polarised. This is an important question given the anatomical differences between rodent and human islets. The authors used pancreatic slices to preserve islet structure and 3D immunostaining to show that human beta cells are polarised with an apical–basal orientation, locating the basal pole of each cell at the capillary interface. Presynaptic scaffold proteins were enriched in this basal region, suggesting local specialisation for insulin granule exocytosis. The authors provide functional evidence indicating that the orientation of human beta cells is a focal adhesion-mediated response to extracellular matrix proteins secreted by capillary endothelial cells. They conclude that this evidence—that human beta cells are polarised—advances our understanding of normal islet function. They state that, clinically, these findings are relevant for understanding type 2 diabetes, in which islet capillary structure changes, and for cell-based treatments for type 1 diabetes.
Inna Y. Gong, Matthew C. Cheung, Stephanie Read, Yingbo Na, Iliana C. Lega, Lorraine L. Lipscombe
While diabetes has been implicated as a risk factor for cancer, much of the data to date have focused on solid malignancies, while less conclusive data exist for diabetes and haematological malignancies. In this issue, Gong et al (https://doi.org/10.1007/s00125-020-05338-7) used Canadian population-based data to evaluate the incidence and prognosis of haematological malignancies among individuals with diabetes. They showed that diabetes is associated with a higher likelihood of developing a haematological malignancy. The authors also demonstrated that individuals with diabetes and haematological malignancy have higher all-cause mortality and cancer-specific mortality than those without diabetes. Importantly, these associations were seen even beyond 1 year after a diabetes diagnosis, which argues against a detection bias due to enhanced health contact. These findings suggest that diabetes adversely affects risk and prognosis of haematological malignancy , and that diabetes prevention strategies may not only reduce diabetes burden but may also potentially improve the risk of haematological malignancy.
Rongrong Yang, Hui Xu, Nancy L. Pedersen, Xuerui Li, Jing Yu, Cuiping Bao, Xiuying Qi, Weili Xu
To date, epidemiological studies have shown that type 2 diabetes increases the risk of cardiovascular disease, which includes coronary heart disease and stroke. However, it is still unclear whether type 2 diabetes is specifically associated with the risk of heart disease and its subtypes, and whether a healthy lifestyle could reduce the risk of heart disease related to type 2 diabetes. In this issue, Yang, Xu et al (https://doi.org/10.1007/s00125-020-05324-z) report that type 2 diabetes is associated with a more than fourfold increased risk of heart disease, including coronary heart disease, cardiac arrhythmias and heart failure. Genetic and early-life familial environmental background did not account for the association between type 2 diabetes and heart disease. However, findings suggested that adulthood lifestyle factors were important in this association: patients with type 2 diabetes who maintained a healthy lifestyle (consisting of being a non-smoker, no/mild alcohol consumption, regular physical activity and not being overweight) had a significantly lower risk of heart disease than those with an unfavourable lifestyle. The authors concluded that these findings highlight the importance of a healthy lifestyle in the prevention of heart disease among individuals with type 2 diabetes.
Katherine A. Sauder, Natalie D. Ritchie
Strategies promoting the health of women of reproductive age are urgently needed to reduce intergenerational transmission of obesity and diabetes risk. In this issue, Sauder and Ritchie (https://doi.org/10.1007/s00125-020-05341-y) summarise findings and gaps arising from published studies of prenatal and preconception lifestyle interventions. They demonstrate that prenatal interventions have shown some success in limiting gestational weight gain and reducing risk of gestational diabetes but have had little impact on offspring outcomes at birth or beyond. Preconception interventions have been successful in reducing weight and improving glucose metabolism by the end of intervention, but whether effects were sustained to conception or whether the interventions had an impact on offspring outcomes is unclear. The authors conclude that future clinical trials should include interventions with high potential for dissemination, diverse populations, thorough maternal phenotyping from enrolment through to conception and pregnancy, and rigorous assessment of offspring obesity and diabetes risks from birth onwards, including into the third generation. The figure from this review is available as a downloadable slide
Christine P. Limonte, Leila R. Zelnick, John Ruzinski, Andrew N. Hoofnagle, Ravi Thadhani, Michal L. Melamed, I-Min Lee, Julie E. Buring, Howard D. Sesso, JoAnn E. Manson, Ian H. de Boer
Immune system activation contributes to the development of diabetes complications. Vitamin D and n-3 fatty acids have been recognised for their anti-inflammatory effects in laboratory models, with mixed evidence from trials in diabetes populations. In this issue, Limonte et al (https://doi.org/10.1007/s00125-020-05300-7) report results of changes in serum concentrations of inflammatory and cardiovascular biomarkers from the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease (VITAL-DKD), in which 1312 adults with type 2 diabetes were randomised to supplementation with vitamin D3 (2000 IU/day) and/or n-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/day) or placebo and followed for 5 years. The authors found that supplementation did not lead to a decline in serum levels of IL-6, high-sensitivity C-reactive protein or N-terminal pro-B-type natriuretic peptide. They conclude that this study tilts the balance of available evidence to favour no benefit of these interventions on inflammation and suggests that supplementation is unlikely to have a positive impact on diabetes complications for which inflammation is an underlying cause.
Luiz Sérgio F. Carvalho, Isabela M. Benseñor, Ana C. C. Nogueira, Bruce B. Duncan, Maria I. Schmidt, Michael J. Blaha, Peter P. Toth, Steven R. Jones, Raul D. Santos, Paulo A. Lotufo, Andrei C. Sposito, on behalf of the ELSA-Brasil study
Little is known regarding risk prediction of type 2 diabetes before the detection of glucose abnormalities; however, up to 3% of individuals in the general population who are not in the impaired fasting glucose range develop diabetes each year. In this issue, Carvalho et al (https://doi.org/10.1007/s00125-020-05322-1) hypothesise that, among the pathophysiological processes that play a role in type 2 diabetes, the loading of triacylglycerol-enriched remnant lipoproteins (TRLs) with lipids (resulting in large particles) could be useful for risk prediction. The authors report that, when included in a risk prediction model, TRL particle diameter improved the risk prediction of diabetes after 3.7 years of follow-up as compared with a model that did not include this variable, particularly in individuals with normal HbA1c levels at baseline. These data support TRL particle size as a risk factor that is changed early in the pathophysiological processes that lead to the development of type 2 diabetes, even before glucose abnormalities are established.
Christopher Rohde, Jakob S. Knudsen, Norbert Schmitz, Søren Dinesen Østergaard, Reimar W. Thomsen
Incident depression in type 2 diabetes is associated with poor self-care and suboptimal treatment adherence. However, it is not known how pre-existing depression treatment relates to quality of care for individuals with newly diagnosed type 2 diabetes. In this issue, Rohde et al (https://doi.org/10.1007/s00125-020-05303-4) report that individuals with newly diagnosed type 2 diabetes who already receive treatment for depression are more likely than others to initiate and be adherent to glucose-lowering and lipid-modifying treatment. Pre-existing depression treatment was also associated with successful attainment of LDL-cholesterol and HbA1c treatment targets among individuals with type 2 diabetes. The authors suggest that these findings may be driven by the fact that individuals with ongoing depression treatment are already familiar with the healthcare system and drug treatment, and that effective treatment of depression, in itself, may improve diabetes care.
Natalie Nanayakkara, Andrea J. Curtis, Stephane Heritier, Adelle M. Gadowski, Meda E. Pavkov, Timothy Kenealy, David R. Owens, Rebecca L. Thomas, Soon Song, Jencia Wong, Juliana C.-N. Chan, Andrea O.-Y. Luk, Giuseppe Penno, Linong Ji, Viswanathan Mohan, Anandakumar Amutha, Pedro Romero-Aroca, Danijela Gasevic, Dianna J. Magliano, Helena J. Teede, John Chalmers, Sophia Zoungas
Type 2 diabetes is increasingly diagnosed in younger adults; however, the relationship between age at diagnosis and diabetes complications is unclear. In this issue, Nanayakkara et al (https://doi.org/10.1007/s00125-020-05319-w) integrate data from 1.3 million individuals from 30 countries to conduct the first systematic review and meta-analyses exploring associations between age at diabetes diagnosis and subsequent complications. Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The authors propose that, over time, the effects of both ageing and diabetes duration may be compounded, resulting in premature complications and death in people diagnosed with type 2 diabetes at a younger age. Early and sustained interventions to optimise glycaemic control and cardiovascular risk profiles in those with established type 2 diabetes, and measures to delay the onset of type 2 diabetes in high-risk groups are crucial to reduce future diabetes-related morbidity and mortality.
Rubén Nogueiras, Guadalupe Sabio
Obesity has become a global epidemic. In recent years, major efforts have been made to define the role played by the central nervous system (CNS) in this disease. Several CNS circuits are altered in obese individuals, and these changes can induce uncontrolled hunger and/or decreased energy expenditure, the latter being associated with physical inactivity, reduced baseline metabolism and poor thermogenic capacity. c-Jun N-terminal kinases (JNKs) in the hypothalamus are among the signalling molecules activated during obesity that may contribute to deleterious molecular adaptations. In this issue, Nogueiras and Sabio (https://doi.org/10.1007/s00125-020-05327-w) review recent findings that reveal opposing pro- and anti-obesogenic actions of JNK family members in the CNS—more precisely the hypothalamus—with regard to the control of food intake and energy expenditure. The authors also discuss the future potential of these kinases as targets in the treatment of obesity. The figures from this review are available as a downloadable slideset
Leticia Maria de Souza Cordeiro, Arwa Elsheikh, Nagavardhini Devisetty, Donald A. Morgan, Steven N. Ebert, Kamal Rahmouni, Kavaljit H. Chhabra
Obesity and increased plasma insulin levels (insulin resistance) are major risk factors for type 2 diabetes in the general population. Yet, individuals with melanocortin 4 receptor (MC4R) deficiency either do not develop, or are at a relatively lower risk of developing, diabetes. To understand why MC4R deficiency prevents diabetes despite obesity and insulin resistance, de Souza Cordeiro et al (https://doi.org/10.1007/s00125-020-05289-z) investigated the function of this protein in glucose regulation using mouse models. The authors observed that lack of MC4R in mice increased glucosuria, thereby keeping blood glucose levels normal. The increase in urinary glucose excretion was due to reduced plasma adrenaline and expression of the glucose transporter GLUT2 in the kidneys. These findings demonstrate that elevated glucosuria may be one of the reasons why MC4R deficiency prevents diabetes. Based on the study findings, the authors propose that blocking kidney-specific GLUT2 has the potential to treat diabetes.
Berit Svendsen, Jens J. Holst
The alpha and beta cells of the islets of Langerhans secrete glucagon and insulin, which play an important role in regulating plasma glucose concentration, whilst the islet delta cells produce somatostatin, which is known to be able to inhibit the secretion of the other two hormones. In the islets, the three cell types are arranged in a complex pattern that, together with the capillary network, seems to be consistent with extensive paracrine interactions. For example, insulin is thought to directly inhibit glucagon secretion and recent research has revealed that local glucagon secretion is also essential for protein-stimulated insulin secretion. However, whether somatostatin secretion is regulated by paracrine signalling from glucagon and insulin is less clear. In this issue, Svendsen and Holst (https://doi.org/10.1007/s00125-020-05288-0) describe how somatostatin powerfully inhibits glucagon secretion and, conversely, how glucagon secretion provides a powerful local stimulus for somatostatin secretion, linking the two in a reciprocal feed-back circuit. Insulin did not directly affect secretion of somatostatin in mouse islets. The authors conclude that the results underline the importance of paracrine intra-islet regulation and suggests that a defect in one hormone will affect the secretion of other islet hormones. Thus, knowledge about islet somatostatin secretion appears to be essential for the understanding of integrated islet function.
Ellen C. Francis, Dana Dabelea, Brandy M. Ringham, Katherine A. Sauder, Wei Perng
Maternal blood glucose status during pregnancy is associated with offspring adiposity and metabolic health; however, it is unclear whether offspring adiposity at birth and/or in childhood mediates the association between maternal glucose and offspring glucose–insulin homeostasis. In this issue, Francis et al (https://doi.org/10.1007/s00125-020-05294-2) report that higher maternal HbA1c was associated with higher fasting glucose and lower insulin sensitivity in offspring. Further, this relationship was not mediated by offspring adiposity at birth, at age 4–7 years, or cumulatively across the two life stages. The authors suggest that the effect of maternal glucose on offspring glucose–insulin homeostasis may operate through alternate pathways, such as fetal programming of the adipoinsular axis or pancreatic beta cell development and function. This highlights the importance of the pregnancy period for prevention efforts aimed at improving early childhood metabolic health.
Alexia Carré, Sarah J. Richardson, Etienne Larger, Roberto Mallone
It is increasingly recognised that autoimmune type 1 diabetes is a tale of two main characters that both play a role in disease pathogenesis: the T cell and the beta cell. On one hand, the presumption of innocence traditionally granted to beta cells requires revision, as recently reviewed in Diabetologia by Mallone and Eizirik (https://doi.org/10.1007/s00125-020-05176-7) . On the other hand, the presumption of guilt that T cells are often charged with may also need to be reconsidered. In this review, Carré et al (https://doi.org/10.1007/s00125-020-05298-y) evaluate genetic, histopathological, functional and clinical evidence to argue that T cells may behave as ‘lead culprits’ or ‘partners in crime’ in type 1 diabetes, depending on specific disease endotypes, mostly related to age. Increasing evidence points to the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Current challenges and opportunities for dissecting this disease heterogeneity are discussed. The figures from this review are available as a downloadable slideset.
Kimberly M. Alonge, David A. D’Alessio, Michael W. Schwartz
In this issue, Alonge and colleagues (https://doi.org/10.1007/s00125-020-05293-3) present a framework for understanding the brain’s role in glucose homeostasis. Their review outlines a crucial role for the brain in sensing blood glucose levels and they cite evidence in support of the concept that defects in this process are fundamental to the pathogenesis of type 2 diabetes. This framework also proposes that the close association between obesity and type 2 diabetes arises from a shared defect in overlapping and highly integrated brain neurocircuitry governing energy homeostasis and glucose homeostasis. The authors highlight the translational potential of this framework by summarising evidence that, in preclinical models of type 2 diabetes, blood glucose levels can be restored to normal in a sustained manner by therapies targeting the brain. They conclude that these considerations suggest that, unlike current non-surgical treatment options, strategies targeting the brain have the potential to induce sustained remission of type 2 diabetes. The figures from this review are available as a downloadable slideset.
Isabelle Chareyron, Stefan Christen, Sofia Moco, Armand Valsesia, Steve Lassueur, Loïc Dayon, Claes B. Wollheim, Jaime Santo Domingo, Andreas Wiederkehr
Type 2 diabetes causes mitochondrial dysfunction in pancreatic beta cells. In this issue, Chareyron et al (https://doi.org/10.1007/s00125-020-05275-5) studied whether glucose stress alone results in gradual loss of mitochondrial function in human beta cells in vitro. Unexpectedly, at early stages, chronic glucose stress (4 day exposure to 11 mmol/l glucose) was found to over-activate mitochondria. Basal mitochondrial respiration and the cytosolic ATP/ADP ratio remained markedly elevated when human islets were returned to resting glucose conditions. The inability of mitochondria to return to a resting state was associated with metabolic dysregulation, including the accumulation of glycerol-3-phosphate and elevation of tricarboxylic acid (TCA) cycle and pentose phosphate pathway metabolites. This resulted in a slight elevation of basal insulin secretion and poor glucose-induced beta cell activation. Inhibition of mitochondrial pyruvate transport partially reversed the negative effects of chronic glucose overload. The authors propose that protecting mitochondria from nutrient overload may allow beta cells to return to a resting state and regain nutrient responsiveness in a way that may prevent the conversion from impaired fasting glucose and/or glucose tolerance to overt type 2 diabetes.
Emelie Andersson, Sofie Persson, Nino Hallén, Åsa Ericsson, Desirée Thielke, Peter Lindgren, Katarina Steen Carlsson, Johan Jendle
The medical consequences of the complications of type 2 diabetes are well known. There is less evidence, however, on the impact of individual diabetic complications on the overall societal burden, including its impact on work life. In this issue, Andersson, Persson et al (https://doi.org/10.1007/s00125-020-05277-3) analysed the costs of hospital-based care and work absence related to individual macrovascular and microvascular complications of type 2 diabetes. The authors used individual-level data from 1997–2016 in a nationwide study of 392,200 people with type 2 diabetes in Sweden. Costs directly attributed to complications were derived by comparison with control participants from the general population who were matched for year of birth, sex and region of residence in the index year. High costs of hospital-based care were directly attributed to diabetes complications, but costs of work absence were found to be almost twice as high per person using regression analyses. Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke, and the microvascular complications eye disease, kidney disease and neuropathy. The authors conclude that these findings highlight the need to consider outcomes beyond health when developing treatments for type 2 diabetes, as well as health policy.
Vito Lampasona, Massimiliano Secchi, Marina Scavini, Elena Bazzigaluppi, Cristina Brigatti, Ilaria Marzinotto, Alberto Davalli, Amelia Caretto, Andrea Laurenzi, Sabina Martinenghi, Chiara Molinari, Giordano Vitali, Luigi Di Filippo, Alessia Mercalli, Raffaella Melzi, Cristina Tresoldi, Patrizia Rovere-Querini, Giovanni Landoni, Fabio Ciceri, Emanuele Bosi, Lorenzo Piemonti
Diabetes has been associated with an excess risk of severe coronavirus disease 2019 (COVID-19) pneumonia. However, it is unclear whether the poor clinical outcome of COVID-19 in individuals with diabetes is associated with a quantitative or qualitative defect in the antibody response against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In this issue, Lampasona et al (https://doi.org/10.1007/s00125-020-05284-4) report that the antibody response against multiple SARS-CoV-2 antigens in individuals with diabetes was superimposable to that of non-diabetic participants with regard to timing, titres and classes, and responses were not influenced by glucose levels. Moreover, blood glucose levels, per se, were strongly positively associated with increased mortality risk for COVID-19 pneumonia, even in individuals without previously diagnosed diabetes. SARS-CoV-2 spike receptor-binding domain IgG positivity was associated with a remarkable protective effect (about 60% reduction in mortality rate) in participants with diabetes. The authors conclude that this evidence allows for cautious optimism regarding the efficacy of future vaccines against SARs-COV-2 in individuals with diabetes.
Hilde Herrema, Jan Hendrik Niess
High-throughput technologies have helped to characterise the microbiome in individuals with the metabolic syndrome and type 2 diabetes. Emerging evidence suggests that it is not only the microorganisms and their structural components that contribute to the development of these conditions, but also the metabolites that they produce. In this issue, Herrema and Niess (https://doi.org/10.1007/s00125-020-05268-4) discuss recent advances in our understanding of how gut bacterial metabolites are sensed by individuals with the metabolic syndrome, potentially contributing to the development of type 2 diabetes. They explain how the gut microbiome, in response to dietary components, produces bacterial metabolites which influence processes implicated in the development of type 2 diabetes, including the intestinal immune system and the entero-endocrine system. Further studies on the impact of dietary components on gut bacterial metabolite production, as well as research into the receptors that recognise bacterial metabolites, promise to reveal new pathways that could be targeted for the treatment of the metabolic syndrome and type 2 diabetes. The figure from this review is available as a downloadable slide.
Paul W. Franks, Hugo Pomares-Millan
Major advances in technologies that allow detailed molecular characterisations of many thousands of people have transformed epidemiology into a discipline at the forefront of biomedicine. In this issue, Franks and Pomares-Millan (https://doi.org/10.1007/s00125-020-05246-w) summarise recent advances in diabetes epidemiology that have been made possible through the availability of detailed genetic and molecular phenotype data in large cohorts, combined with the development and application of complex analytical processes. They explain that these studies have revealed novel molecular pathways that harbour promising targets for drug discovery, yielded evidence of gene–environment interactions that might facilitate targeted prevention of diabetes, and enabled the restratification of diabetes into aetiological subtypes that help elucidate the heterogeneous nature of type 2 diabetes. The figure from this review is available as a downloadable slide.
Giuseppe Daniele, Carolina Solis-Herrera, Angela Dardano, Andrea Mari, Andrea Tura, Laura Giusti, Jancy J. Kurumthodathu, Beatrice Campi, Alessandro Saba, Anna Maria Bianchi, Carla Tregnaghi, Maria Francesca Egidi, Muhammad Abdul-Ghani, Ralph DeFronzo, Stefano Del Prato
The expected reduction in plasma glucose concentration mediated by sodium–glucose cotransporter 2 (SGLT2) inhibitors is partially offset by a concomitant increase in endogenous glucose production. The signal mediating such a paradoxical response to SLT2-inhibition is currently unknown. In this issue, Daniele, Solis-Herrera et al (https://doi.org/10.1007/s00125-020-05254-w) demonstrate that SGLT2 inhibition in non-diabetic individuals who have undergone kidney transplantation with removal of native kidneys is associated with attenuation of the paradoxical stimulation of endogenous glucose production. They explain that these results suggest the existence of a neuronal axis linking the kidney and the liver that modulates endogenous glucose production in response to urinary glucose loss induced by SGLT2 inhibition. Based on these findings, the authors propose that SGLT2 inhibition can activate efferent renal nerves, generating a signal that augments endogenous (hepatic) glucose production to compensate for the urinary glucose loss.
Shuai Yuan, Susanna C. Larsson
Observational studies have revealed a large number of possible risk factors for type 2 diabetes but whether the reported associations are causal remains unclear. In this issue, Shuai Yuan and Susanna Larsson (https://doi.org/10.1007/s00125-020-05253-x) identified causal associations of 34 exposures (18 risk factors and 16 protective factors) with type 2 diabetes under a wide-angled Mendelian randomisation framework. Insomnia was identified as a novel causal risk factor for type 2 diabetes. Eight associations remained after adjustment for adulthood BMI. In addition, there were 21 possible associations. The authors conclude that these findings imply that prevention strategies for type 2 diabetes need to be considered from multiple perspectives.
Sung Min Kim, Gyeongsil Lee, Seulggie Choi, Kyuwoong Kim, Su-Min Jeong, Joung Sik Son, Jae-Moon Yun, Sin Gon Kim, Seung-sik Hwang, Seong Yong Park, Yeon-Yong Kim, Sang Min Park
Recently, the increasing incidence of diabetes among young adults aged 20-30 years has added to the overall disease burden. Individuals with early-onset diabetes have similar or higher cardiovascular risk than those with late-onset diabetes. In this issue, Kim and Lee and colleagues (https://doi.org/10.1007/s00125-020-05252-y) investigated whether newly diagnosed early-onset diabetes, prediabetes and glycaemic recovery among young adults is associated with incident cardiovascular disease or mortality using data from a nationwide cohort study of 2,502,375 young adults without cardiovascular disease at baseline. They report that individuals with early-onset diabetes and prediabetes had increased risks of incident CVD and all-cause mortality at the 10 year follow up. Notably, in individuals with early glycaemic recovery from diabetes or prediabetes, the risks of incident 10-year CVD and all-cause or CVD mortality were reduced. The authors conclude that maintenance of glycaemic control in young adults may be important for the prevention of CVD and all-cause mortality
Struan F. A. Grant, Andrew D. Wells, Stephen S. Rich
Type 1 diabetes is characterised by young age at onset, requirement for exogenous insulin for survival and a strong genetic predisposition in the absence of family history. Genetics account for approximately half of total risk, yet, unlike other diseases, a single genomic region (HLA) constitutes ~50% of that genetic component. Much of the remaining genetic risk has been identified, with the vast majority of variants residing in DNA regulatory regions. In this issue, Grant et al (https://doi.org/10.1007/s00125-020-05248-8) provide a perspective on the transition from an allelic association to the effect of genetic variation on tissue-specific expression, identification of target genes of the associated variants and use of genetic data to identify those individuals at risk of type 1 diabetes prior to clinical presence of symptoms. The authors suggest that functional genomic studies, increased ethnic diversity of individuals included in such studies, and improved characterisation of chromosomal landscapes will be necessary to reveal novel prevention and treatment strategies. The figure in this review is available as a downloadable slide.
John A. Hawley, Paolo Sassone-Corsi, Juleen R. Zierath
In the current ‘obesogenic’ environment there is growing popular and scientific interest in how the timing and frequency of meals impacts metabolic health, with an appreciation that the duration of which food is consumed effects numerous physiological and metabolic processes. Such ‘chrono-nutrition’ is aimed at optimising metabolism by timing nutrient intake to the acrophases of daily metabolic rhythms via manipulation of the feeding–fasting cycle. In this issue, Hawley and colleagues (https://doi.org/10.1007/s00125-020-05238-w) review recent research from both animal and human studies demonstrating that dietary protocols incorporating chronic energy restriction, intermittent fasting and time-restricted feeding improve multiple cardiometabolic markers associated with obesity and type 2 diabetes risk. The figure in this review is available as a downloadable slide.
The focus of this year’s special issue is ‘The pancreas in health and in diabetes’, introduced in an editorial (https://doi.org/10.1007/s00125-020-05235-z). Atkinson et al (https://doi.org/10.1007/s00125-020-05203-7)begin by reviewing the current evidence on human pancreatic anatomy and the changes that occur in individuals with type 1 or type 2 diabetes. Jennings and colleagues (https://doi.org/10.1007/s00125-020-05161-0) go on to discuss how alterations in important steps in the development of the mammalian pancreas may contribute to the abnormalities seen in diabetes. Abnormal insulin production by the pancreas underlies the pathogenesis of diabetes, and Vasiljević and coauthors (https://doi.org/10.1007/s00125-020-05192-7) outline the post-transcriptional mechanisms regulating insulin production and how their deficits can cause diabetes. The sole source of circulating insulin is the pancreatic beta cell. In their review, Rutter et al (https://doi.org/10.1007/s00125-020-05205-5) discuss the specialisations that allow this cell to perform its unique role. Autoimmune beta cell destruction results in type 1 diabetes and Mallone and Eizirik (https://doi.org/10.1007/s00125-020-05176-7) consider why beta cells are vulnerable autoimmune targets. Esser et al (https://doi.org/10.1007/s00125-020-05245-x) go on to describe models to explain the pathogenesis of hyperglycaemia in type 2 diabetes. Age is one of the main risk factors for developing type 2 diabetes and Cristina Aguayo-Mazzucato (https://doi.org/10.1007/s00125-020-05185-6) summarises the functional changes that occur in ageing beta cells. Diabetes can also occur as a consequence of a wide variety of exocrine pancreas diseases, as discussed by Rickels et al (https://doi.org/10.1007/s00125-020-05210-8). Redondo et al (https://doi.org/10.1007/s00125-020-05211-7) propose a paradigm to help explain the heterogeneity within and between diabetes types, concluding that this new approach may facilitate personalised medicine in diabetes. In their review, Bellin and Dunn (https://doi.org/10.1007/s00125-020-05184-7) detail the variety of transplant strategies available for individuals with type 1 diabetes. Looking more closely at the islet itself, Mark Huising (https://doi.org/10.1007/s00125-020-05213-5) describes the cellular components of this special structure that are important to its role. Moede et al (https://doi.org/10.1007/s00125-020-05196-3) focus specifically on the importance of islet alpha cell–beta cell communication for glucose homeostasis, while Almaça et al (https://doi.org/10.1007/s00125-020-05186-5) summarise how different cellular and acellular components of the islet microenvironment can have an impact on endocrine cell function. Faber et al (https://doi.org/10.1007/s00125-020-05204-6) describe both the anatomy of autonomic nervous system input to the islet and the functional importance of autonomic nervous system outflow to the islet across a variety of physiological challenges to glucose homeostasis. Finally, Arrojo e Drigo et al (https://doi.org/10.1007/s00125-020-05159-8) conclude by discussing approaches to connect molecular profiles with functional properties underlying insulin secretion.
Dale McAninch, Tina Bianco-Miotto, Kathy L. Gatford, Shalem Y. Leemaqz, Prabha H. Andraweera, Amy Garrett, Michelle D. Plummer, Gus A. Dekker, Claire T. Roberts, Lisa G. Smithers, Jessica A. Grieger
The metabolic syndrome is a clustering of cardiovascular risk factors. In the adult population, the metabolic syndrome associates with increased risk for cardiovascular and related diseases. Telomere length is a biomarker of ageing and is associated with the development of future chronic diseases. Maternal exposures in utero impact offspring health. In this issue, McAninch et al (https://doi.org/10.1007/s00125-020-05242-0) investigated whether maternal metabolic syndrome associates with telomere length, a biomarker of ageing, in the child. The authors found that the 10-year-old children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers who did not have the metabolic syndrome during pregnancy. Interestingly, anthropometric measures were similar in children of mothers who did and did not have the metabolic syndrome in pregnancy. The authors conclude that, although further studies are warranted, early assessment of telomere length in children may provide insight into their potential future chronic disease risk.
Christin Krause, Cathleen Geißler, Heidi Tackenberg, Alexander T. El Gammal, Stefan Wolter, Joachim Spranger, Oliver Mann, Hendrik Lehnert, Henriette Kirchner
Epigenetic regulation of gene expression is altered in type 2 diabetes. However, epigenetic regulation of insulin signalling in key metabolic tissues in type 2 diabetes is largely unknown. In this issue, Krause et al (https://doi.org/10.1007/s00125-020-05212-6) analysed the epigenetic gene regulation of IRS2, which encodes a crucial mediator of insulin signal transduction, in liver biopsies of obese individuals with and without type 2 diabetes. They found that hepatic expression of IRS2 is decreased in type 2 diabetes, which is accompanied by decreased intronic DNA methylation and enhanced binding of two transcriptional repressors. They also report that the microRNA let-7e-5p is increased in the liver in diabetes, correlates with the decreased IRS2expression, and might represent a complementary mechanism of IRS2 regulation. The authors conclude that these findings contribute to an improved understanding of dysregulated pathways in the liver of individuals with type 2 diabetes and illustrate the complexity and multifactorial nature of mechanisms involved in the regulation of glucose homeostasis.
Shitaye A. Balcha, Abayneh G. Demisse, Rajashree Mishra, Tanwi Vartak, Diana L. Cousminer, Kenyaita M. Hodge, Benjamin F. Voight, Kim Lorenz, Stanley Schwartz, Samuel T. Jerram, Arla Gamper, Alice Holmes, Hannah F. Wilson, Alistair J. K. Williams, Struan F. A. Grant, R. David Leslie, David I. W. Phillips, Elisabeth R. Trimble
From sub-Saharan Africa, a region of enormous genetic diversity, reports of insulin-dependent diabetes associated with both a low autoantibody prevalence and a low incidence in childhood have raised questions about its relationship to classic type 1 diabetes. In this issue, Balcha et al (https://doi.org/10.1007/s00125-020-05229-x) performed an immunogenetic study of insulin-dependent diabetes in individuals from the Amhara, the second-largest ethnic group in Ethiopia. The authors found that, although the genomes of the Amhara were distinct from European and other African genomes, individuals with insulin-dependent diabetes (89.4% born in rural areas) had the same principal HLA-DRB1 allele associations as cases of European-background type 1 diabetes. In contrast to previous reports, at diagnosis, the age-related total autoantibody prevalence was similar to that in many industrialised countries. However, the autoantibody profile was different; this was most marked in childhood cases, where the majority had a single autoantibody (to GAD), and the prevalence of autoantibodies to ZnT8 and IA-2 was very low. The authors conclude that these Ethiopian cases have the immunogenetic characteristics of autoimmune type 1 diabetes associated with an autoantibody profile that differs somewhat from cases of European background.
Emma E. Vincent, Hanieh Yaghootkar
The global prevalence of type 2 diabetes is estimated to reach over 500 million by 2030. To compound this health crisis, observational epidemiological studies have consistently reported that people with type 2 diabetes have a higher risk of certain types of cancer. To direct prevention and intervention strategies the association between the two disease states needs to be understood. In this issue, Vincent and Yaghootkar (https://doi.org/10.1007/s00125-020-05228-y) review how large-scale genome-wide association studies (GWAS) have been employed to investigate a possible relationship between type 2 diabetes and cancer. The evidence for shared genetic aetiology between alleles predisposing to type 2 diabetes and the observationally associated cancers is explored. The authors also discuss how GWAS and techniques such as Mendelian randomisation are used to investigate whether type 2 diabetes causes cancer or whether this association is driven by a particular metabolic feature, such as elevated insulin levels, or by an associated trait, such as obesity. Finally, the authors discuss areas for future study, including genetics studies of type 2 diabetes and cancer progression. The figure from this review is available as a downloadable slideset.
Mugdha Gokhale, Til Stürmer, John B. Buse
The healthcare community is abuzz with discussions about real world evidence (RWE), which provides evidence regarding the utilisation and potential benefits and harms of healthcare interventions, based on data from routine clinical practice. While the reflection of diverse real-world patterns increases the attractiveness of RWE, it also increases the chance of several biases in real-world studies. In this issue (https://doi.org/10.1007/s00125-020-05217-1), Gokhale et al summarise key elements in RWE studies, including commonly encountered issues and methods to address these. While there is no one-size-fits-all solution to designing RWE studies, the authors explain that critical elements include a clear prespecified protocol with a well-defined research question, a fit-for-purpose data source, therapeutically equivalent treatments as comparators, robust state-of-the-art study design, analytical techniques to minimise biases, and clearly reported methods and results per published guidelines. The review also points to some newer areas of application of RWE that are relevant to diabetes research and beyond. The figures from this review are available as a downloadable slideset.
Sufei Wang, Pei Ma, Shujing Zhang, Siwei Song, Zhihui Wang, Yanling Ma, Juanjuan Xu, Feng Wu, Limin Duan, Zhengrong Yin, Huilin Luo, Nian Xiong, Man Xu, Tianshu Zeng, Yang Jin
Diabetes is associated with an elevated risk of mortality in most infectious diseases. In this issue, Wang et al (https://doi.org/10.1007/s00125-020-05209-1) performed a retrospective study of the relationship between hyperglycaemia and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed with diabetes. They report that, of 605 COVID-19 patients at two hospitals based in Wuhan, China, 176 (29.1%) had hyperglycemia (≥7.0 mmol/l) at admission without a previous diagnosis of diabetes. These patients had more than twice the risk of death as those with normal blood glucose. Even patients with a CRB score (an effective measure for assessing the severity of pneumonia) that was low or zero were more likely to die if they had increased fasting blood glucose levels. The authors conclude that most COVID-19 patients are prone to glucose metabolic disorders, and that glycaemic testing and addressing elevations in fasting blood glucose at an early stage might help improve the overall outcomes.
Lei Chen, Rakibul M. Islam, Joanna Wang, Thomas R. Hird, Meda E. Pavkov, Edward W. Gregg, Agus Salim, Maryam Tabesh, Digsu N. Koye, Jessica L. Harding, Julian W. Sacre, Elizabeth L.M. Barr, Dianna J. Magliano, Jonathan E. Shaw
Some studies have reported falling mortality among populations with diabetes, but consistency of this trend among various populations with diabetes is unclear. In this issue, Chen and colleagues (https://doi.org/10.1007/s00125-020-05199-0) report a systematic review of 35 studies on the trends in all-cause mortality in people with diabetes from 1970 to 2016. They found that all-cause mortality has declined in nearly 80% of predominantly Europid populations with diabetes from 2000 to 2016. Furthermore, for nearly 60% of the populations, the reduction in mortality seen among those with diabetes was greater than or similar to the reductions observed in those without diabetes. However, there was under-representation of younger age groups and non-Europid populations in the published literature, and lack of mortality data from low- and middle-income countries. Thus, patterns of diabetes mortality remain uncertain in these populations. These findings highlight the significance of maintaining and improving cardiometabolic management in diabetes in order to achieve ongoing reductions in mortality in people with diabetes.
Akira Asai, Mototsugu Nagao, Koji Hayakawa, Teruo Miyazawa, Hitoshi Sugihara, Shinichi Oikawa
Even in the modern ‘obesogenic’ environment of plentiful food supply, not all people become obese by overeating. However, it remains poorly understood what determines individual differences in spontaneous meal size. In this issue, Asai and Nagao et al (https://doi.org/10.1007/s00125-020-05191-8) investigate the potential role of leptin production capacity in determining spontaneous meal size and consequent susceptibility to obesity-induced diabetes using selectively bred Oikawa–Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice. The authors demonstrate that, prior to the development of obesity-induced diabetes, the spontaneously hyperphagic ON-DP mice had a lower circulating leptin level than the control ON-DR mice. ON-DP mice had a lower leptin production capacity in adipose tissue, probably because of the higher DNA methylation level in the Lep promoter region compared with that in ON-DR mice. The authors conclude that leptin production capacity, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity and future onset of type 2 diabetes.
Michael Due Larsen, Dorte Møller Jensen, Jens Fedder, Line Riis Jølving, Bente Mertz Nørgård
Type 1 and type 2 diabetes are among the most common chronic diseases in women during the fertile years and previous studies have indicated that women with diabetes have difficulty conceiving compared with reference populations. However, the efficacy of assisted reproductive technology (ART) in women with diabetes has never been studied. In this issue, Larsen and colleagues (https://doi.org/10.1007/s00125-020-05193-6) report the results of a nationwide study of 594 women with either type 1 or type 2 diabetes in the Danish ART Registry, between 2006 and 2017. The authors found that women with type 2 diabetes have a decreased chance of live birth per embryo transfer compared with women without diabetes. Furthermore, the results suggested that the decrease is related to a lower chance of implantation of the embryo. Women with type 1 diabetes had an equivalent chance of a live birth per embryo transfer as women without diabetes. The findings in women with type 2 diabetes did not seem to be driven by obesity as the same pattern was seen in both normal-weight and obese women. The authors conclude that their findings should provide reassurance for women with type 1 diabetes considering ART treatment but that prospective studies need to be performed to confirm the findings for women with types 2 diabetes in other settings and to investigate the underlying mechanisms.
The best-laid schemes o’ mice an’ men gang aft agley (To a Mouse, Robert Burns, 1785). We planned this series of mini-reviews in Diabetologia to coincide with the 2020 Olympic Games. Instead, I hope the articles will provide a timely stimulus to us all, to increase our activities again as we emerge from COVID-19 lockdown.
Regular exercise is known to improve insulin sensitivity and metabolic health in people with type 1 and type 2 diabetes, but how exactly does it do this and how should these individuals exercise? In this issue, we have commissioned a mini-series of reviews to try to answer these questions. Gemmink et al (https://doi.org/10.1007/s00125-020-05170-z) begin this series by providing a muscle-centred view on the beneficial impact of exercise on fat metabolism and, consequently, insulin sensitivity. The authors explain how regular exercise may alter lipid droplet characteristics in the human muscle (and liver) in insulin-resistant individuals, resulting in an ‘athlete-like’ phenotype that is associated with improved insulin sensitivity. Other than the muscle, the liver, adipose tissue, vasculature and pancreas also play a role in the beneficial effects of exercise. Thyfault and Bergouignan (https://doi.org/10.1007/s00125-020-05177-6) explain how exercise activates metabolic changes in these non-skeletal-muscle tissues and how the adaptations can protect against metabolic diseases. So, it is clear that exercise is beneficial for individuals with diabetes, but how in practice should exercise be carried out? In their review, Riddell and colleagues (https://doi.org/10.1007/s00125-020-05183-8) specifically focus on the competitive athlete with type 1 diabetes. They explain the challenges that athletes with type 1 diabetes face in trying to maintain normal glucose levels during training, travel and competition, and how these challenges may be overcome, such as with the use of insulin pumps and continuous glucose monitors. In addition, they discuss how adjustment of carbohydrate intake can improve performance in athletes with type 1 diabetes. Exercise training can also improve glycaemic control in individuals with type 2 diabetes, but it is not known which training regime is likely to elicit the most benefit with regards to this. In their review, Savikj and Zierath (https://doi.org/10.1007/s00125-020-05166-9) discuss how exercise type, intensity and modality affects the impact of exercise on glycaemic control in individuals with type 2 diabetes. They also discuss the impact of nutritional status on exercise-associated benefits, indicating that training with low carbohydrate availability may improve cardiorespiratory function and skeletal muscle oxidative capacity vs conventional training. They conclude that, just like competitive athletes, individuals with type 2 diabetes should be encouraged to adopt training regimens that improve fitness and metabolism.
The figures from these reviews are available as downloadable slidesets.
Kameron B. Rodrigues, Matthew J. Dufort, Alba Llibre, Cate Speake, M. Jubayer Rahman, Vincent Bondet, Juan Quiel, Peter S. Linsley, Carla J. Greenbaum, Darragh Duffy, Kristin V. Tarbell
Although type 1 IFN (IFN-1) has been implicated in the early stages of type 1 diabetes pathogenesis, less is known about key innate immune alterations in individuals with established type 1 diabetes. In this issue, Rodrigues, Dufort et al (https://doi.org/10.1007/s00125-020-05179-4) report findings from their study, which used ex vivo whole blood immune stimulation to show that individuals with type 1 diabetes display higher IFN-1 responses after innate immune stimulation. Furthermore, they show that IFN-γ- and IL-1b-driven responses were not significantly different. Monocytes from NOD mouse models, a strain that develops autoimmune diabetes, also displayed increased IFN-1 responses after treatment with CpG, which stimulates the innate immune system. These findings indicate that increased responsiveness to IFN-1 is a feature of both mouse autoimmune diabetes and human established type 1 diabetes. The authors suggest that a stimulated IFN-1 gene signature could be used as a potential biomarker to identify individuals with type 1 diabetes who may be successfully treated with therapies targeting the IFN-1 pathway.
Bertrand Cariou, Samy Hadjadj, Matthieu Wargny, Matthieu Pichelin, Abdallah Al-Salameh, Ingrid Allix, Coralie Amadou, Gwénaëlle Arnault, Florence Baudoux, Bernard Bauduceau, Sophie Borot, Muriel Bourgeon-Ghittori, Olivier Bourron, David Boutoille, France Cazenave-Roblot, Claude Chaumeil, Emmanuel Cosson, Sandrine Coudol, Patrice Darmon, Emmanuel Disse, Amélie Ducet-Boiffard, Bénédicte Gaborit, Michael Joubert, Véronique Kerlan, Bruno Laviolle, Lucien Marchand, Laurent Meyer, Louis Potier, Gaëtan Prevost, Jean-Pierre Riveline, René Robert, Pierre-Jean Saulnier, Ariane Sultan, Jean-François Thébaut, Charles Thivolet, Blandine Tramunt, Camille Vatier, Ronan Roussel, Jean-François Gautier, Pierre Gourdy, for the CORONADO investigators
Diabetes has been shown to be a major comorbidity that affects the severity of Coronavirus disease-2019 (COVID-19). However, precise data regarding diabetes characteristics and their prognostic relevance in inpatients with COVID-19 are still lacking. In this issue, Cariou, Hadjadj, Wargny et al (https://doi.org/10.1007/s00125-020-05180-x) report the first results from the Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, an observational, multicentric (68 centres), French nationwide study. With a prespecified design and protocol, the CORONADO study aims to explore the phenotypes of diabetic individuals with COVID-19. The authors found that patients with diabetes requiring hospital admission for COVID-19 were more likely to be elderly (mean age, 70 years; 38% ≥75 years old) and male (65%), and more commonly had type 2 (90%) than type 1 diabetes (3%). One in ten patients (10.3%) died by day 7 following hospital admission; age and advanced diabetic complications were independently associated with mortality on day 7 of admission. Thus, people with this profile should follow all rules to avoid infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). In addition, severe forms of COVID-19 were associated with macrovascular complications, as indicated previously, and also microvascular complications, as established for the first time by this study. Long-term glycaemic control (HbA1c) showed no obvious association with prognosis; however, increased BMI appeared to be an independent prognostic factor for COVID-19 severity and, hence, the authors suggest that individuals with a high BMI require special attention.
Mi-Hyang Jung, Sang-Wook Yi, Sang Joon An, Beverley Balkau, Jee-Jeon Yi, Hyeongsu Kim
Lean diabetes (diabetes in people with a low BMI [<25 kg/m2]) is emerging as a pathological condition that is associated with a higher mortality risk than excessive weight or grade I obese diabetes. However, it is not clear whether low BMI and hyperglycaemia have a joint effect on mortality and whether combined associations of fasting glucose levels and BMI with mortality differ by age and sex. In this issue, Jung et al (https://doi.org/10.1007/s00125-020-05160-1) use a Korean cohort study to report that: (1) the adverse effects of hyperglycaemia on mortality risk are more marked in leaner than more overweight individuals, particularly in young men and middle-aged women; and (2) the interpretation of mortality risk associated with fasting blood glucose–BMI subgroups is not straightforward because of complex interactions between fasting glucose, BMI, age and sex. For example, people with a fasting glucose level of 6.1–6.9 mmol/l and a lower normal weight (BMI 20–22.4 kg/m2) had similar or higher mortality risk than people with a fasting glucose level of 7.0–9.9 mmol/l and BMI ≥22.5 kg/m2, while obese people with diabetes had higher mortality risk than overweight people with diabetes. The authors state that this study calls for sophisticated management of patients according to the detailed metabolic profiles of each individual, including fasting glucose and BMI, as well as sex and age, to achieve better health outcomes.
Luciana Mateus Gonçalves, Elizabeth Pereira, João Pedro Werneck de Castro, Ernesto Bernal-Mizrachi, Joana Almaça
Vascular fibrosis is a very common lesion in islets from individuals with type 2 diabetes but its aetiology has not yet been determined. Until now, mouse models that enable us to study the role of dysfunctional islet microvasculature in diabetes pathogenesis have not been available. In this issue, Mateus Gonçalves et al (https://doi.org/10.1007/s00125-020-05168-7) report that a transgenic mouse model of beta cell expansion (the AktTg mouse) exhibits an increased deposition of extracellular matrix proteins around islet blood vessels, allowing for the study of cellular mechanisms that lead to islet vascular fibrosis and its functional consequences. They found that islet pericytes proliferated extensively in this model and were converted into profibrotic myofibroblasts. Vascular alterations were associated with diminished islet blood perfusion and impaired islet vascular responses to noradrenaline and glucose, which led to a decrease in glucose-stimulated insulin secretion per beta cell unit in these transgenic mice. The authors conclude that the AktTg mouse model can now be used to conduct studies aimed at elucidating the role of insulin or other beta cell secretory products in determining the number, phenotype and function of islet pericytes. They state that elucidating the crosstalk between pericytes and beta cells is necessary to fully understand the pathogenesis of islet adaptation in diabetes.
Jie V. Zhao, C. Mary Schooling
Chronic kidney disease (CKD) contributes substantially to the global burden of morbidity and mortality. Notably, CKD has a sexual disparity that is not fully understood. To provide further insight, in this issue Zhao and Schooling (https://doi.org/10.1007/s00125-020-05163-y) contextualise these differences within evolutionary biology theory, which suggests a sex-specific growth and reproduction trade-off against longevity. As such, insulin, a key driver of this trade-off, may have different roles in men and women. Given fasting insulin, fasting glucose and HbA1c are related, the authors used the novel Mendelian randomisation-Bayesian model-averaging (MR-BMA) method to identify the best-fitting model and most influential exposure, followed by univariable or multivariable Mendelian randomisation, as appropriate. Fasting insulin was selected as the most likely exposure by both overall and sex-specific MR-BMA. Genetically predicted insulin was associated with CKD and unfavourable kidney function in men but not women. The authors suggest that clarifying the underlying pathways by which insulin has these sex-specific renal effects could provide new insights for prevention and treatment strategies for CKD.
Jordan J. Wright, Diane C. Saunders, Chunhua Dai, Greg Poffenberger, Brynn Cairns, David V. Serreze, David M. Harlan, Rita Bottino, Marcela Brissova, Alvin C. Powers
Individuals with type 1 diabetes have a reduced total pancreas size; however, the cellular and tissue changes responsible for this size reduction are not well characterised. In this issue, Wright et al (https://doi.org/10.1007/s00125-020-05155-y) report that pancreases from donors with type 1 diabetes were approximately 45% smaller than those from non-diabetic donors. They also had fewer total acinar cells and, as expected, a lower beta cell mass. Acinar cell size was similar between pancreases from diabetic and non-diabetic donors, regardless of location within pancreatic lobes or proximity to islets. Compared with non-diabetic donors, pancreases from donors with type 1 diabetes also had increased fibrosis. Based on the analysis of size and cell composition of pancreases from donors with a wide range of type 1 diabetes duration, the authors speculate that the decline in acinar cell number begins very early in disease progression and that type 1 diabetes pathogenesis involves both the exocrine and endocrine compartments of the pancreas.
Geltrude Mingrone, Simona Panunzi, Andrea De Gaetano, Sofie Ahlin, Valerio Spuntarelli, Isabel Bondia-Pons, Chiara Barbieri, Esmeralda Capristo, Amalia Gastaldelli, John J Nolan
Bariatric surgery results in a rapid improvement in insulin resistance long before weight loss, focusing attention on the role of the small intestine in insulin resistance. In this issue, Mingrone et al (https://doi.org/10.1007/s00125-020-05157-w) compared glucose metabolism in obese participants who were administered oral glucose and, after 7–10 days, i.v. glucose (plasma glucose during i.v. administration was matched to plasma glucose during oral challenge). They also analysed the differences in insulin effect on proteolysis, ketogenesis and lipolysis. The authors found that the oral route led to increased insulin secretion and a complementary 40% reduction in glucose clearance, as compared with the i.v. route. The efficacy of insulin to reduce lipolysis and proteolysis also decreased after oral glucose administration. The authors suggest that an unknown mechanism, triggered by the presence of glucose in the intestinal lumen, counterbalances the effect of incretins (gut hormones that stimulate insulin secretion) by limiting the effect of insulin that has been released in response to glucose. They conclude that these findings indicate that insulin sensitivity depends on the route of glucose administration and that (as yet unknown) intestinal factors are crucial to these underlying metabolic processes.
Eleni Georgiadou, Elizabeth Haythorne, Matthew T. Dickerson, Livia Lopez-Noriega, Timothy J. Pullen, Gabriela da Silva Xavier, Samuel P. X. Davis, Aida Martinez-Sanchez, Francesca Semplici, Rosario Rizzuto, James A. McGinty, Paul M. French, Matthew C. Cane, David A. Jacobson, Isabelle Leclerc, Guy A. Rutter
Impaired Ca2+ signalling in the pancreatic beta cell contributes to deficiencies in insulin secretion in type 2 diabetes. Intramitochondrial oxidative metabolism is thought to be stimulated by increases in cytosolic Ca2+; the mitochondrial uniporter (MCU) complex and its associated regulatory proteins are proposed to be the main driving force of Ca2+ entry into mitochondria. In this issue, Georgiadou et al (https://doi.org/10.1007/s00125-020-05148-x) tested this hypothesis by selectively eliminating Mcu expression in the beta cells of mice. Mitochondrial Ca2+ uptake, ATP production, and insulin secretion in response to glucose stimulation were all substantially impaired, in vitro, in the absence of Mcu. However, the in vivo phenotype of mice lacking Mcu was more complex, with glucose-stimulated insulin release varying depending on test conditions (e.g. time after glucose injection, method of glucose administration and age of animals). The authors conclude that these findings suggest that altered mitochondrial Ca2+ uptake may contribute to defective insulin secretion in some forms of diabetes, and highlight MCU as a potential therapeutic target.
Theresia M. Schnurr, Hermina Jakupović, Germán D. Carrasquilla, Lars Ängquist, Niels Grarup, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Oluf Pedersen, Torben Hansen, Tuomas O. Kilpeläinen
Type 2 diabetes is a common disease with a rapidly increasing global prevalence that has been largely attributed to the ongoing pandemic of obesity and a sedentary lifestyle. However, it is unclear whether the effects of obesity and unfavourable lifestyle on diabetes risk may vary depending on genetic variation. In this issue, Schnurr, Jakupović et al (https://doi.org/10.1007/s00125-020-05140-5) investigated whether the associations of obesity and unfavourable lifestyle with increased risk of type 2 diabetes are accentuated by genetic predisposition. Analysing data from 4729 individuals who developed incident type 2 diabetes and a randomly selected cohort sample of 5402 individuals, the authors found that obesity and unfavourable lifestyle are associated with increased diabetes risk irrespective of genetic predisposition. The authors conclude that weight management by healthy lifestyle should be recommended as a prevention strategy for type 2 diabetes, regardless of genetic predisposition.
K. M. Venkat Narayan, Alka M. Kanaya
People of South Asian ancestry, who total nearly 2 billion worldwide, are at heightened risk of type 2 diabetes, even at low body weights. Challenging the idea that this high risk for type 2 diabetes is primarily due to the population’s susceptibility to adiposity-driven insulin resistance, Narayan and Kanaya (https://doi.org/10.1007/s00125-020-05132-5) offer a novel hypothesis using data on underexplored pathways. Based on evidence from evolutionary biology and recent epidemiological data, the authors state that, compared with other ethnic groups, South Asians have evolutionarily acquired impaired insulin secretion resulting from compromised beta cell function, as well as impaired insulin action due to low lean-muscle mass. These features lower the population’s metabolic capacity, and the reduced insulin action is further accentuated by increased fat deposition in the liver and muscle in response to lifestyle factors. Thus, the authors conclude that investigating the reasons for impaired insulin secretion in South Asians, and approaches to improve beta cell insulin secretion, insulin action in the muscle and hepatic fat deposition, are warranted. They suggest that lessons learnt from studying South Asians may be generalisable to other populations residing in or originating from low- and middle-income countries. The figure from this review is available as a downloadable slide.
Anastasia Tsakmaki, Patricia Fonseca Pedro, Gavin A. Bewick
Disease modelling is a cornerstone of translational medicine and drug discovery. However, meeting future healthcare challenges will require models that more accurately mimic disease pathology. Organoid technology, developed over the last decade, has enabled the long-term culture of stem cell-derived 3D tissue cultures that closely mirror their tissue of origin. Organoids have increased fidelity compared with traditional tissue culture methods and present a tantalising opportunity to supercharge our understanding of disease. In this issue, Tsakmaki et al (https://doi.org/10.1007/s00125-020-05126-3) review organoid technology and discuss the opportunities these mini organs have to offer researchers in the diabetes field. The authors provide a brief overview of the development of organoids from tissues important for glucose homeostasis and those associated with diabetic complications and discuss how they could be utilised. Organoid technology is likely to facilitate a greater understanding of the pathophysiology of diabetes at the cellular and tissue levels and aid the identification of novel pathways for drug development. The figures from this review are available as a downloadable slideset.
Lena Bilet, Esther Phielix, Tineke van de Weijer, Anne Gemmink, Madeleen Bosma, Esther Moonen-Kornips, Johanna A. Jorgensen, Gert Schaart, Dongyan Zhang, Kenneth Meijer, Maria Hopman, Matthijs K. C. Hesselink, D. Margriet Ouwens, Gerald I. Shulman, Vera B. Schrauwen-Hinderling, Patrick Schrauwen
Physical inactivity is suggested to lead to insulin resistance. An imbalance between skeletal muscle fat accumulation and a low mitochondrial oxidative capacity could determine the development of insulin resistance. However, direct evidence for the role of low mitochondrial function in insulin resistance in humans is lacking. In this issue, Bilet et al (https://doi.org/10.1007/s00125-020-05128-1) investigated whether inactivity-mediated lowering of mitochondrial oxidative capacity affects intramyocellular lipid (IMCL) content and skeletal muscle insulin signalling upon lipid infusion in humans. They report that the lowering of skeletal muscle mitochondrial function by one-legged immobilisation resulted in IMCL accumulation. In addition, the inactivated leg became more prone to lipid-induced insulin resistance via the activation of protein kinase C θ (PKCθ), as compared with the active leg. The authors conclude that these results illustrate the importance of mitochondrial function in the development of insulin resistance in humans and that lipid-induced insulin resistance occurs via the activation of PKCθ. They suggest that these findings stress the importance of physical activity in the prevention of diabetes.
Pia Leete, Richard A. Oram, Timothy J. McDonald, Beverley M. Shields, Clemens Ziller, TIGI study team, Andrew T. Hattersley, Sarah J. Richardson, Noel G. Morgan
The aetiology of type 1 diabetes has been difficult to explore in the pancreas due to the limited availability of suitable specimens for study. In this issue, Leete et al (https://doi.org/10.1007/s00125-020-05115-6) employed the world’s largest collections of pancreas samples recovered from young people with recent-onset type 1 diabetes to demonstrate that abnormalities in insulin processing occurred at high frequency in the beta cells of the youngest donors (those diagnosed at <7 years of age) but were much less evident in those who were older at diabetes onset (≥13 years of age). These differences correlated with previously defined immune phenotypes found in the islets of people of equivalent ages. Importantly, among children in the intermediate age range (7–12 years), abnormalities in insulin processing also correlated closely with islet immune phenotype. These histological differences were mirrored by proinsulin:C-peptide ratio in the blood. From these findings, the authors suggest that type 1 diabetes exists as two mechanistically distinct endotypes, which they coin ‘type 1 diabetes endotype 1 (T1DE1)’ and ‘type 1 diabetes endotype 2 (T1DE2)’. They conclude that stratification of children and young people according to endotype will be important in the effective design of future immunotherapeutic trials in type 1 diabetes.
Marianne Benn, Børge G. Nordestgaard, Anne Tybjærg-Hansen, Ruth Frikke-Schmidt
Observational studies have reported an increased risk of dementia in individuals with diabetes mellitus, but it is not known whether high plasma glucose has a causal impact on risk of dementia. In this issue, Benn et al (https://doi.org/10.1007/s00125-020-05124-5) used Mendelian randomisation with data from 115,875 individuals from the Danish general population to examine this. The authors found that a 1 mmol/l higher plasma glucose level was associated with a 2.4-fold higher risk of unspecified dementia, but did not increase the risk of Alzheimer’s disease or vascular dementia. The authors state that the finding that high plasma glucose is causally related to the risk of unspecified dementia underscores the importance of glycaemic control in individuals with diabetes mellitus and, potentially, also in those with impaired glucose tolerance.
Jing Zhang, Longmin Chen, Faxi Wang, Yuan Zou, Jingyi Li, Jiahui Luo, Faheem Khan, Fei Sun, Yang Li, Jing Liu, Zhishui Chen, Shu Zhang, Fei Xiong, Qilin Yu, Jinxiu Li, Kun Huang, Bao-Ling Adam, Zhiguang Zhou, Decio L. Eizirik, Ping Yang, Cong-Yi Wang
Although extracellular high-mobility group box 1 (HMGB1), an evolutionarily conserved chromosomal protein, contributes to the pathogenesis of autoimmune diabetes, its impact on the initiation and progression of type 1 diabetes and the underlying mechanisms largely remain to be elucidated. In this issue, Zhang, Chen, et al (https://doi.org/10.1007/s00125-020-05105-8) report that blockade of HMGB1 not only attenuated autoimmune initiation and progression, but also reversed diabetes in a NOD mouse model of new-onset diabetes. Neutralising HMGB1 also prevented islet isografts from recurrent autoimmune attack. Using a Foxp3 lineage tracing model, the authors found that HMGB1 impairs regulatory T cell (Treg) stability and function via altered receptor for AGE (RAGE) and toll-like receptor 4 (TLR4) activation, leading to enhanced phosphatidylinositol 3-kinase (PI3K)–Akt– mechanistic target of rapamycin (mTOR) signalling. In addition, higher circulating HMGB1 in individuals with type 1 diabetes was noted, which contributed to the impaired Treg stability. According to the authors, their data suggest that HMGB1 could be a viable target for the prevention and treatment of type 1 diabetes in a clinical setting.
Romane Manceau, Danie Majeur, Thierry Alquier
In addition to food intake and body weight regulation, it has become clear that specific brain regions and neurocircuits orchestrate the metabolic fate of nutrients in peripheral tissues in rodents and humans. Increasing evidence suggests that alterations in these processes can contribute to the development of obesity and diabetes. In this issue, Manceau et al (https://doi.org/10.1007/s00125-020-05104-9) review historical evidence and recent studies demonstrating that specific neuronal populations of the hypothalamus regulate the utilisation, storage and conversion of nutrients (referred to as nutrient partitioning) in peripheral tissues via the autonomic nervous system. In addition, this review summarises the molecular and biochemical mechanisms involved in regulation of peripheral nutrient partitioning by hypothalamic cells. Finally, the authors discuss the contribution of impaired neuronal control of nutrient partitioning to metabolic pathologies in humans. The figures from this review are available as a downloadable slideset
Josephine Mollon, Joanne E. Curran, Samuel R. Mathias, Emma E. M. Knowles, Phoebe Carlisle, Peter T. Fox, Rene L. Olvera, Harald H. H. Göring, Amanda Rodrigue, Laura Almasy, Ravi Duggirala, John Blangero, David C. Glahn
Type 2 diabetes is associated with cognitive impairment, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognitive impairment. In this issue, using two quantitative methods for genetic analysis, Mollon et al (https://doi.org/10.1007/s00125-020-05101-y) found evidence for pleiotropy between type 2 diabetes and cognitive impairment. Using one approach, negative genetic correlations between type 2 diabetes and performance in measures of attention, working memory and face memory suggested genetic overlap between type 2 diabetes risk and poor performance in these cognitive domains. Similar results were obtained using the second approach, such that performance in these cognitive domains was lowest in individuals with type 2 diabetes, highest in individuals who were unaffected/unrelated to an affected individual and intermediate in those related to an individual with type 2 diabetes. The authors conclude that these findings suggest that cognitive impairment is genetically related to type 2 diabetes and may, therefore, be useful in elucidating the biological underpinnings of this disease.
Fang Fang Zhang, Yu Hong Liu, Dan Wei Wang, Ting Sheng Liu, Yue Yang, Jia Min Guo, Yi Pan, Yan Feng Zhang, Hong Du, Ling Li, Liang Jin
Abnormal expression of long non-coding RNAs (lncRNAs) has been associated with a variety of human diseases, including diabetes. However, it is unclear whether islet lncRNAs are involved in obesity-mediated beta cell dysfunction, which is associated with diabetes. In this issue, Zhang et al (https://doi.org/10.1007/s00125-020-05090-y) report that obesity reduces the expression of the lncRNA 1810019D21Rik (referred to as regulator of insulin transcription [ROIT]), as assessed by RNA sequencing analysis. They also show that over-expression of ROIT lncRNA leads to improved glucose homeostasis and insulin transcription. The authors suggest that this may be because ROIT lncRNA can downregulate the methylation of the Nkx6.1 promoter by binding to DNA methyltransferase 3a and causing its degradation. The authors conclude that these findings indicate that at least some of the harmful effects of obesity on beta cell function may be mediated by obesity-induced alterations in the level of the ROIT lncRNA.
Amra Jujić, Naeimeh Atabaki-Pasdar, Peter M. Nilsson, Peter Almgren, Liisa Hakaste, Tiinamaija Tuomi, Lisa M. Berglund, Paul W. Franks, Jens J. Holst, Rashmi B. Prasad, Signe S. Torekov, Susana Ravassa, Javier Díez, Margaretha Persson, Olle Melander, Maria F. Gomez, Leif Groop, Emma Ahlqvist, Martin Magnusson
Glucagon-like peptide 1 (GLP-1) analogue therapy has proven to be beneficial for cardiovascular protection. On the contrary, evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) have untoward effects on cardiovascular biology has recently emerged. In this issue, Jujić et al (https://doi.org/10.1007/s00125-020-05093-9) report that, in two prospective, community-based studies, elevated levels of fasting GIP were associated with greater risk of cardiovascular disease-associated and total mortality within 5–9 years of follow-up. Further, Mendelian randomisation analyses provided novel evidence of the involvement of GIP in coronary artery disease and myocardial infarction. The authors suggest osteopontin to be the mediator of the possible detrimental cardiovascular effects of GIP, and call for a more thorough investigation of the potential risks associated with pharmacological stimulation of the GIP pathway.
Brian C. Callaghan, Gary Gallagher, Vera Fridman, Eva L. Feldman
New treatments for diabetic neuropathy are needed since glycaemic control is not the complete answer. In this issue, Callaghan et al (https://doi.org/10.1007/s00125-020-05085-9) discuss recent evidence, which points to new metabolic risk factors for diabetic neuropathy, and novel disease-modifying strategies. Specifically, obesity is an important metabolic risk factor for neuropathy, and this may have treatment ramifications. Diet and exercise have emerged as promising interventions, but future studies are needed to determine their effects on neuropathy outcomes. In addition, dyslipidaemia and altered sphingolipid metabolism are potential mechanisms for nerve injury; it is suggested that a better understanding of these could provide hope for new targeted therapies. Regarding diagnostic testing, Callaghan et al state that the evaluation of neuropathy requires a good clinical history, neurological examination and a few simple blood tests. In their review, they also discuss painful diabetic neuropathy, outlining guidelines that propose that this condition should be treated with tricyclic antidepressants, serotonin-reuptake inhibitors and gabapentinoids. However, opioids should be avoided since data supporting long term opioid use for painful diabetic neuropathy are lacking and data supporting the downsides of these medications are mounting quickly. The authors conclude that there is a clear need for new medications and other interventions for the treatment of painful diabetic neuropathy.
The figure from this review is available as a downloadable slide.
Min Jeong Choi, Saet-Byel Jung, Seong Eun Lee, Seul Gi Kang, Ju Hee Lee, Min Jeong Ryu, Hyo Kyun Chung, Joon Young Chang, Yong Kyung Kim, Hyun Jung Hong, Hail Kim, Hyun Jin Kim, Chul-Ho Lee, Adil Mardinoglu, Hyon-Seung Yi, Minho Shong
Adipose tissue mitochondrial oxidative phosphorylation is critical for systemic energy homeostasis, and its dysfunction has been suggested in the aetiology of insulin resistance and diabetes. To date, there is limited experimental evidence on the systemic effects of mitochondrial oxidative phosphorylation on glucose and energy homeostasis. In this issue, Choi et al (https://doi.org/10.1007/s00125-019-05082-7) report that knockout of the gene encoding mitochondrial large ribosomal subunit protein (CRIF1) paradoxically improves systemic energy homeostasis via cell-autonomous activation of the mitochondrial unfolded protein response, and via the non-cell-autonomous mitokine actions of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21). The authors state that these findings suggest that mitokines and their receptor modulators may be potential targets for the treatment of obesity and metabolic disease.
Ivy C. Mason, Jingyi Qian, Gail K. Adler, Frank A. J. L. Scheer
In this issue, Mason et al (https://doi.org/10.1007/s00125-019-05059-6) provide an overview of the influence of the endogenous circadian system and its disruption on glucose control in healthy individuals and individuals with type 2 diabetes. The circadian system, a multi-oscillator system composed of the suprachiasmatic nucleus and peripheral clocks, generates endogenous 24 h rhythms in physiological functions and biological processes. The authors explain that, in healthy individuals, circadian rhythms in glucose control have been well established. However, while diurnal rhythms of glucose control in individuals with type 2 diabetes are well documented under regular sleep cycles, future studies are required to determine endogenous circadian contributions in this population. Furthermore, disruption of circadian organisation results in dysglycaemia, with converging evidence derived from epidemiological, genetic and experimental studies, although experimental and longer-term randomised controlled trials in individuals with type 2 diabetes are lacking. According to the authors, the available evidence indicates that, in healthy individuals and in those with type 2 diabetes, glycaemic control may be improved by appropriately aligning endogenous, environmental and behavioural rhythms. The figures from this review are available as a downloadable slideset.
Pablo Aschner, Juan J. Gagliardino, Hasan Ilkova, Fernando Lavalle, Ambady Ramachandran, Jean Claude Mbanya, Marina Shestakova, Jean-Marc Chantelot, Juliana C. N. Chan
Management of type 2 diabetes has advanced considerably over the past decade, but there are limited data from developing countries. The International Diabetes Management Practices Study (IDMPS) is an ongoing, international, observational study that documents current practices in diabetes management in developing countries. In this issue, Aschner et al (https://doi.org/10.1007/s00125-019-05078-3) report that data from across seven cross-sectional ‘waves’, from 2005 to 2017 (including >65,000 people with type 2 diabetes), indicate that HbA1c target attainment in these countries remains poor and has, in fact, decreased significantly over time; this is despite increased use of insulin and a higher proportion of patients undergoing frequent HbA1c measurements. While receipt of diabetes education increased over time, this was predominantly provided only by physicians. In summary, the authors state that, while some encouraging trends in care improvements were observed, system changes are needed to improve access to structured education, self-monitoring tools and appropriate medications. They propose that such changes will support self-management and enable care providers to intensify treatment as recommended in guidelines.
Amy S. Shah, Kristen J. Nadeau
Paediatric diabetes is on the rise. In the last decade there has been extensive research dedicated to understanding its pathophysiology and its associated comorbidities and complications. In this issue, Shah and Nadeau (https://doi.org/10.1007/s00125-019-05075-6) summarise the current state of knowledge of type 1 and type 2 diabetes in children and adolescents. They review the current epidemiology and address the importance of differentiating between the two main types of diabetes, especially in the setting of obesity. The authors go on to discuss the observed comorbidities and complications in type 1 and type 2 diabetes in youth, pointing out that abnormalities in heart physiology, blood dynamics and renal hyperfiltration are more common in individuals with either type of diabetes than in peers without diabetes. Finally, currently available treatments and novel treatments on the horizon are discussed. The figure from this review is available as a downloadable slide.
John B. Buse, Deborah J. Wexler, Apostolos Tsapas, Peter Rossing, Geltrude Mingrone, Chantal Mathieu, David A. D’Alessio, Melanie J. Davies
In 2018, the ADA/EASD published a consensus report for the management of hyperglycaemia in type 2 diabetes (https://link.springer.com/article/10.1007/s00125-018-4729-5). Patient-centred care that was focused on reducing the burden of complications represented a paradigm shift in the approach to diabetes management, with the preferred use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium–glucose cotransporter 2 (SGLT2) inhibitors in those with established atherosclerotic cardiovascular disease (ASCVD). Since then, there has been an unprecedented release of new outcome data, mandating a brief update to the 2018 consensus. In this issue, the ADA/EASD (https://doi.org/10.1007/s00125-019-05039-w) present important changes to the 2018 consensus, including consideration of GLP-1 RAs and SGLT2 inhibitors for beneficial cardiorenal outcomes in individuals with type 2 diabetes, independently of HbA1c levels. Where major adverse cardiovascular events are the gravest threat, the evidence favours the preferred use of GLP-1 RAs; as well as being used in those with type 2 diabetes and established ASCVD, their use should be considered in those with specific indicators of high cardiovascular risk. When it comes to the use of SGLT-2 inhibitors in type 2 diabetes, the evidence is now much clearer for their benefit, particularly in those with heart failure with reduced ejection fraction and in those with chronic kidney disease (CKD), and in the prevention of CKD progression. Thus, SGLT-2 inhibitors are preferred for diabetes management in individuals with these comorbidities.
Joanne E. Hurst, Ruth Barn, Lesley Gibson, Hamish Innes, Sicco A. Bus, Brian Kennon, David Wylie, James Woodburn
Social deprivation is a reported risk factor for foot ulceration, lower extremity amputation and subsequent mortality in people with diabetes. However, it is unclear if the prevalence of these outcomes is random or forms patterns according to the geographical distribution of social deprivation. In this issue, Hurst et al (https://doi.org/10.1007/s00125-019-05056-9) report the use of routinely collected health data, its linkage, and visualisation of foot outcomes by deprivation status over the large health administrative area of National Health Service (NHS) Greater Glasgow and Clyde. The authors report that foot ulceration, amputation and subsequent mortality are highly prevalent in areas with the worst social deprivation, with distinct geographical near-neighbour clustering of areas with similar characteristics. Conversely, low prevalence is associated with areas of relatively low deprivation, confirming stark inequalities across the health board. They suggest that this technique of geospatial mapping can inform health service redesign by targeting resources at identified hot spot regions, potentially improving outcomes and reducing inequalities.
Marco Colombo, Stuart J. McGurnaghan, Samira Bell, Finlay MacKenzie, Alan W. Patrick, John R. Petrie, John A. McKnight, Sandra MacRury, Jamie Traynor, Wendy Metcalfe, Paul M. McKeigue, Helen M. Colhoun, on behalf of the Scottish Diabetes Research Network (SDRN) Type 1 Bioresource Investigators and the Scottish Renal Registry
Kidney disease is a major cause of loss of quality and length of life in type 1 diabetes. Improvements in diabetes care should be reducing this complication but there are few large incidence studies in type 1 diabetes to confirm whether this is the case. Furthermore, we know that some people seem to be more susceptible to this complication than others but how to predict those most at risk is unclear. Accordingly, in this issue, Colombo et al (https://doi.org/10.1007/s00125-019-05052-z) quantified the extent to which kidney disease occurs in a large nationally representative cohort of people with type 1 diabetes and attempted to maximise prediction of kidney disease progression. The authors found that current rates of kidney disease are much lower than in historical reports and that the majority of people with type 1 diabetes have fairly stable kidney function. However, there remains a small proportion who develop this complication quickly, as well as having more cardiovascular and retinal disease, and the early identification of these individuals is challenging.
Casey Crump, Jan Sundquist, Kristina Sundquist
Preterm birth has previously been associated with insulin resistance early in life. However, no large cohort studies have examined preterm birth in relation to both type 1 and type 2 diabetes from childhood into adulthood. In a national cohort of over 4 million people, Crump et al (https://doi.org/10.1007/s00125-019-05044-z) found that preterm birth was linked with higher risks of both type 1 and type 2 diabetes from childhood into early- to mid-adulthood. An analysis of siblings further suggested that these findings were only partially explained by shared genetic or environmental factors in families. Instead, preterm birth and its treatment may have direct effects on later development of diabetes. The authors conclude that preterm birth should be recognised as a chronic condition that predisposes individuals to diabetes across the life course. Children and adults born prematurely may need early preventive evaluation and long-term monitoring for timely detection and treatment of diabetes.
Masaya Oshima, Séverine Pechberty, Lara Bellini, Sven O. Göpel, Mélanie Campana, Claude Rouch, Julien Dairou, Cristina Cosentino, Federica Fantuzzi, Sanna Toivonen, Piero Marchetti, Christophe Magnan, Miriam Cnop, Hervé Le Stunff, Raphaël Scharfmann
Rodent beta cells are highly sensitive to treatment with saturated NEFA, leading to their impairment and death. However, translating data from rodent to human beta cells remains challenging. Previous data indicate that treatment of a recently engineered functional beta cell line, EndoC-βH1, with palmitate does not induce lipotoxicity under standard culture conditions. In this issue, Oshima et al (https://doi.org/10.1007/s00125-019-05046-x) report that, upon stearoyl CoA desaturase (SCD) knockdown, EndoC-βH1 cells are sensitive to lipotoxicity and that they dedifferentiate. Treatment with long chain saturated NEFA exacerbates dedifferentiation and induces markers of inflammation and endoplasmic reticulum stress. The authors suggest that characterising the factors that govern SCD activity may lead to new approaches to overcome pancreatic beta cell dedifferentiation, dysfunction and apoptosis during type 2 diabetes.
Marion M. Mafham, Louise J. Bowman, Richard J. Haynes, Jane M. Armitage
Randomised trials have become so costly and complex to conduct that many important research questions go unanswered. Novel streamlined methodologies, including the use of registry trials, have been proposed. In this issue, Mafham et al (https://doi.org/10.1007/s00125-019-05049-8) outline the lessons learned from A Study of Cardiovascular Events iN Diabetes (ASCEND), a large mail-based trial of aspirin and of n-3 fatty acid supplementation for the primary prevention of serious vascular events in people with diabetes. The authors describe how this trial obtained reliable randomised evidence at a fraction of the cost of traditional clinic-based trials, and how insights from its design and conduct will inform future studies. They also consider the limitations of the study and how these could be circumvented in future studies. The authors conclude that similar approaches should be adopted by other researchers in order to answer important clinical questions that are relevant to improving health.
Blandine Tramunt, Sarra Smati, Naia Grandgeorge, Françoise Lenfant, Jean-François Arnal, Alexandra Montagner, Pierre Gourdy
Understanding sex differences has recently emerged as a priority for research in numerous medical areas, including metabolic diseases. In this issue, Tramunt et al (https://doi.org/10.1007/s00125-019-05040-3) review how many aspects of energy balance and glucose metabolism are differently regulated in men and women, influencing their predisposition to type 2 diabetes. Insulin sensitivity and beta cell function are better in premenopausal women vs age-matched men, and this review details the clinical and experimental observations that have recently provided important new insights into the role of sex steroids, especially oestrogens, in these sex disparities. The contribution of additional mechanisms, including the role of sex chromosomes and epigenetic modifications, is also discussed; the authors advise that these require further attention. They conclude that, overall, evidence of sex-related differences in metabolic regulation and diabetes pathogenesis highlights the need to promote sex-based strategies for the prevention and treatment of type 2 diabetes. The figures from this review are available as a downloadable slideset.
Hiroshi Nomoto, Lina Pei, Chiara Montemurro, Madeline Rosenberger, Allison Furterer, Giovanni Coppola, Brian Nadel, Matteo Pellegrini, Tatyana Gurlo, Peter C. Butler, Slavica Tudzarova
Prospective studies of individuals at high risk of type 1 diabetes established that the interval between initiation of beta cell autoimmunity and diabetes onset can be up to 10 years. In this issue, Nomoto, Pei and colleagues (https://doi.org/10.1007/s00125-019-05030-5) investigated whether activation of the hypoxia inducible factor 1 α (HIF1α) signalling pathway plays a role in this prolonged prediabetes phase. Evaluation of residual beta cells from individuals with recent-onset and pre-type 1 diabetes revealed activation of a highly conserved pro-survival injury response program initiated by HIF1α, as recently also shown in beta cells in type 2 diabetes. According to the authors, the unexplained slow rate of beta cell attrition but early attenuation of glucose-induced insulin secretion in evolving type 1 diabetes is likely to be due, at least in part, to activation of pro-survival signalling pathways at the expense of beta cell function. They conclude that, since HIF1α signalling has an impact on multiple cell functions, observable changes in beta cells in type 1 and type 2 diabetes may be protective rather than mediating cell toxicity, implying that caution should be used when selecting potential therapeutic targets.
Bryan M. Williams, Davide Borroni, Rongjun Liu, Yitian Zhao, Jiong Zhang, Jonathan Lim, Baikai Ma, Vito Romano, Hong Qi, Maryam Ferdousi, Ioannis N. Petropoulos, Georgios Ponirakis, Stephen Kaye, Rayaz A. Malik, Uazman Alam, Yalin Zheng
Diabetic neuropathy is the strongest initiating risk factor for foot ulceration and amputations. Current ‘screening’ practices are highly subjective and only diagnose diabetic neuropathy when well-established, which is in stark contrast to the tools available for the early diagnosis of other diabetic complications, such as retinopathy. Future development of valid screening programmes utilising technology that detects early neuropathy is, therefore, of paramount importance and clinical need. In this issue, Williams et al (https://doi.org/10.1007/s00125-019-05023-4) present an artificial intelligence-based algorithm that accurately and rapidly detects diabetic neuropathy through non-invasive assessment of the corneal sub-basal nerve plexus using corneal confocal microscopy. They show that this approach outperforms the currently used automated software, with superior intraclass correlation coefficients for all major corneal nerve biomarkers. The authors conclude that these findings indicate that corneal confocal microscopy is now primed for population-based screening of diabetic neuropathy.
Martijn C. G. J. Brouwers, Nynke Simons, Coen D. A. Stehouwer, Aaron Isaacs
Non-alcoholic fatty liver disease (NAFLD) has emerged as a risk factor for type 2 diabetes and cardiovascular disease (CVD). In this issue, Brouwers and colleagues (https://doi.org/10.1007/s00125-019-05024-3) elaborate on potential mediators of the relationship between NAFLD and CVD, such as plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines. By summarising recent advances in genetic studies that focused on the relationship between NAFLD susceptibility genes (PNPLA3, TM6SF2, GCKR and MBOAT7) and CVD, it appears that plasma lipids are an important mediator of that relationship. This has therapeutic implications, particularly for the design of anti-NAFLD drugs that affect lipid metabolism. Since these agents are aimed primarily at preventing end-stage liver disease, it is important to underscore the fact that the principal cause of death in individuals with NAFLD is CVD. The figures from this review are available as a downloadable slideset.
The time in range (TIR) metric has emerged as being a key indicator of the quality of glucose control in diabetes. In this issue, Andrew Advani (https://doi.org/10.1007/s00125-019-05027-0) summarises recent TIR research with the aim of assisting healthcare professionals and individuals living with diabetes in interpreting TIR data and setting TIR goals. Evidence is beginning to emerge linking reduced TIR with increased risk of long-term diabetes complications and adverse pregnancy outcomes. This association may be expected given the inverse correlation between TIR and HbA1c levels. The author explains that, because of the skewed distribution of glucose levels outside the target range, TIR (on its own) is a poor indicator of the frequency and severity of hypoglycaemia. Thus, all TIR discussions should separately consider time below range and, by inference, time above range. In this review, the recent consensus recommendations for time in ranges goals are summarised, although, as is always the case, glycaemic targets should be individualised. The figures from this review are available as a downloadable slideset.
Naveed Akbar, Valerio Azzimato, Robin P. Choudhury, Myriam Aouadi
Extracellular vesicles (EVs) are considered promising candidates for the diagnosis and treatment of metabolic diseases. EVs are membrane-enclosed lipid spheres that serve as messengers by transporting lipids, proteins, RNA and/or DNA from the parent cell of origin to other cells. EVs present a potential major advantage over current blood-borne diagnostic markers as they can provide new functional insights into the cells and tissues implicated in metabolic disease. Recent discoveries in clinical cohorts and animal models has led to a blossoming of publications, implicating EVs in the biology and development of metabolic diseases. In this this issue, Akbar et al (https://doi.org/10.1007/s00125-019-05014-5) discuss the role of platelet, endothelial, adipocyte, immune cell and gut-microbiome EVs in metabolic dysfunction, focusing on EV-dependent communication between adipocytes, the vasculature and immune cells in type 2 diabetes. They also explore potential issues associated with translating early biomarker discoveries into therapeutic targets. The figures from this review are available as a downloadable slideset.
Mohammed Bensellam, Yan-Chuan Shi, Jeng Yie Chan, D. Ross Laybutt, Heeyoung Chae, Michel Abou-Samra, Evan G. Pappas, Helen E. Thomas, Patrick Gilon, Jean-Christophe Jonas
The mechanisms of beta cell adaptation to insulin resistance in obesity and of beta cell failure in type 2 diabetes are poorly defined. Several metallothionein genes are upregulated in islets from type 2 diabetic donors, but their role in beta cells is unclear. In this issue, Bensellam et al (https://doi.org/10.1007/s00125-019-05008-3) report that beta cell compensation in murine models of obesity correlates with downregulation of islet metallothionein 1 (Mt1) and Mt2 gene expression, while beta cell failure correlates with their upregulation. They also confirm that MT1X expression is upregulated in islets isolated from type 2 diabetic donors. Combining in vivo, ex vivo and in vitro complementary approaches, the authors demonstrate that Mt1 inhibition enhances glucose-stimulated insulin secretion and improves glucose tolerance, whereas its overexpression attenuates the secretory response. They conclude that MT1 negatively regulates beta cell function and propose that MT1 inhibition may represent a potential strategy to enhance insulin secretion in (pre)diabetes.
Hannah R. Elliott, Gemma C. Sharp, Caroline L. Relton, Deborah A. Lawlor
Gestational diabetes (GDM) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. Epigenetic mechanisms have been hypothesised to mediate an effect of GDM on offspring adiposity and type 2 diabetes and therefore could provide a modifiable mechanism to reduce type 2 diabetes in future generations. Epigenetic mechanisms have also been proposed as useful clinical biomarkers for predicting future adverse outcomes, irrespective of their causal role in disease. In this issue, Elliott, Sharp et al (https://doi.org/10.1007/s00125-019-05011-8) summarise recent advances in the epigenetic epidemiology of GDM. They identify a nascent research area that is likely to benefit from triangulation of different methods for exploring causal effects of epigenetic mechanisms on disease. They also identify the need to determine the value of epigenetic markers measured in samples collected in early pregnancy as accurate predictors of GDM and associated adverse outcomes. The figures from this review are available as a downloadable slideset.
Johan Verhagen, Norkhairin Yusuf, Emma L. Smith, Emily M. Whettlock, Kerina Naran, Sefina Arif, Mark Peakman
The HLA-DR3-DQ2 haplotype represents a major risk factor for the development of type 1 diabetes. However, it is not fully established which antigen presented on these HLA molecules is important in disease development. In this issue, Verhagen and colleagues (https://doi.org/10.1007/s00125-019-04994-8) report a novel two-stage in vivo approach to identify these antigens. The authors first generated a new transgenic mouse model expressing HLA-DR3-DQ2 and found a high rate of spontaneous autoimmune diabetes. They then used adjuvanted priming with candidate antigens to demonstrate that only proinsulin is capable of further accelerating diabetes development. Moreover, this diabetogenicity maps to a 15-mer residue, with its core MHC-binding region in the N-terminal of C-peptide, which was not previously known to be disease relevant. The authors suggest that the identification of diabetogenic peptides in this way will provide new insights into the role of HLA in diabetes development, which could be relevant to human studies and therapies.
Ari V. Ahola-Olli, Linda Mustelin, Maria Kalimeri, Johannes Kettunen, Jari Jokelainen, Juha Auvinen, Katri Puukka, Aki S. Havulinna, Terho Lehtimäki, Mika Kähönen, Markus Juonala, Sirkka Keinänen-Kiukaanniemi, Veikko Salomaa, Markus Perola, Marjo-Riitta Järvelin, Mika Ala-Korpela, Olli Raitakari, Peter Würtz
Increased risk for type 2 diabetes is consistently associated with widespread metabolic aberrations in young adults from multiple cohorts with a mean age of 31–36 years at baseline. Among the strongest predictors of incident type 2 diabetes are circulating branched-chain amino acids, VLDL-particle measures and enrichment of triacylglycerol in all lipoprotein subclasses. Previous animal studies and Mendelian randomisation studies performed in humans have suggested causal relationships between increased concentrations of branched-chain amino acids and type 2 diabetes. In this issue, Ahola-Olli et al (https://doi.org/10.1007/s00125-019-05001-w) used NMR metabolomics to quantify 229 circulating metabolic measures in individuals from four Finnish observational cohorts (n=11,896; baseline age 24–45 years) and tested associations with risk of developing diabetes, fasting glucose, 2 h glucose and HOMA-IR at follow-up (range 8–15 years). The authors explain that their results extend previously detected epidemiological associations (in middle-aged and older individuals) to young adults and demonstrate that branched-chain amino acids can predict the development of type 2 diabetes up to 15 years prior to disease onset. By summarising the information from multiple metabolic measures, the authors were able to derive and validate a multi-metabolite score identifying a subgroup of patients with a greatly increased risk for type 2 diabetes after adjusting for BMI and fasting glucose (OR 10.1 for individuals in upper vs lower fifth of the multi-metabolite score). They conclude that comprehensive metabolic profiling may eventually help target interventions for young people at increased risk for developing type 2 diabetes.
Sofia Carlsson, Tomas Andersson, Mats Talbäck, Maria Feychting
While previous studies have shown that diabetes risk increases with lower socioeconomic status, little research exists on occupation and risk of type 2 diabetes. In this issue, Carlsson et al (https://doi.org/10.1007/s00125-019-04997-5) investigated the incidence and prevalence of type 2 diabetes across all occupational groups in Sweden. The association between occupation and type 2 diabetes coincided with vast differences in prevalence of lifestyle factors, far greater than any analyses of socioeconomic groups have revealed: drivers, factory workers and cleaners were three times more likely to develop type 2 diabetes than teachers and physiotherapists. Individuals in occupations associated with a high risk of diabetes were more likely to be overweight, smoke and have lower physical fitness than those in low-risk occupations. The differences were apparent from a young age, even at the time of entering the work force, among men. The authors conclude that if workplace interventions could target unhealthy lifestyle factors among employees in these occupations, major health gains may be made.
Jorge Postigo-Fernandez, Donna L. Farber, Rémi J. Creusot
Type 1 diabetes, like many other autoimmune disorders, results, in part, from a failure to maintain peripheral tolerance. This failure is often associated with defects in professional antigen-presenting cells (APCs) (i.e. dendritic cells), which lose their tolerogenic potential, driving inflammatory responses. However, other, less well-known APCs (lymph node stromal cells) are particularly interesting because of their inherent capacity to induce self-tolerance. In this issue, Postigo-Fernandez et al (https://doi.org/10.1007/s00125-019-04984-w) study these cell populations in the context of autoimmune diabetes. Data collected from multiple human pancreatic lymph nodes reveal alterations in the relative frequency of these stromal cells, as well as an increase in their expression of MHC-II and programmed death-ligand 1 (PD-L1). These changes correlate with increased expression of a number of tolerance-related genes in human type 1 diabetes donors. The authors conclude that these unexpected findings could pave the way to immunotherapies targeting these cells to help re-establish peripheral tolerance.
Yanbo Zhang, Xiong-Fei Pan, Junxiang Chen, Lu Xia, Anlan Cao, Yuge Zhang, Jing Wang, Huiqi Li, Kun Yang, Kunquan Guo, Meian He, An Pan
Maintaining a healthy body weight and diet, keeping physically active, and avoiding smoking and heavy drinking have been reported to be associated with a lower risk of type 2 diabetes and with a lower risk of mortality and cardiovascular disease among individuals with diabetes. However, no study has systematically summarised the current evidence, and variability existed across studies. In this issue, Zhang et al (https://doi.org/10.1007/s00125-019-04985-9) report the results of a meta-analysis of prospective cohort studies investigating the relationship of combined lifestyle factors with incident type 2 diabetes and with mortality and morbidity in individuals with type 2 diabetes. Individuals with the healthiest lifestyle according to different lifestyle factors had a 75% lower risk of incident type 2 diabetes than those with the least-healthy lifestyle. Furthermore, among individuals with diabetes, adopting the healthiest lifestyle was associated with risk reductions of 31–56% for total and cause-specific deaths and incident cardiovascular disease. According to the authors, these findings indicate that promotion of comprehensive healthy lifestyle factors should be a public health priority for all countries.
This issue features a special series of reviews on different aspects of diabetes throughout the life course. Jonathan Wells (https://doi.org/10.1007/s00125-019-4944-8) begins the series by considering diabetes risk from an evolutionary perspective to explain how adverse environments can increase diabetes risk and that this risk can be passed on to subsequent generations. Next, Golden et al (https://doi.org/10.1007/s00125-019-4968-0) summarise racial/ethnic differences in the frequencies of type 2 diabetes across the life course, while Huebschmann et al (https://doi.org/10.1007/s00125-019-4939-5) discuss the physiological and behavioural mechanisms that may underlie variations between the sexes with respect to diabetes prevalence and cardiovascular risk over a life time. The next two reviews by Stein et al (https://doi.org/10.1007/s00125-019-4930-1) and Perng et al (https://doi.org/10.1007/s00125-019-4914-1) focus on developmental under- and overnutrition, respectively, and obesity/diabetes risk. Fernandez-Twinn et al (https://doi.org/10.1007/s00125-019-4951-9) look at how in utero exposures lead to the ‘developmental programming’ of offspring obesity and diabetes in later life via a variety of mechanisms, including epigenetics, while Sharp and Lawlor (https://doi.org/10.1007/s00125-019-4919-9) discuss how fathers might influence the development of obesity and diabetes in their offspring.
Besides maternal nutrition, another in utero exposure that has been linked to offspring obesity and diabetes in later life is exposure to environmental toxicants. In their review, Sargis and Simmons (https://doi.org/10.1007/s00125-019-4940-z) discuss how endocrine-disrupting chemicals in the environment have been implicated in diabetes pathogenesis throughout the life course.
With regard to type 1 diabetes, Craig et al (https://doi.org/10.1007/s00125-019-4942-x) look at how early life exposures contribute to type 1 diabetes risk. In terms of potential treatments for diabetes, Palmer et al (https://doi.org/10.1007/s00125-019-4934-x) explore the biological links between ageing and diabetes, with a specific focus on cellular senescence. We conclude with a review by Timpel et al (https://doi.org/10.1007/s00125-019-4941-y) discussing what governments should be doing. The reviews are accompanied by an editorial (https://doi.org/10.1007/s00125-019-4954-6).
Christine W. Hockett, Kylie K. Harrall, Brianna F. Moore, Anne P. Starling, Anna Bellatorre, Katherine A. Sauder, Wei Perng, Ann Scherzinger, Kavita Garg, Brandy M. Ringham, Deborah H. Glueck, Dana Dabelea
Previous studies have shown that exposure to gestational diabetes mellitus (GDM) in utero is associated with increased levels of adiposity in the offspring. However, few studies have investigated the effects of intrauterine GDM exposure on fat patterning and distribution in offspring, specifically over time, while they are transitioning through puberty. In this issue, Hockett et al (https://doi.org/10.1007/s00125-019-04981-z) report that, on average, offspring exposed to GDM in utero have higher levels of adiposity compared with offspring not exposed to GDM, and that the magnitude of these differences do not change over time. They state that these findings provide evidence that the effects of fetal overnutrition on offspring adiposity are established early in life, likely before puberty, and track throughout adolescence. The authors suggest that efforts to prevent childhood obesity should focus on the pre-conception and prenatal periods of life.
Claire L. Williams, Anna E. Long
Zinc transporter 8 (ZnT8) is a major target of humoral immunity in pancreatic beta cells. Autoantibodies to ZnT8 help to define risk of type 1 diabetes accurately, particularly after childhood. In this issue, Williams and Long (https://doi.org/10.1007/s00125-019-04975-x) summarise the lessons learnt from research into this islet antigen and highlight important questions that remain to be answered. They explain that antibody recognition of ZnT8 is influenced by a non-synonymous single nucleotide polymorphism, uniquely providing evidence of true autoimmunity. Why the immune system reacts to this protein in type 1 diabetes is still unclear. ZnT8 responses appear later in the autoimmune process leading to diabetes and often are lost rapidly after diagnosis. The authors discuss how the development of novel assays to measure ZnT8 autoantibodies will provide quicker and cheaper methods of detection and may uncover additional important epitopes for antibody binding. They state that this should reveal improved biomarkers of disease and will aid our understanding of the role of ZnT8 autoimmunity in type 1 diabetes. The figures from this review are available as a downloadable slideset.
Marc Prentki, Barbara E. Corkey, S. R. Murthy Madiraju
Insulin secretion in response to nutrients and hormones is regulated by multiple metabolic signals originating either within the beta cell or exogenously. Despite significant advances in the understanding of the insulin secretion process per se, the different signalling pathways and the metabolite signals involved are not fully understood. Furthermore, the intricate mechanisms that govern insulin granule exocytosis and secretion, and the complexities inherent to the methodologies employed, have given rise to results that are often not uniform and that are influenced by the system studied and conditions employed. Glucose-stimulated insulin secretion is known to be amplified by lipid signalling, though the precise mechanisms and the lipid molecules involved remain a matter of discussion. In this issue, Prentki et al (https://doi.org/10.1007/s00125-019-04976-w) review the current knowledge about the importance of the acetyl-CoA carboxylase/malonyl-CoA/carnitine palmitoyltransferase-1 axis and the glycerolipid/NEFA cycle as the members of the lipid signalling network with key roles controlling insulin secretion in the beta cell. The figures from this review are available as a downloadable slideset.
Geert J. Biessels, Rachel A. Whitmer
Individuals with diabetes are at increased risk of cognitive impairment and this has consequences for aspects of their daily life, diabetes treatment and prognosis. Recent diabetes guidelines, therefore, recommend routine screening for cognitive impairment, particularly in older individuals with diabetes. However, this is not yet common practice. In this issue, Biessels and Whitmer (https://doi.org/10.1007/s00125-019-04977-9) review cognitive impairment in individuals with diabetes, including its clinical features at different stages of cognitive dysfunction and its impact on those affected. They address the emerging guidelines and pinpoint issues that will need to be resolved to effectively put this guidance into practice to optimise individualised care for people with diabetes and cognitive impairment.
Chelsea R. Hutch, Karen Roelofs, April Haller, Joyce Sorrell, Kyle Leix, David D. D’Alessio, Robert Augustin, Randy J. Seeley, Thomas Klein, Darleen A. Sandoval
Several effective glucoregulatory pharmaceuticals target incretin peptides, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). One such class of pharmaceuticals prolongs the half-life of these peptides by inhibiting the degradation enzyme, dipeptidyl peptidase-4 (DPP-4). It is commonly thought that the intestinal source of GLP-1 is responsible for improved glucose homeostasis by DPP-4 inhibitors. In this issue, Hutch et al (https://doi.org/10.1007/s00125-019-4963-5) studied transgenic mouse models in which GLP-1 is solely expressed in the pancreas or the intestine. Their findings indicate that pancreatic GLP-1 contributes to the effectiveness of DDP-4 inhibitors. In addition, in a mouse model with no GLP-1 production, DPP-4 inhibitors retained a full glucoregulatory effect through the actions of GIP. The authors conclude that these findings suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance in mice.
Willem Staels, Yves Heremans, Harry Heimberg, Nico De Leu
In recent years, studies in transgenic mice have been particularly informative with regard to the crosstalk between endothelial cells and beta cells in beta cell development, physiology and disease. In this issue, Staels et al (https://doi.org/10.1007/s00125-019-4969-z) summarise current knowledge on these complex interactions, with special emphasis on the role of vascular endothelial growth factor-A (VEGF-A). They discuss the involvement of vascular changes in the pathogenesis of type 1 and type 2 diabetes. In addition, the authors explain how impaired revascularisation of islets transplanted in individuals with type 1 diabetes is linked to islet graft failure and graft loss, and outline preclinical strategies used to improve the rate of revascularisation. Finally, the authors highlight how the vasculature could provide an opportunity for the development of new diabetes therapies. The figure from this review is available as a downloadable slide.
Madelon L. Geurtsen, Eef E. L. van Soest, Ellis Voerman, Eric A. P. Steegers, Vincent W. V. Jaddoe, Romy Gaillard
Gestational diabetes mellitus (GDM) is a major risk factor for perinatal complications. Recent studies suggest that, in mid- and late pregnancy, high maternal glucose levels below the threshold of GDM are associated with increased risks of adverse birth outcomes. In this issue, Geurtsen et al (https://doi.org/10.1007/s00125-019-4957-3) performed a population-based prospective cohort study of 6116 pregnant women to investigate the direct effects of impaired maternal glucose metabolism from early pregnancy onwards on fetal growth throughout pregnancy and on adverse birth outcomes. They report that higher maternal non-fasting glucose levels in early pregnancy are associated with altered fetal growth patterns, characterised by decreased fetal growth rates in mid-pregnancy and increased fetal growth rates from late pregnancy onwards, leading to an increased risk of delivering a large-for-gestational-age infant. The authors suggest that these findings indicate that instead of targeting maternal glucose metabolism in the second half of pregnancy, as is current clinical practice, future preventive strategies need to focus on screening for impaired maternal glucose metabolism from preconception and early pregnancy onwards. In addition, there is a need for intervention programmes to improve fetal growth and birth outcomes.
Sharon T. Mackin, Scott M. Nelson, Sarah H. Wild, Helen M. Colhoun, Rachael Wood, Robert S. Lindsay, on behalf of the SDRN Epidemiology Group and Scottish Diabetes Group Pregnancy subgroup
Stillbirth rates are up to fivefold higher in mothers with diabetes compared with those without. Identification of at-risk pregnancies is challenging for clinical teams. In this issue, Mackin et al (https://doi.org/10.1007/s00125-019-4943-9) explored Scottish obstetric data to better identify the risk profile of affected pregnancies in women with type 1 and type 2 diabetes. In type 1, higher glycaemia throughout pregnancy was linked with stillbirth, whilst in type 2, higher pregestational glycaemia and maternal BMI had the strongest association, highlighting the importance of preconceptual preparation. Stillbirth risk was increased at the extremes of birthweight and, whilst the majority of stillbirths occurred preterm (under 37 weeks), one-third occurred at term. The authors conclude that more accurate prediction of pregnancies at risk of stillbirth is urgently needed.
Sarah-Naomi James, Andrew Wong, Therese Tillin, Rebecca Hardy, Nishi Chaturvedi, Marcus Richards
Type 2 diabetes, hyperglycaemia and insulin resistance are considered risk factors for cognitive impairment. In this issue, James et al (https://doi.org/10.1007/s00125-019-4949-3) analysed data from the National Survey for Health and Development, a birth cohort established in 1946, to show that childhood advantage (childhood cognitive ability, socioeconomic status and education) drives this association, by separately benefitting older-age insulin resistance and cognition. They found no direct connection between the latter two variables. The authors used an alternative genetic approach, a polygenic risk score for insulin resistance, to confirm the lack of association with cognition. The authors conclude that these findings suggest that glucose-lowering agents are unlikely to have a beneficial impact on cognitive decline and dementia, and that strategies to improve childhood circumstances may be better placed to impact both later life diabetes and cognitive impairment risk.
Stephanie Eid, Kelli M. Sas, Steven F. Abcouwer, Eva L. Feldman, Thomas W. Gardner, Subramaniam Pennathur, Patrice E. Fort
The mechanisms driving the onset and progression of diabetic complications have been extensively studied individually, but the commonalities and specificities between them have received very little attention. The review by Eid et al (https://doi.org/10.1007/s00125-019-4959-1) in this issue specifically discusses omics-based studies of microvascular complications in both the experimental and clinical settings. The authors place a special emphasis on the emerging role of lipids and lipid metabolism as a central mechanism underlying diabetic complications. The omics-based non-targeted analyses of tissues from diabetic individuals and preclinical models following interventions have been key in reshaping our understanding of the pathophysiological mechanisms involved in microvascular complications, forming new hypotheses for therapeutic leads. The figures from this review are available as a downloadable slideset.
Christa D. Bowes, Lillian F. Lien, Javed Butler
Cardiovascular outcome (CVO) trials with novel glucose-lowering therapies have provided us with a deeper understanding of the risks and benefits of these agents with respect to cardiovascular outcomes. In turn, CVO trials have allowed individualisation of therapy for patients with diabetes. Since individuals with diabetes are at a higher risk of developing heart failure (HF) and, subsequent to HF development, have much worse prognosis, it is important to consider the issues concerning HF risk and management in these individuals. In this issue, Bowes et al (https://doi.org/10.1007/s00125-019-4958-2) summarise available data on the impact of various glucose-lowering therapies on the risks of developing HF and their role in the prevention of incident HF. They state that these data will provide clinicians with further insights to help optimise the management of patients with diabetes with and without HF. The figure from this review is available as a downloadable slide.
Rick Hogenboom, Martin J. Kalsbeek, Nikita L. Korpel, Paul de Goede, Marit Koenen, Ruud M. Buijs, Johannes A. Romijn, Dick F. Swaab, Andries Kalsbeek, Chun-Xia Yi
The molecular clock is disturbed in peripheral tissues of individuals with type 2 diabetes. However, it is not known whether the brain master clock in the hypothalamic suprachiasmatic nucleus is also affected. In this issue, Hogenboom, Kalsbeek et al (https://doi.org/10.1007/s00125-019-4953-7) report data obtained from a unique collection of post-mortem human brain tissue donated for research by individuals with and without type 2 diabetes. Compared with non-diabetic donors, in donors with type 2 diabetes they found a loss of key neuropeptides and decreased numbers of the neuron-supporting astroglial cells that are of utmost importance for proper functioning of the neuronal clock network. According to the authors, the data suggest that disturbances in the daily physiology of people with type 2 diabetes, such as an irregular sleep/wake cycle and dysregulated glucose metabolism, may be due to impaired functioning of the central master clock. They, therefore, propose that, in addition to glucose-lowering medication, normalisation of circadian rhythms by behavioural and/or pharmacological interventions might be helpful to treat type 2 diabetes more effectively.
David M. Nathan, Peter H. Bennett, Jill P. Crandall, Sharon L. Edelstein, Ronald B. Goldberg, Steven E. Kahn, William C. Knowler, Kieren J. Mather, Sunder Mudaliar, Trevor J. Orchard, Marinella Temprosa, Neil H. White and the DPP Research Group
Numerous trials have demonstrated the ability to prevent or delay the development of type 2 diabetes. Whether these efforts also reduce the long-term microvascular and cardiovascular complications that usually accompany diabetes is not as clear. In this issue, Nathan et al and the Diabetes Prevention Program (DPP) Research Group (which includes investigators of the long-term follow-up DPP Outcomes Study) (https://doi.org/10.1007/s00125-019-4928-8) review the major studies that have examined this question. One study with very long follow-up (20–30 years) suggests that complications can be reduced, but confirmation through further long-term follow-up of prevention studies is necessary. The authors conclude that the reduction of complications is a critical public health issue when considering the worth of diabetes prevention strategies. The figure from this review is available as a downloadable slide.
Physical activity triggers the release of a host of myokines, a group of molecules that integrate contracting muscle into the complex network of organ communication, consisting of metabolites, exosomes and many other crosstalk signals. In this issue, Jürgen Eckel (https://doi.org/10.1007/s00125-019-4927-9) reviews how myokines, as part of the organ crosstalk network, serve to communicate immediate and long-term information for functional adjustments in different tissues, with a significant role in positive metabolic control. In humans, the functional allocation of myokines has remained rather limited. Eckel suggests that future studies are needed to address the specific role of myokines in concert with other crosstalk molecules in humans, and the auto- and paracrine actions of these molecules. This may provide new insight into muscle physiology, as well as indicating myokines with therapeutic potential in diabetes. The figure from this review is available as a downloadable slide.
Juan Martinez-Pinna, Laura Marroqui, Abdelkrim Hmadcha, Javier Lopez-Beas, Sergi Soriano, Sabrina Villar-Pazos, Paloma Alonso-Magdalena, Reinaldo S. Dos Santos, Ivan Quesada, Franz Martin, Bernat Soria, Jan-Åke Gustafsson, Angel Nadal
Bisphenol-A (BPA) is an endocrine-disrupting chemical (EDC) found in many widely used products. BPA was detected in the urine of 93% of US citizens and its concentration in serum reaches between 1 and 25 nmol/l. Epidemiological studies have associated EDC exposure with type 2 diabetes in humans. BPA increases insulin levels and release in the presence of stimulatory glucose concentrations. In this issue, Martinez-Pinna, Marroqui et al (https://doi.org/10.1007/s00125-019-4925-y) report that BPA, at environmentally relevant doses, modulates the expression of more than 50 genes encoding Na+ and K+ ion channel subunits in mouse beta cells. BPA treatment resulted in decreased Na+ and K+ currents in islets, as well as modifying glucose-induced electrical activity. Using beta cells from oestrogen receptor β (Erβ) knockout mice, the authors demonstrated that the BPA-induced effects in pancreatic islets were dependent on oestrogen receptor β. They suggest that these results help to explain how BPA regulates insulin content and release and shed light upon the mechanisms by which EDCs with oestrogenic activity exert their diabetogenic activity.
Camille E. Powe, Larraine P. Huston Presley, Joseph J. Locascio, Patrick M. Catalano
Augmentation of insulin secretory response in pregnancy has been attributed to a pregnancy-associated reduction in insulin sensitivity. In this issue, findings reported by Powe et al (https://doi.org/10.1007/s00125-019-4881-6) challenge this widely held theory. The authors conducted a longitudinal study of 34 pregnant women using well-validated methods for assessing insulin sensitivity (euglycaemic clamp) and insulin secretory response (IVGTT). Assessments were conducted prior to pregnancy, in early pregnancy and in late pregnancy. The authors found that the insulin secretory response increased markedly in early pregnancy, and that this occurred prior to and independent of the decrement in insulin sensitivity in late pregnancy. The authors conclude that elucidation of the mediators of the pregnancy-associated augmentation in insulin secretory response could potentially identify targets for the development of therapeutic agents for use in diabetes.
Victoria Tyndall, Roland H. Stimson, Nicola N. Zammitt, Stuart A. Ritchie, John A. McKnight, Anna R. Dover, Fraser W. Gibb
Flash glucose monitoring is known to reduce hypoglycaemia events but little evidence supports its efficacy in reducing HbA1c in type 1 diabetes. In this issue, Tyndall and Stimson et al (https://doi.org/10.1007/s00125-019-4894-1) prospectively assessed the effect of introducing flash monitoring in a diabetes centre. Compared with the total type 1 population, flash monitor users were typically younger, more affluent and had lower baseline HbA1c. There was a 49% increase in the proportion achieving a target HbA1c of <58 mmol/mol (<7.5%) and a >50% decrease in the proportion with an HbA1c of >75 mmol/mol (>9.0%). Flash monitor use was also associated with a reduction in admissions for diabetic ketoacidosis. Self-reported hypoglycaemia increased with flash monitoring use, although this was likely to be a consequence of greater recognition of events. User satisfaction was extremely high; however, there was an increase in anxiety and depression symptoms. Taken together, the authors conclude that these findings suggest that flash monitoring is capable of reducing HbA1c in a ‘real-world’ setting.
Ewan R. Pearson
Type 2 diabetes is a complex disease which, in the broader sense, can be considered a composite of ‘missed’ cases of monogenic and other forms of diabetes, as a result of poor diagnostics, and true polygenic type 2 diabetes. In this issue, Ewan Pearson (https://doi.org/10.1007/s00125-019-4909-y) summarises the recent advances in dissecting the aetiological processes that drive the development of diabetes using measures of phenotype and genotype, including partitioned polygenic scores. Consideration of these aetiological processes can provide insight into the variation in diabetes progression, drug response and risk of complications, supporting a precision medicine approach to diabetes care. The figure from this review is available as a downloadable slide.
Diego Balboa, Rashmi B. Prasad, Leif Groop, Timo Otonkoski
Genome engineering technologies, in particular, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9), have revolutionised the possibilities for genome manipulation. In this issue, Balboa et al (https://doi.org/10.1007/s00125-019-4908-z) summarise the progress and challenges in applying CRISPR-Cas9 to different human beta cell models to dissect the mechanisms behind diabetes-associated genetic variants. Genome editing can most effectively be used in induced pluripotent stem cells prior to their differentiation into beta cells. This method has the unique advantage of allowing studies in patient-derived cells. However, the functional immaturity of stem-cell derived islets is currently still a major limitation of this approach. At present, genome editing in primary human beta cells has not been possible, but new technologies may enable this in the future. Ingenious use of CRISPR-Cas9 and similar techniques will undoubtedly accelerate advances in our understanding of the interplay between type 1 diabetes and type 2 diabetes risk-associated genetic variants and their functional role in predisposing to the disease. The figure from this review is available as a downloadable slide.
Camilla H. F. Hansen, Christian S. Larsen, Henriette O. Petersson, Line F. Zachariassen, Andreas Vegge, Charlotte Lauridsen, Witold Kot, Łukasz Krych, Dennis S. Nielsen, Axel K. Hansen
The influence of the intestinal environment on autoimmunity has become very relevant of late. As such, identifying means to target specific microbes and improve intestinal function would be a valuable achievement for future prevention/treatment strategies for dysbiosis. In this issue, Hansen et al (https://doi.org/10.1007/s00125-019-4910-5) present results that: (1) demonstrate how prebiotic xylooligosaccharides (XOS) can delay diabetes onset and reduce autoimmune reactions towards the pancreatic beta cells and salivary glands in NOD mice; and (2) show that the protective effects offered by XOS were regulated by both microbe-dependent and -independent pathways. The authors suggest that reduced gut permeability and associated induction of anti-inflammatory mucosal immune responses play a central role in protection against autoimmune destruction of beta cells and salivary glands. Considering that many individuals with autoimmunity have dysfunctional barrier function, these findings strongly encourage further testing of the beneficial effects of prebiotics in individuals predisposed to autoimmune diseases, such as type 1 diabetes.
Nathalie Esser, Sakeneh Zraika
Neprilysin is a peptidase that hydrolyses oligopeptide substrates, such as glucagon-like peptide-1, which are known to regulate glucose homeostasis. Recent studies in humans with diabetes have demonstrated that a new class of drug for heart failure, which combines a neprilysin inhibitor with an angiotensin receptor blocker, improves glycaemic control, enhances insulin sensitivity and reduces the need for initiation of insulin therapy. In this issue, Esser and Zraika (https://doi.org/10.1007/s00125-019-4889-y) summarise these data, with an emphasis on neprilysin inhibition as the principal contributor to these positive clinical outcomes. The authors also review supporting data from preclinical studies to make the case that neprilysin inhibition may be a novel therapeutic approach for the treatment of type 2 diabetes. Potential mechanisms underlying beneficial glycaemic effects are discussed, as well as possible deleterious effects that may limit the clinical use of neprilysin inhibitors. Beyond its beneficial impact on glycaemic control, neprilysin inhibition could also exert favourable effects in treating complications of diabetes. The figures from this review are available as a downloadable slideset.
Jean Strelitz, Amy L. Ahern, Gráinne H. Long, Matthew J. L. Hare, Greg Irving, Clare E. Boothby, Nicholas J. Wareham, Simon J. Griffin
Cardiovascular disease (CVD) is the most common complication of diabetes. Evidence of the impact of weight loss on incidence of CVD events among adults with diabetes is sparse and conflicting. In this issue, Strelitz et al (https://doi.org/10.1007/s00125-019-4886-1) report the results of a cohort analysis of 725 adults with screen-detected diabetes recruited from general practices across eastern England. They found that people with type 2 diabetes who achieved ≥5% weight loss in the year after diabetes diagnosis had a 48% lower hazard of CVD after 10 years of follow-up compared with people who maintained their weight. Associations between weight gain and CVD were less clear. Participants did not receive tailored weight loss support and most participants were overweight or obese at the time of diabetes diagnosis. According to the authors, the results suggest that moderate weight loss may lead to substantial long-term CVD reduction and may be achievable among individuals with a new diagnosis of type 2 diabetes.
Thomas R. Hird, Ella Zomer, Alice Owen, Lei Chen, Zanfina Ademi, Dianna J. Magliano, Danny Liew
Diabetes can cause reduced workforce participation and productivity whilst at work. However, current estimates of the economic burden of diabetes in China do not incorporate diabetes-related productivity loss. In this issue, Hird et al (https://doi.org/10.1007/s00125-019-4875-4) used life table modelling to estimate productivity-adjusted life years (PALYs) lost among those with diabetes over the working lifetime of the Chinese population. Among the 56.4 million people with diabetes of working age in China in 2017 with simulated follow-up to retirement age, diabetes was predicted to reduce years of life lived by 22.7 million (3.7%). Taking into account diabetes-related labour force dropout, absenteeism, presenteeism (reduced efficiency at work) and premature mortality, diabetes also caused the loss of 75.8 million PALYs (15.1%). This equates to an estimated Chinese ¥17.4 trillion (US$2.6 trillion) loss in gross domestic product (GDP) over the working lifetime of the cohort, highlighting the long-term economic consequences of diabetes in the Chinese population. The authors state that, given the considerable economic impact of these productivity losses, prevention of diabetes and its complications should be considered an investment with potentially large economic benefits in the longer term.
Evita C. Wiegers, Hanne M. Rooijackers, Jack J.A. van Asten, Cees J. Tack, Arend Heerschap, Bastiaan E. de Galan, Marinette van der Graaf
Chronic hyperglycaemia in type 1 diabetes affects the structure and function of the brain. Diabetes onset in early childhood and poor glycaemic control are known risk factors for these effects. Many fear that recurrent hypoglycaemia may induce similarly devastating effects on the brain. Changes in the neurochemical profile of the brain may be early signs of altered brain structure/function. In this issue, Wiegers et al (https://doi.org/10.1007/s00125-019-4862-9) studied the effects of type 1 diabetes and the burden of hypoglycaemia on brain metabolite levels using 1H magnetic resonance spectroscopy. They found higher cerebral glutamate levels in individuals with type 1 diabetes compared with control participants without diabetes, irrespective of the state of hypoglycaemia awareness (impaired awareness vs normal awareness). Among those with type 1 diabetes, cerebral glutamate levels correlated with glycaemic control (HbA1c levels) and the age of disease diagnosis. The burden of hypoglycaemia had, at most, a limited impact on the neurochemical profile of individuals with type 1 diabetes. The authors conclude that glutamate could potentially act as an early marker of hyperglycaemia-induced cerebral complications.
Lars C. Gormsen, Esben Søndergaard, Nana L. Christensen, Kim Brøsen, Niels Jessen, Søren Nielsen
Although metformin is the endorsed first-line glucose-lowering drug for individuals with type 2 diabetes, the exact mechanisms by which the drug exerts its effects are still debated. Studies in individuals with poorly controlled diabetes have indicated that the main site of action is the liver, through reduced hepatic gluconeogenesis, whereas others have demonstrated that the drug may increase intestinal glucose uptake. In this issue, Gormsen et al (https://doi.org/10.1007/s00125-019-4872-7) report that 3 months of metformin treatment lowered blood glucose as expected but, surprisingly, it increased endogenous glucose production. This effect was observed both in individuals with recent-onset type 2 diabetes and age-matched non-diabetic healthy individuals. The authors suggest that the primary glucose-lowering effect of metformin may, thus, be extra-hepatic, at least in healthy individuals and patients with recent-onset diabetes.
Rongzi Shan, Sudipa Sarkar, Seth S. Martin
Mobile health (mHealth) for diabetes is a new but rapidly growing field that can potentially increase access to healthcare and improve self-management of diabetes. In this issue, Shan et al (https://doi.org/10.1007/s00125-019-4864-7) review state-of-the-art mHealth interventions for diabetes, discussing how components and features of existing interventions vary according to the specific patient needs to be addressed. The clinical outcomes of mHealth interventions are generally modest but promising. Currently, it is unknown which features are most effective at promoting clinical improvement, but expanding usage, personalisation and the incorporation of techniques for precision medicine are key future directions. Addressing barriers, such as cost, sustainability and integration with the healthcare system, is necessary for mHealth tools to be more widely adopted. The figure from this review is available as a downloadable slide.
Qian Yu, Hongyan Shuai, Parvin Ahooghalandari, Erik Gylfe, Anders Tengholm
Despite the importance of glucagon in glycaemic control, it remains unclear how glucose regulates glucagon secretion from pancreatic alpha cells. In this issue, Yu et al (https://doi.org/10.1007/s00125-019-4857-6) investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release. The authors report that glucose-induced alterations of glucagon release are paralleled by changes in subplasmalemmal cAMP concentration in alpha cells. In support of a regulatory role for cAMP, glucose-induced suppression of glucagon release was prevented by imposed elevations in cAMP, while inhibition of protein kinase A (a mediator of the effects of cAMP) mimicked the suppressive effect of glucose on glucagon. Yu and colleagues provide evidence that glucose acts directly on alpha cells to regulate glucagon secretion independent of paracrine signalling from insulin or somatostatin. The authors conclude that these findings point to a new mechanism for glucose control of glucagon release and indicate that the counter-regulatory glucagon response to hypoglycaemia could be enhanced by agents that increase cAMP concentration in alpha cells.