Follow us on twitter

Editor’s Choice

Competition for publication in Diabetologia is greater than ever, and less than 20% of papers are accepted. Of all the high-quality papers that appear in this month’s issue I want to share with you some articles that I find to be of particular interest. These will be featured ‘up front’ in the print issue and here on our website. Sally Marshall, Editor

Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions

Fig from Hart paper

Nathaniel J. Hart, Alvin C. Powers

Over the past 15 years, a marked increase in access to human islets for research and work by hundreds of investigators has greatly expanded our understanding of human islet biology. In this issue, Hart and Powers ( highlight and summarise some of these findings, especially those showing similarities and differences between human islets and islets from rodent models of diabetes. In reviewing more than 200 manuscripts reporting research on human islets, published between 2013 and 2017, the authors noted that most publications lacked critical information about the human islets used in experiments, possibly hindering the ability to reproduce and compare experimental outcomes between laboratories. The authors urge the ‘human islet research ecosystem’ to work cooperatively to develop ways to foster collaboration, transparency and experimental rigour for research using human islets. They suggest a checklist of characteristics and information about human islets that should be reported when these samples are used for research. The figures from this review are available as a downloadable slideset.


As discussed in an accompanying editorial (, Diabetologia and Diabetes have adopted a modified version of Hart and Powers’ checklist, to be completed by authors on submission.

The many secret lives of adipocytes: implications for diabetes

Fig from Scherer paper

Philipp E. Scherer

In the context of the physiological control of systemic metabolism, hardly any other cell type has undergone more of an image change than the adipocyte over the past two decades. Previously viewed mostly as a relatively inert and passive cell with a primary focus on energy storage and release, it is now appreciated for its numerous endocrine functions. In this issue, Philipp E. Scherer ( summarises several of the key aspects that keep the adipocyte at centre stage in the quest for novel endocrine mediators. The author outlines key adipocyte-associated enzymatic targets for the discovery of new therapeutic agents for use in diabetes, specifically those aimed at normalising carbohydrate and lipid metabolism. These factors include adipokines, important lipid-signalling molecules (such as ceramides) and key metabolites (such as uridine). Many of these can be released from adipose tissue in the classical endocrine fashion, or they may be packaged into exosomal vesicles that adipose tissue very effectively releases. The author also comments on the remarkable versatility of the cellular physiology of the adipocyte in terms of its anatomical location, its ability to act as a storage cell (the white adipocyte) or a thermogenic cell (beige and brown adipocytes) and its ability to de-differentiate into adipogenic precursor populations and even myofibroblasts, which are critically involved in fibrotic responses. The author concludes that, despite advances in adipocyte knowledge, there are many unresolved issues that await targeted research in order to identify novel means by which disease-associated adipose tissue can be reprogrammed into being the benign protective bystander that it was originally meant to be, before we provided massive insults to the tissue through excess energy intake. The figures from this review are available as a downloadable slideset.

Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial

Fig from Savikj paper

Mladen Savikj, Brendan M. Gabriel, Petter S. Alm, Jonathon Smith, Kenneth Caidahl, Marie Björnholm, Tomas Fritz, Anna Krook, Juleen R. Zierath, Harriet Wallberg-Henriksson

Glucose tolerance, insulin sensitivity and skeletal muscle oxidative capacity undergo circadian oscillations, and the interaction of these factors could lead to divergent adaptations to exercise. High-intensity interval training (HIIT) has a beneficial effect on blood glucose concentration in individuals with type 2 diabetes. However, the time of day that results in the strongest adaptations of blood glucose levels to HIIT remains unknown. In this issue, Savikj, Gabriel et al ( report on a randomised crossover trial of 11 men with type 2 diabetes. They demonstrate that afternoon HIIT is more efficacious than morning HIIT at lowering blood glucose values in this cohort. Furthermore, morning HIIT had early deleterious effects on blood glucose values. The authors’ data highlight the importance of optimising the timing of exercise when prescribing HIIT in the clinical management of type 2 diabetes.

Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population

Fig from Waateringe paper

Robert P. van Waateringe, Bernardina T. Fokkens, Sandra N. Slagter, Melanie M. van der Klauw, Jana V. van Vliet-Ostaptchouk, Reindert Graaff, Andrew D. Paterson, Andries J. Smit, Helen L. Lutgers, Bruce H. R. Wolffenbuttel

Autofluorescence measurements are based on the detection of AGEs in the skin.  High skin autofluorescence is associated with high risk of cardiovascular complications and mortality in people with type 2 diabetes, as well as renal failure. However, whether this non-invasive measurement can be used as a predictive biomarker in the general population has not been elucidated. In this issue, van Waateringe et al ( examined whether measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. They report that a higher skin autofluorescence is associated with a higher risk of developing type 2 diabetes and CVD in people free of these diseases at baseline. In addition, they found that baseline skin autofluorescence was elevated in individuals who had died over the follow-up period, compared with individuals who survived. These findings were independent of other important risk factors, such as blood glucose, HbA1c and classical risk factors, including high blood pressure, high cholesterol and smoking. These findings suggest that measurement of skin autofluorescence is of clinical value for screening for future risk of type 2 diabetes, CVD and mortality and can improve risk estimates for these conditions.

A variant of the glucose transporter gene SLC2A2 modifies the glycaemic response to metformin therapy in recently diagnosed type 2 diabetes

Fig from Rathmann paper

Wolfgang Rathmann, Klaus Strassburger, Brenda Bongaerts, Oliver Kuss, Karsten Müssig, Volker Burkart, Julia Szendroedi, Jörg Kotzka, Birgit Knebel, Hadi Al-Hasani, Michael Roden, for the GDS Group


Genetic factors play a role in the highly variable glycaemic response to metformin. The SLC2A2 gene encodes the glucose transporter isoform GLUT2. In this issue, Rathmann et al ( investigated the interaction between the single nucleotide polymorphism rs8192675 in SLC2A2 and glycaemic response to metformin (reduction of fasting glucose) in individuals with recently diagnosed type 2 diabetes. Among a cohort of 508 adults with type 2 diabetes, C allele carriers (TC/CC genotypes) more frequently presented with diabetes symptoms (polyuria, thirst) at diagnosis. During the first year after diagnosis, C allele carriers on metformin monotherapy showed a greater reduction in fasting glucose compared with individuals homozygous for the T allele, after adjusting for age, sex, BMI, diabetes duration and baseline glucose. In addition, in the metformin therapy group, C-peptide secretion was higher in individuals with TC/CC genotypes than in individuals with the TT genotype. These findings indicate that a variant in the SLC2A2 gene (encoding GLUT2) modifies the glycaemic response to metformin in individuals recently diagnosed with type 2 diabetes.

Global trends in diabetes complications: a review of current evidence

Fig from Harding paper

Jessica L. Harding, Meda E. Pavkov, Dianna J. Magliano, Jonathan E. Shaw, Edward W. Gregg

As the prevalence of diabetes continues to increase around the world, the profile of diabetes complications is likely to change. In this issue, Harding et al ( summarise the available evidence on current trends in diabetes complications. Overall, data primarily from high-income countries report that rates of amputations, acute complications, cardiovascular disease and mortality among people with diabetes are declining. In spite of this, people with diabetes remain at significantly higher risk for these complications compared with those without diabetes. Notable declines in mortality, coinciding with increased survival, may lead to proportional increases in other forms of morbidity (e.g. renal disease, infections, cancers and physical and cognitive disability), with important implications for the clinical and public health burden of diabetes. The continued monitoring of global trends in diabetes complications, particularly in low- and middle-income countries, will be essential to understanding the burden of diabetes moving into the future. The figures from this review are available as a downloadable slideset.

Dynamics of adipose tissue turnover in human metabolic health and disease

Figure from White paper

Ursula White, Eric Ravussin

The magnitude of adipose tissue mass is determined by dynamic changes in the synthesis and breakdown (i.e. turnover) of adipocytes and triacylglycerols. Obesity is characterised by excessive adiposity and is a risk factor for many cardiometabolic disorders, including the metabolic syndrome and type 2 diabetes. Evidence suggests that the manner of subcutaneous adipose expansion (hypertrophy vs hyperplasia), as well as adipocyte death, can contribute to the pathogenesis of obesity-related disorders. Despite the plausible role of adipose turnover in human health and pathology, little is known about the in vivo kinetics of adipose tissue components. In this issue, White and Ravussin ( provide an overview of current in vivo approaches that are being implemented to assess the turnover of adipose cells and triacylglycerols, namely, 2H labelling and 14C dating. In addition, the authors summarise findings from in vitro studies and discuss the role of adipose tissue turnover in metabolic health and disease in humans. The figures from this review are available as a downloadable slideset.

Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Fig from Cantley paper

James Cantley, Aimee Davenport, Laurène Vetterli, Nandor J. Nemes, P. Tess Whitworth, Ebru Boslem, Le May Thai, Natalie Mellett, Peter J. Meikle, Kyle L. Hoehn, David E. James, Trevor J. Biden

The role of glucose oxidation in triggering insulin secretion from pancreatic beta cells is well characterised. Glucose also drives anaplerotic flux, leading to the production of malonyl-CoA by the enzyme acetyl-CoA carboxylase 1 (ACC1), yet the role of ACC1 in beta cell function in vivo is not clear. In this issue, using tissue-specific ACC1 gene (Acaca) knockout mouse models and a combination of in vivo and ex vivo experiments, Cantley et al ( report that beta cell ACC1 activity is necessary for normal insulin secretion profiles and whole body glucose homeostasis. Moreover, they reveal that long-term loss of beta cell ACC1 leads to reductions in beta cell size and levels of enzymes involved in protein synthesis. These results demonstrate the importance of the ACC1-coupled pathway in sustaining adequate beta cell growth and function and suggest that potential strategies to enhance this pathway could promote a functional beta cell mass during diabetes.

A cost analysis of intensified vs conventional multifactorial therapy in individuals with type 2 diabetes: a post hoc analysis of the Steno-2 study

Fig from Gaede paper

Joachim Gæde, Jens Oellgaard, Rikke Ibsen, Peter Gæde, Emil Nørtoft, Hans-Henrik Parving, Jakob Kjellberg, Oluf Pedersen

Intensified multifactorial therapy in type 2 diabetes patients with microalbuminuria increased median life span by 7.9 years and delayed incident cardiovascular disease by 8.1 years in the Steno-2 Study. However, the economic implications of this approach are unclear. In this issue, Steno-2 study investigators ( report that, over 21.2 years of follow-up, there was no significant difference in total direct medical costs between the intensive-therapy group vs the conventional therapy group. Furthermore, they showed a reduced cost per person-year in the intensive-therapy group. Cost of medications was highest with intensive therapy, but this additional cost was offset by the reduction in expenses for inpatient admissions for late complications and primary healthcare costs with conventional therapy. These findings emphasise that investment in early intensified multifactorial therapy may lead to an initial increase in healthcare expenditure; this investment appears, however, to be returned over time by health benefits and increased longevity.

Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes

Fig from Weightman-Potter paper

Paul G. Weightman Potter, Julia M. Vlachaki Walker, Josephine L. Robb, John K. Chilton, Ritchie Williamson, Andrew D Randall, Kate L. J. Ellacott, Craig Beall

Hypoglycaemia is a major limiting factor for good glycaemic control in diabetes. Brain glucose-sensing mechanisms are incompletely understood and the contribution of glia, such as astrocytes, to hypoglycaemia detection and defective glucose counter-regulation requires more study. In this issue, Weightman Potter et al ( characterise the intrinsic mechanisms by which human primary astrocyte function is altered by acute and recurrent low glucose (RLG) exposure in vitro. They report that astrocytic AMP-activated protein kinase (AMPK) is activated by physiologically relevant reductions in glucose concentration. In addition, they found that basal fatty acid oxidation rates were increased by RLG, as were markers of mitochondrial dysfunction. Glycolytic rates were enhanced after RLG exposure, but this was not due to increased glucose uptake, nor did this lead to increased glycogen content. Moreover, following a recovery period, aspects of mitochondrial function were restored. These novel observations demonstrate that human primary astrocytes adapt to RLG to successfully maintain intracellular nucleotide levels. These data suggest the potential involvement of glial mitochondrial adaptations in defective glucose counterregulation or protection against hypoglycaemia. Studies are needed to further elucidate interactions between neurons and glial cells during and after recurrent hypoglycaemia.

Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Figure 2 of consensus report

Melanie J. Davies, David A. D’Alessio, Judith Fradkin, Walter N. Kernan, Chantal Mathieu, Geltrude Mingrone, Peter Rossing, Apostolos Tsapas, Deborah J. Wexler, John B. Buse


In this issue, the 2018 joint ADA/EASD consensus report ( incorporates a comprehensive review of the literature from 2014 and interprets this new evidence into a series of pragmatic, practical road maps to help clinicians navigate the increasingly complex area of management of hyperglycaemia in adults with type 2 diabetes. It emphasises the patient-centred approach to care and recognises the ongoing therapeutic value of comprehensive lifestyle management and patient self-management education.

Since 2015, the rapid accumulation of evidence, particularly from cardiovascular outcomes trials, has clearly demonstrated that some glucose-lowering agents confer cardiovascular outcome benefit. These findings have precipitated a fundamental change in approach. For an increasing number of patients, the presence of specific comorbidities (e.g. atherosclerotic cardiovascular disease, chronic kidney disease, heart failure, obesity), safety concerns (e.g. risk of hypoglycaemia) or the healthcare environment (e.g. cost of medication) mandate a specific approach to the choice of glucose-lowering medication, and recommendations are given in this report. The report also tackles important barriers to improving patient outcomes, such as therapeutic inertia and medication adherence, including persistence. It explains that patient preference is a major factor driving the choice of medication and that a coordinated chronic care model that promotes interaction between more empowered patients and proactive healthcare teams is central to improving outcomes.

Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made

Figure from paper

Noel G. Morgan, Sarah J. Richardson

It is a sobering statistic that, although millions of people worldwide live with type 1 diabetes, fewer than 600 pancreas samples have become available for the study of the pathology of the disease. Nevertheless, important progress has been made and, in this issue, Morgan and Richardson ( review the current understanding of pancreatic islet pathology. They consider the evidence that islets become inflamed during disease progression and discuss the different types of immune cell involved in this process, as well as how these cells may influence the rate and extent of beta cell loss. The importance of the peri-islet membrane as a barrier to immune cell infiltration is assessed and the notion that beta cells may contribute to their own demise by signalling to the immune system is explored. The authors suggest that type 1 diabetes is not a single disease and argue that this insight is critical to the targeted design of effective interventions. The figures from this review are available as a downloadable slideset.

Relation of plasma ceramides to visceral adiposity, insulin resistance and the development of type 2 diabetes mellitus: the Dallas Heart Study

Fig from Neeland paper

Ian J. Neeland, Shruti Singh, Darren K. McGuire, Gloria L. Vega, Thomas Roddy, Dermot F. Reilly, Jose Castro-Perez, Julia Kozlitina, Philipp E. Scherer

Ceramides are sphingolipids involved in the regulation of signal transduction pathways. Although they have been found to contribute to insulin resistance in preclinical models, epidemiological data evaluating the relationship between plasma ceramides, indicators of dysfunctional adiposity and type 2 diabetes are lacking. In this issue, using data from the Dallas Heart Study, Neeland et al ( report that shorter-chain fatty acid ceramides were associated with an unfavourable adiposity, lipid and insulin resistance profile. In contrast, longer-chain unsaturated fatty acid ceramides were inversely associate with this phenotype. The authors show that plasma ceramides were not independently associated with impaired fasting glucose or incident type 2 diabetes after adjustment for clinical factors. These findings suggest a role for ceramides in a shared pathway of metabolic dysfunction that links dysfunctional adiposity with insulin resistance. They also provide a nuanced perspective on the relationship between ceramides and metabolic phenotypes. Further investigation is needed to evaluate the potential role of plasma-based ceramide screening in metabolic risk stratification.

Müller glial dysfunction during diabetic retinopathy in rats is reduced by the acrolein-scavenging drug, 2-hydrazino-4,6-dimethylpyrimidine

Fig from Muller paper

Rosemary E. McDowell, Peter Barabas, Josy Augustine, Olivier Chevallier, Philip McCarron, Mei Chen, J. Graham McGeown, Tim M. Curtis

Müller cells play a critical role in maintaining retinal function and survival. These cells are particularly vulnerable to damage in diabetes and their dysfunction has been linked to the pathogenesis of diabetic retinopathy. Up to now, the mechanisms through which diabetes affects these cells has remained unclear. In this issue, McDowell et al ( report that accumulation of the acrolein-derived advanced lipoxidation end-product, Nε-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine), on Müller cell proteins contributes to the dysfunction of these cells during diabetes. They identify a new drug called 2-hydrazino-4,6-dimethylpyrimidine (2-HDP) as a potent acrolein scavenger and demonstrate that this compound prevents Müller cell FDP-lysine accumulation and dysfunction in the retina in vivo, in rat models of diabetes. This drug also reduced oxidative and inflammatory responses in the retina and improved neuroretinal function during experimental diabetes. These findings suggest that acrolein scavenging may represent a novel therapeutic approach for the early-stage treatment of diabetic retinopathy.

Immunological biomarkers for the development and progression of type 1 diabetes

Immunological biomarkers for the development and progression of type 1 diabetes

Chantal Mathieu, Riitta Lahesmaa, Ezio Bonifacio, Peter Achenbach, Timothy Tree

The target organ of immune destruction in type 1 diabetes is the insulin-producing beta cell. As overall beta cell mass is too small for easy imaging or tissue access, the identification of circulating biomarkers reflecting ongoing immune destruction of beta cells would greatly help the prediction and earlier diagnosis of type 1 diabetes, before onset of hyperglycaemia. In this issue, Mathieu et al ( provide a review of these immunological biomarkers. Some immune biomarkers have reached clinical practice, such as autoantibodies against beta cell antigens, including insulin, GAD, islet antigen-2 or zinc transporter-8. These autoantibodies are highly predictive for type 1 diabetes risk, both in first-degree family members of people with type 1 diabetes and in the general population. Novel immune biomarkers are emerging, in particular, profiles of circulating T lymphocyte subsets and their cytokine-producing activity. High hopes have been placed on the upcoming biomarkers, such as microRNA profiles and metabolomic, lipidomic and other ‘omic’ profiles. These will add power to the more established biomarkers for prediction and diagnosis of type 1 diabetes at earlier stages. The authors note that it is likely that personalised biomarker signatures, combining autoantibodies, T cell profiles and other biomarkers, will be required to categorise at-risk patients, which will facilitate personalised prediction, prevention and treatment approaches.

Biomarkers of islet beta cell stress and death in type 1 diabetes

Image for Sims review

Emily K. Sims, Carmella Evans-Molina, Sarah A. Tersey, Decio L. Eizirik, and Raghavendra G. Mirmira

Recent studies have highlighted the heterogenous nature of type 1 diabetes and have suggested that, in some cases, beta cell stress and dysfunction may contribute to and exacerbate autoimmune-mediated beta cell destruction. Robust biomarkers of beta cell stress and death are needed to reflect the pathological contributions of beta cells to this process and to monitor the effect of therapeutic agents that target beta cells in type 1 diabetes prevention or treatment efforts. In this issue, Sims et al ( provide a review summarising the current beta cell biomarkers, including circulating prohormones, RNA species, extracellular vesicles and differentially methylated DNA species. They also discuss ongoing challenges, such as gaining an understanding of how beta cell health changes as disease develops over time. The authors conclude that a well-validated toolkit of biomarkers of beta cell health will allow for a more personalised approach to type 1 diabetes prevention and care. The figure from this review is available as a downloadable slide.

Associations of maternal type 1 diabetes with childhood adiposity and metabolic health in the offspring: a prospective cohort study

Image for Pitchika article

Anitha Pitchika, Manja Jolink, Christiane Winkler, Sandra Hummel, Nadine Hummel, Jan Krumsiek, Gabi Kastenmüller, Jennifer Raab, Olga Kordonouri, Anette-Gabriele Ziegler, Andreas Beyerlein

Children exposed to increased glucose levels in utero may carry additional risks for being overweight and having impaired metabolic health. However, there is only scant evidence from previous studies to support worsening of metabolic health in children of mothers with type 1 diabetes, and potential pathways have not been investigated in detail. In this issue, Pitchika et al ( report findings from three large studies that examined nearly 2800 children with a first-degree relative with type 1 diabetes. The authors found that children of mothers with type 1 diabetes had a higher risk for being overweight and had increased insulin resistance during childhood and adolescence compared with children of mothers without diabetes. Higher birthweight may partially contribute to this association, but changes in the offspring’s metabolome are unlikely to be part of the causal pathway. These findings indicate that children exposed to maternal type 1 diabetes may need closer attention to combat overweight and metabolic risk in later life.

Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes

Image for Liu article

Mengju Liu, Jian Peng, Ningwen Tai, James A. Pearson, Changyun Hu, Junhua Guo, Lin Hou, Hongyu Zhao, F. Susan Wong, Li Wen

Toll-like receptors (TLRs) are known for their role in innate immunity, but information is sparse on their role in tissue development. In this issue, Liu, Peng et al ( demonstrate that TLR9 regulates islet beta cell growth and function in a mouse model of diabetes. They report that TLR9 deficiency results in enhanced beta cell growth, leading to improved glucose tolerance, insulin sensitivity and first-phase insulin secretory response. This effect is mediated, in part, by upregulation of CD140a (also known as platelet-derived growth factor receptor-α). This novel finding identifies TLR9 as a potential target for the prevention and/or treatment of diabetes.

Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes

Image for Cabrera article

Susanne M. Cabrera, Samuel Engle, Mary Kaldunski, Shuang Jia, Rhonda Geoffrey, Pippa Simpson, Aniko Szabo, Cate Speake, Carla J. Greenbaum, Type 1 Diabetes TrialNet CTLA4-Ig (Abatacept) Study Group, Yi-Guang Chen, Martin J. Hessner

Recent studies have drawn attention to the phenotypic heterogeneity that exists among individuals with type 1 diabetes. In trials of disease-modifying immunotherapy conducted at clinical onset, heterogeneity in the rate of disease progression poses challenges in detecting the effect of treatment on preservation of stimulated C-peptide. In this issue, Cabrera et al ( investigated whether discrete subtypes of type 1 diabetes exist, based on immunoregulatory profiles at clinical onset. They report that levels of innate inflammation at clinical onset were very heterogeneous among newly diagnosed individuals. Importantly, the post-onset duration of persistent insulin secretion was negatively related to baseline inflammation and positively associated with baseline abundance of circulating activated regulatory T cells. Furthermore, in an ancillary analysis of TrialNet CTLA4-Ig trial (TN-09) participants, the therapeutic response to CTLA4-Ig was associated with higher levels of baseline inflammation. These findings suggest that measures that predict the post-onset disease course and the response to therapeutic intervention could enable individual stratification that will lead to the development of individualised therapies.

The bark giving diabetes therapy some bite: the SGLT inhibitors

SGLT apple tree image

This issue features a special series of reviews that focus on the newest class of glucose-lowering agents, the sodium–glucose cotransporter (SGLT) inhibitors. Rieg and Vallon ( begin the series by tracing the development of the SGLT inhibitor class of drugs, including SGLT1 inhibitors, SGLT2 inhibitors and dual inhibitors. Wright and colleagues ( go on to discuss the mechanisms of actions of these drugs; they explain that SGLT1 and SGLT2 (and GLUT2) are key players in renal glucose transport and describe how inhibition of either SGLT2 or SGLT1 promotes glucose excretion in the urine. However, as discussed by Thomas and Cherney (, SGLT inhibitors not only affect glucose metabolism, but also body weight, renal function and blood pressure in type 2 diabetes. In terms of their pleiotropic actions, the most striking results so far come from SGLT2 inhibitor studies investigating the cardiovascular effects of these drugs. In their review, Verma and McMurray ( outline the proposed mechanisms underpinning the unprecedented benefit of reduced cardiovascular disease risk with SGLT2 inhibitor use, observed in people with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors. Despite their glucose-lowering ability, pleiotropic effects and potential cardioprotective outcomes, the place of SGLT2 inhibitors in the management of type 2 diabetes is still hotly debated. To explain why, Lupsa and Inzucchi ( review the benefits and adverse effects of SGLT2 inhibitors approved for use in the USA and Europe in individuals with type 2 diabetes. What about individuals with type 1 diabetes? Research is much sparser in this area but McCrimmon and Henry ( discuss the results of two recent 24 week Phase III randomised controlled clinical trials, inTandem3 and DEPICT-1, which studied sotagliflozin (a dual SGLT1/2 inhibitor) and dapagliflozin (an SGLT2 inhibitor), respectively. Wanner and Marx ( conclude the series by discussing SGLT2 inhibitors in the context of the future of diabetes therapy. They also discuss the effects of SGLT2 inhibitors on other chronic diseases and outline future treatment strategies. This review set is accompanied by an editorial by Sally Marshall (

Sex differences in the association between diabetes and cancer: a systematic review and meta-analysis of 121 cohorts including 20 million individuals and one million events

Image for Ohkuma review

by Toshiaki Ohkuma, Sanne A. E. Peters, Mark Woodward

In several systematic reviews and meta-analyses, diabetes has been associated with the risk of all-site and some site-specific cancers. However, there has been no systematic overview of the evidence available on sex differences in the association between diabetes and cancer. In this issue, Ohkuma et al ( report that diabetes was associated with a higher risk of all-site cancer in both sexes, but there was a ~6% greater risk in women compared with men. Diabetes was also associated with several site-specific cancers and conferred a significantly greater excess risk in women than men for oral, stomach and kidney cancer, and for leukaemia, but a lower excess risk for liver cancer. These findings indicate the importance of a sex-specific approach to analysis of the role of diabetes for cancer prevention and treatment.


Gluten intake and risk of type 2 diabetes in three large prospective cohort studies of US men and women

by Geng Zong, Benjamin Lebwohl, Frank B. Hu, Laura Sampson, Lauren W. Dougherty, Walter C. Willett, Andrew T. Chan, Qi Sun

Avoidance of gluten intake is crucial for the management of coeliac disease, in which gluten triggers an autoimmune response. However, adoption of a gluten-free diet among people without apparent gluten-related disorders in the USA and many other countries has become increasingly popular, with the belief that eating a gluten-free diet is associated with health benefits. Despite this perception, evidence is lacking to support or refute the belief that avoidance of gluten is associated with cardiometabolic health benefits in populations without coeliac disease. To fill this knowledge gap, in this issue, Zong, Lebwohl et al ( report findings from a large-scale analysis in three long-running cohorts of US men and women. They found an inverse association between gluten intake and risk of type 2 diabetes. This association was independent of established diabetes risk factors and appeared to be stronger when added bran intake was also higher. These results suggest that gluten intake is unlikely to exert adverse effects on diabetes risk and that the avoidance of gluten intake, often at the price of reducing fibre intake, should not be recommended for diabetes prevention.

Programming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice

Image for Berends upfront

by Lindsey M. Berends, Laura Dearden, Yi Chun L. Tung, Peter Voshol, Denise S. Fernandez-Twinn, Susan E. Ozanne

Low birthweight followed by accelerated postnatal growth is associated with increased risk of type 2 diabetes. It is well established that this is, at least in part, due to programmed peripheral insulin resistance. However, it is unclear if a suboptimal early-life environment also programs central insulin resistance. In this issue, Berends, Dearden et al ( use a mouse model of diet-induced intra-uterine growth restriction (IUGR) followed by accelerated postnatal catch-up growth to show that a suboptimal early-life environment causes insulin to be less effective at signalling to the brain to reduce food intake in later life. Central insulin resistance in IUGR followed by accelerated postnatal growth was shown to be related to altered expression of insulin-signalling components in the brain, as compared with control offspring born to dams fed a control diet. These findings indicate that promoting accelerated growth in offspring born small for gestational age could have negative effects on long-term metabolic health and that central insulin resistance may contribute to this phenomenon. If extrapolated to humans, these findings also suggest that individuals exposed to a suboptimal early-life environment may be less responsive to both lifestyle and pharmaceutical interventions for metabolic improvements in type 2 diabetes

A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes

Khan upfront

by Md Abdul Hye Khan, Lauren Kolb, Melissa Skibba, Markus Hartmann, René Blöcher, Ewgenij Proschak, John D. Imig

Despite significant progress in diabetes management, approximately 50% of people with type 2 diabetes fail to achieve therapeutic goals. Consequently, rates of diabetes-associated morbidity and mortality are high, mainly due to complications such as cardiovascular, liver and kidney disease. Poor clinical outcomes with current therapies for diabetes are associated with their lack of ability to simultaneously lower blood glucose and treat comorbidities. Consequently, the majority of patients with type 2 diabetes with a comorbid condition require a multi-drug approach to treatment. In this issue, Hye Khan et al ( report data from a study in which they developed a novel dual-acting molecule, RB394, that concurrently acts as an inhibitor of soluble epoxide hydrolase (sEH) and an activator of peroxisome proliferator-activated receptor-γ (PPAR-γ). In rat models of the metabolic syndrome and type 2 diabetes, which are associated with comorbid cardiovascular, liver and kidney disease, the authors demonstrated that RB394 not only ameliorated type 2 diabetes and its comorbid conditions, but also treated multiple diabetic complications, including diabetic nephropathy and liver injury. The authors conclude that RB394 is a promising molecule with the potential for development into a therapeutic agent for the metabolic syndrome, type 2 diabetes and associated complications.

Novel approaches to restore beta cell function in prediabetes and type 2 diabetes

Image for Salunkhe Up Front

by Vishal A. Salunkhe, Rajakrishnan Veluthakal, Steven E. Kahn, Debbie C. Thurmond

Beta cell dysfunction and/or demise are the critical components responsible for the development of prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and progression to frank type 2 diabetes. While tangible progress on improving beta cell function has been made, current clinical approaches do not reliably provide durable glucose control. In this issue, Salunkhe, Veluthakal and colleagues ( summarise recent advances towards improving beta cell function by improving peripheral insulin sensitivity (as a means of reducing beta cell workload). They explain how a group of factors, which in preclinical studies have been shown to multitask in both beta cells and peripheral insulin-sensitive cells, help to coordinate glucose control. The authors state that new multi-tissue-based therapeutic approaches should dovetail with efforts to formulate precision-medicine-based therapies for the variety of type 2 diabetes phenotypes. They propose that advances in genomic, epigenetic and exosome regulation of the central and tissue-specific landscape of metabolic control should facilitate efforts to refine the phenotypic cluster stratifications for optimal treatment strategies. Integration of these recent advances carries immense potential for the development of more effective medications to achieve durable glucose control in individuals with prediabetes and type 2 diabetes. The figures from this review are available as a downloadable slideset.


Neurodegeneration in diabetic retinopathy: does it really matter?

Simo up front image

by Rafael Simó, Alan W. Stitt, Thomas W. Gardner

Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy. In fact, the ADA has recently defined diabetic retinopathy as a highly tissue-specific neurovascular complication. In this issue, Simó et al ( provide a critical review on the role of neurodegeneration in the pathogenesis of diabetic retinopathy. A special emphasis is placed on the pathophysiology of the neurovascular unit (NVU). In addition, the authors provide an overview of the usefulness of retinal assessment as an indirect method to explore brain neurodegeneration. Simó and colleagues emphasise that retinal neurodegeneration is a critical endpoint in the development of diabetic retinopathy and that neuroprotection, itself, can be considered a therapeutic target, independent of its potential impact on microvascular disease. The authors conclude that more interventional studies targeting pathogenic pathways that impact on the NVU and which offer both vaso- and neuroprotection are needed. This will be crucial for implementing a timely and efficient personalised medicine approach for diabetic retinopathy. The figures from this review are available as a downloadable slideset.

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

Proietto up front image

by Joseph Proietto, Jaret Malloy, Dongliang Zhuang, Mark Arya, Neale D. Cohen, Ferdinandus J. de Looze, Christopher Gilfillan, Paul Griffin, Stephen Hall, Thomas Nathow, Geoffrey S. Oldfield, David N. O’Neal, Adam Roberts, Bronwyn G. A. Stuckey, Dennis Yue, Kristin Taylor, Dennis Kim

Animal and human studies indicate a beneficial effect of methionine aminopeptidase 2 (MetAP2) inhibitors on glycaemic control and other metabolic markers. In this issue, Proietto et al ( report results from the first study of the effects of the MetAP2 inhibitor beloranib in individuals with type 2 diabetes and obesity. The clinical trial was stopped early due to an unexpected imbalance in venous thromboembolism events in beloranib-treated vs placebo-treated individuals across beloranib clinical trials, during late-stage development of the drug. However, in individuals who had completed 26 weeks of treatment, beloranib produced statistically significant placebo-corrected reductions in both HbA1c (−15.3 mmol/mol [−1.4%]) and body weight (−10%). The authors conclude that these data exemplify MetAP2 inhibition as a novel treatment for metabolic disease. Since this trial, a next-generation MetAP2 inhibitor with an improved safety profile has been developed and has shown encouraging efficacy and safety in an ongoing Phase 2 clinical trial in individuals with type 2 diabetes and obesity.

Association between diabetes distress and all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 18])

Hayashino up front image

by Yasuaki Hayashino, Shintaro Okamura, Satoru Tsujii, Hitoshi Ishii, for the Diabetes Distress and Care Registry at Tenri Study Group

Many people with diabetes feel burdened by the never-ending challenge of self-management and experience periods of frustration, anger, fear and helplessness; this is collectively referred to as diabetes distress. High levels of diabetes distress have been associated with poor glycaemic control and a high prevalence of complications in cross-sectional studies. However, there has been a lack of data on the direct association between diabetes-specific distress and all-cause mortality in individuals with diabetes. In this issue, Hayashino et al ( report on the association between diabetes distress and subsequent risk of all-cause mortality in a Japanese cohort of 1280 women and 2025 men with type 2 diabetes. They found that higher levels of diabetes distress were associated with subsequent risk of all-cause mortality in men with type 2 diabetes, but not in women. These findings provide new evidence to support   the targeting of diabetes distress in clinical diabetes care.

Magnesium deficiency prevents high-fat-diet-induced obesity in mice

Kurstjens up front image

by Steef Kurstjens, Janna A. van Diepen, Caro Overmars-Bos, Wynand Alkema, René J. M. Bindels, Frances M. Ashcroft, Cees J. J. Tack, Joost G. J. Hoenderop, Jeroen H. F. de Baaij

Mg2+ deficiency is common in type 2 diabetes, affecting approximately 30% of all individuals with this disease. Nevertheless, the metabolic consequences of hypomagnesaemia (blood Mg2+ <0.7 mmol/l) remain largely unknown. In this issue, Kurstjens et al ( demonstrate that Mg2+ deficiency in mice protects against high-fat-diet (HFD)-induced obesity, accompanied by improved insulin sensitivity and dyslipidaemia. Compared with HFD-fed mice with normal Mg2+ levels, body weight was lower in HFD-fed mice with low Mg2+ levels. This reduction in weight occurred as a result of increased lipolysis in white adipose tissue and enhanced brown adipose tissue activity. The authors propose that these effects are due to activation of the β-adrenergic system. The data demonstrate the pivotal role of Mg2+ in lipid metabolism and highlight that individuals with type 2 diabetes and hypomagnesaemia may be at particular risk for dyslipidaemia.

Advances in drug discovery for human beta cell regeneration

Image from Karakose paper

by Esra Karakose, Courtney Ackeifi, Peng Wang, Andrew F. Stewart

Reduced numbers of insulin-secreting beta cells underlie both type 1 and type 2 diabetes. Conversely, residual beta cells are present in people with type 2 diabetes, and even after 50 years of type 1 diabetes. The current diabetes armamentarium includes insulin replacement, and drugs that encourage residual beta cells to secrete more insulin and/or enhance sensitivity to insulin. Beta cell replacement, via transplantation of whole pancreas, cadaveric islets, or stem cell-derived beta cells, is another approach. However, as reviewed in this issue by Karakose et al (, a simpler and more direct alternative would be to expand the numbers of residual beta cells in people with diabetes. Although human beta cells have long been viewed as terminally differentiated and irreversibly quiescent, this notion is changing owing to the recent discovery of pharmacological tools that can induce adult human beta cells to replicate. The authors review progress in this area, and outline remaining obstacles to bringing these novel therapies to patients. The figures from this review are available as a downloadable slideset.

Systematic review assessing the effectiveness of dietary intervention on gut microbiota in adults with type 2 diabetes

by David Houghton, Timothy Hardy, Christopher Stewart, Linda Errington, Christopher P. Day, Michael I. Trenell, Leah Avery

In type 2 diabetes, treatment variability and disease progression remain poorly understood. However, mechanistic pre-clinical studies indicate that the gut microbiome may be involved. In this issue, Houghton et al ( report the results of a systematic review, which included eight eligible studies. They found that dietary modification and various pre-, pro- and symbiotic supplements are able to modulate the composition of the gut microbiome and improve glucose control in people with type 2 diabetes. The findings provide important insight but also highlight the need for further well-conducted interventional studies in humans using standardised approaches to allow direct comparisons to be made. The authors note that a deeper understanding of the interaction between the gut microbiome and the pathophysiology of type 2 diabetes will help to lay the foundations to translate preclinical data into clinical practice. If successful, manipulating the microbiome may provide another pathway for the management of type 2 diabetes, enabling a personalised lifestyle approach.

Reduced risk of heart failure with intensified multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: 21 years of follow-up in the randomised Steno-2 study

by Jens Oellgaard, Peter Gæde, Peter Rossing, Rasmus Rørth, Lars Køber, Hans-Henrik Parving, Oluf Pedersen

In type 2 diabetes, heart failure is a common, late stage complication that is associated with a high mortality rate that, until recently, has been investigated little. In this issue, Oellgaard and colleagues ( present the results of a post hoc analysis from 21.2 years follow-up from the Steno-2 study of intensified vs conventional multifactorial intervention in high-risk individuals. Heart failure hospitalisations were as frequent as atherosclerotic cardiovascular disease and were significantly reduced by 70% in the intensive therapy group. The composite endpoints, heart failure hospitalisation or cardiovascular death and heart failure or all-cause mortality, were significantly reduced by 62% and 49%, respectively. Incident heart failure was associated with, but not explained by, prior myocardial infarction. Along with conventional risk factors, elevated plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline was associated with heart failure and, in the conventional therapy group, an increase in NT-proBNP during the initial 2 years was associated with a poorer outcome. The authors suggest that caregivers should recommend intensified multifactorial intervention to patients with type 2 diabetes to reduce the risk of heart failure.

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

by Christoph Nowak, Axel C. Carlsson, Carl Johan Östgren, Fredrik H. Nyström, Moudud Alam, Tobias Feldreich, Johan Sundström, Juan-Jesus Carrero, Jerzy Leppert, Pär Hedberg, Egil Henriksen, Antonio C. Cordeiro, Vilmantas Giedraitis, Lars Lind, Erik Ingelsson, Tove Fall, Johan Ärnlöv

There is a need to identify those individuals with type 2 diabetes who are at high risk of heart attack and stroke so that they can receive targeted prevention interventions. In this issue, Ärnlöv’s group at the Karolinska Institute in Sweden ( assessed whether blood-borne proteins with presumed roles in inflammation and cardiovascular disease might predict the risk of cardiovascular events in type 2 diabetes. Using an 80-protein multiplex assay, the authors replicated four previously described associations and discovered four novel associations. The addition of protein biomarkers to an available risk model improved the prediction of cardiovascular events in people with type 2 diabetes. The authors conclude that, pending further evaluation in a clinical context, these results suggest that targeted multi-protein assays can improve the risk assessment of serious cardiovascular events in type 2 diabetes. [Text supplied by the authors.]

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes

Image from Astiarraga paper

by Brenno Astiarraga, Valéria B. Chueire, Aglécio L. Souza, Ricardo Pereira-Moreira, Sarah Monte Alegre, Andrea Natali, Andrea Tura, Andrea Mari, Ele Ferrannini, Elza Muscelli

In type 2 diabetes, stimulation of insulin secretion by the entry of glucose into the digestive system (i.e. the incretin effect) is impaired. Recent experimental evidence suggests that NEFA might interfere with incretin function. In this issue, Astiarraga, Chueire et al ( tested this hypothesis by exposing individuals without diabetes to an acute rise in NEFA and by lowering NEFA in participants with type 2 diabetes. The results indicate the presence of a clear asymmetry: while elevation of NEFA disrupted the incretin effect in those without diabetes, lowering NEFA in individuals with type 2 diabetes had no effect. Neither beta cell sensitivity to glucose nor plasma incretin hormone concentrations were altered by NEFA manipulation. Whilst modest elevations of NEFA typically observed in type 2 diabetes are unlikely to be solely responsible for reduced beta cell sensitivity to incretins, they may have some role in disease progression; however, this remains to be demonstrated conclusively. [Text supplied by the authors.]