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
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.
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.
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.
Tatyana Gurlo, Sarah Kim, Alexandra E. Butler, Chang Liu, Lina Pei, Madeline Rosenberger, Peter C. Butler
Gestational diabetes is a risk factor for subsequent type 2 diabetes. As the availability of human pancreas tissue in pregnancy is limited, little is known about the islet changes in women vulnerable to type 2 diabetes, either during or after pregnancy. Moreover, most rodent models of type 2 diabetes do not develop gestational diabetes. This may be because, in humans, beta cell failure in type 2 diabetes is characterised by protein misfolding toxicity mediated by islet amyloid polypeptide (IAPP) but rodent IAPP does not form toxic oligomers. In this issue, Gurlo et al (https://doi.org/10.1007/s00125-019-4843-z) investigated whether mice transgenic for human IAPP develop pregnancy-related diabetes. The transgenic mice showed beta cell stress that mimicked the endoplasmic reticulum stress, oxidative damage and attenuated autophagy observed in beta cells in type 2 diabetes. Moreover, this beta cell damage persisted after pregnancy, leading to subsequent diabetes before or during a second pregnancy, with further exacerbation of beta cell stress during the second pregnancy. The authors conclude that this model offers accessible islet tissue to investigate strategies to mitigate beta cell stress during pregnancy, as well as an opportunity to investigate the effects of gestational diabetes on fetal development.
Caroline K. Kramer, Sara Campbell, Ravi Retnakaran
A series of recent studies has suggested that women who develop gestational diabetes (GDM) have an increased future risk of cardiovascular disease (CVD). However, these studies have yielded varying estimates of the magnitude of risk and offered conflicting evidence on whether this risk is dependent upon the development of type 2 diabetes. In a meta-analysis involving more than 5 million women, Kramer et al (https://doi.org/10.1007/s00125-019-4840-2) report three key findings. First, compared with women who did not have GDM, women with GDM had a twofold higher risk of major cardiovascular events in the years thereafter. Second, this risk was not dependent on the development of intercurrent type 2 diabetes. Third, the risk of CVD in women with GDM was evident as early as the first decade after delivery. Thus, with or without subsequent type 2 diabetes, the diagnosis of GDM should be recognised as a risk factor for future CVD and, hence, an opportunity for early risk modification and, possibly, prevention of the leading cause of mortality in women.
Hadi Harati, Daniela Zanetti, Abhiram Rao, Stefan Gustafsson, Marco Perez, Erik Ingelsson, Joshua W. Knowles
Type 2 diabetes and less marked forms of dysglycaemia have been associated with increased risk of incident atrial fibrillation in epidemiological studies. However, it is unclear whether this association is causal. In this issue, Harati et al (https://doi.org/10.1007/s00125-019-4836-y) used Mendelian randomisation to answer this question. Using publicly available summary statistics data from genome-wide association studies, the authors did not find a causal role between genetically programmed type 2 diabetes, fasting blood glucose or HbA1c and the development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective approach for the prevention of atrial fibrillation. The authors conclude that, in line with the previously reported causal link between BMI and atrial fibrillation, these results suggest that strategies that aim to control type 2 diabetes-related comorbidities (such as obesity) are likely to be more effective in preventing atrial fibrillation than those that aim to control blood glucose.
Gyuri Kim, Sang-Guk Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Ele Ferrannini, Yong-ho Lee, Nam H. Cho
Ketones are regarded as a thrifty fuel for peripheral tissues, but the clinical and prognostic significance of mild ketosis is still uncertain. In this issue, Kim and colleagues (https://doi.org/10.1007/s00125-019-4829-x) investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based, observational study. During 12 years of follow-up, individuals with fasting ketonuria at baseline maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index, even though the groups with and without ketonuria had comparable baseline values. Individuals with spontaneous fasting ketonuria at baseline had a significantly lower risk of incident diabetes compared with individuals without ketonuria, independently of other metabolic variables. The authors suggest that spontaneous fasting ketonuria may be a novel signature in the modulation of glucose metabolism and may have the potential to prevent diabetes.
Xiaomei Teng, Chen Ji, Huiting Zhong, Dong Zheng, Rui Ni, David J. Hill, Sidong Xiong, Guo-Chang Fan, Peter A. Greer, Zhenya Shen, Tianqing Peng
It is well known that cardiomyocyte dysfunction plays a central role in diabetic cardiomyopathy. However, the role of non-cardiomyocytes in this diabetic complication has not been fully addressed. In this issue, Teng et al (https://doi.org/10.1007/s00125-019-4828-y) report that endothelial cell-specific disruption of calpain reduces cardiomyopathy in a mouse model of diabetes and that the protective effect of endothelial cell-specific calpain disruption may be attributed to attenuated endothelial injury and improved angiogenesis in diabetic hearts. The authors suggest that endothelial cell calpain may promote endothelial cell death and inhibit neovascularisation via suppression of β-catenin in diabetes. They conclude that calpain-mediated endothelial cell dysfunction may be important in the pathogenesis of diabetic cardiac complications and, thus, pharmaceutical approaches targeting calpain may prove useful for the treatment of diabetes and its cardiovascular complications.
Niels J. Connell, Riekelt H. Houtkooper, Patrick Schrauwen
Targeting NAD+ metabolism to improve metabolic health through sirtuin activation is a possible avenue for new therapeutic approaches to treat metabolic disorders. In this issue, Connell et al (https://doi.org/10.1007/s00125-019-4831-3) review the advances in and approaches undertaken for targeting NAD+ metabolism in humans and their effects on human metabolism. Preclinical models have demonstrated promising results of metabolic improvement by influencing NAD+ metabolism. The transition from the preclinical to the clinical setting has proven more ambiguous and results seen in preclinical models are yet to be replicated in humans. The targeting of NAD+ metabolism in humans remains promising for improving metabolic health but warrants further exploration. The figures from this review are available as a downloadable slideset.
Oluwatoyosi Bello, Cynthia Mohandas, Fariba Shojee-Moradie, Nicola Jackson, Olah Hakim, K. George M. M. Alberti, Janet L. Peacock, A. Margot Umpleby, Stephanie A. Amiel, Louise M. Goff
Black African populations experience disproportionately high rates of type 2 diabetes but typically present with less visceral fat deposition than other ethnic groups. In this issue, Bello et al (https://doi.org/10.1007/s00125-019-4820-6) use highly sensitive techniques to investigate ethnic differences in visceral fat and tissue-specific insulin sensitivity between men of black African and white European ethnicity with type 2 diabetes. They report comparable insulin sensitivity in the liver, skeletal muscle and adipose tissue in the two groups, despite lower visceral fat in the black African men. The authors suggest that excess adiposity, particularly visceral deposition, is a smaller driver of insulin resistance in black African men than in white European men and this supports the notion that there may be ethnic differences in the development of type 2 diabetes.
Richard A. Oram, Emily K. Sims, Carmella Evans-Molina
Recent in vivo and human pancreatic analyses have challenged the notion that all beta cells are destroyed in longstanding type 1 diabetes. These findings have raised a number of questions regarding how remaining beta cells have escaped immune destruction, whether pools of ‘sleeping’ or dysfunctional beta cells could be rejuvenated and whether there is potential for new growth of beta cells. In this issue, Oram et al (https://doi.org/10.1007/s00125-019-4822-4) address these open questions by reviewing existing clinical and histological data on long-duration type 1 diabetes. They summarise evidence for new growth of beta cells and beta cell turnover in type 1 diabetes and highlight recent data supporting the idea that beta cell abnormalities and heterogeneity contribute to type 1 diabetes pathogenesis. The authors also discuss the possibility that some beta cells in longstanding type 1 diabetes may be ‘sleeping’, dysfunctional or dedifferentiated. Finally, they highlight specific settings where functional recovery seems to occur and suggest ideas for future research. The figure from this review is available as a downloadable slide.
Yasuhiro Kyono, Jacob O. Kitzman, Stephen C. J. Parker
Genome-wide association studies (GWAS) of diabetes and related glycaemic traits have collectively identified hundreds of independent risk-associated single nucleotide polymorphisms (SNPs). The majority of these loci (>90%) localise to non-coding regions of the genome, strongly suggesting gene regulation as a major driving mechanism. In this issue, Kyono et al (https://doi.org/10.1007/s00125-019-4823-3) review how the generation and analysis of epigenomics datasets have enabled insights into the biology that underlies these regions of genetic predisposition to disease. They review existing and emerging tools that can be used to determine which subset of SNPs might be functionally significant and the context in which their function may emerge. Collectively, recent literature suggests that different diabetes and related trait SNPs scattered throughout the genome may operate through the same transcriptional regulatory pathways. The figures from this review are available as a downloadable slideset.
William L. Lowe Jr, Lynn P. Lowe, Alan Kuang, Patrick M. Catalano, Michael Nodzenski, Octavious Talbot, Wing-Hung Tam, David A. Sacks, David McCance, Barbara Linder, Yael Lebenthal, Jean M. Lawrence, Michele Lashley, Jami L. Josefson, Jill Hamilton, Chaicharn Deerochanawong, Peter Clayton, Wendy J. Brickman, Alan R. Dyer, Denise M. Scholtens, Boyd E. Metzger, on behalf of the HAPO Follow-up Study Cooperative Research Group
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study identified continuous associations between maternal glucose levels during pregnancy at ~28 weeks’ gestation and newborn adiposity. In this issue, Lowe Jr et al, on behalf of the HAPO Follow-up Study Cooperative Research Group (https://doi.org/10.1007/s00125-018-4809-6), examined associations between maternal pregnancy glucose, including levels below those diagnostic of gestational diabetes, and offspring adiposity during early adolescence (mean age 11.4 years). The authors report that maternal fasting glucose and glucose post-load levels at 1 and 2 h were associated with childhood obesity and per cent fat >85th percentile across the maternal glucose continuum, independent of the BMI of the mother. Continuous relationships between maternal glucose levels and child adiposity measures were also observed. The authors conclude that these findings demonstrate that the full range of maternal glucose levels are independently associated with child adiposity, which could have implications for glucose treatment targets in mothers with pre-existing or gestational diabetes, especially those with other risk factors for greater offspring adiposity, including obesity.
Stuart J. McGurnaghan, Liam Brierley, Thomas M. Caparrotta, Paul M. McKeigue, Luke A. K. Blackbourn, Sarah H. Wild, Graham P. Leese, Rory J. McCrimmon, John A. McKnight, Ewan R. Pearson, John R. Petrie, Naveed Sattar, Helen M. Colhoun, on behalf of the Scottish Diabetes Research Network Epidemiology Group
Dapagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor, used to treat type 2 diabetes. In this issue, McGurnaghan et al (https://doi.org/10.1007/s00125-018-4806-9) report on a study undertaken using the large Scottish database Scottish Care Information-Diabetes (SCI-Diabetes). The study measured the effects of treatment with dapagliflozin, which was administered in routine clinical practice. Dapagliflozin was associated with decreases in HbA1c, blood pressure and weight, which were maintained over time with no clear effects on kidney function. In addition, although the study was small, dapagliflozin did not increase the rate of adverse events. The authors conclude that the beneficial effects observed in this study are similar to those from clinical trials of dapagliflozin, but that this study includes a wider mix of patients, including off-license users in whom a similar effectiveness of treatment was demonstrated. In summary, the effects of dapagliflozin on lowering blood glucose, blood pressure and weight in a real-world setting appear to be similar to those observed in previously conducted clinical trials.
Martin B. Groen, Trine A. Knudsen, Stine H. Finsen, Bente K. Pedersen, Ylva Hellsten, Stefan P. Mortensen
Type 2 diabetes is associated with vascular complications, including reduced blood flow in tissues. Plasma ATP is a potent vasodilator that is thought to play a role in the local regulation of blood flow, and it is possible that ATP signalling is impaired in individuals with type 2 diabetes. In this issue, Groen et al (https://doi.org/10.1007/s00125-018-4790-0) measured femoral arterial and venous plasma ATP levels during normoxia, hypoxia and one-legged knee-extensor exercise in nine individuals with type 2 diabetes and eight control individuals. They report that individuals with type 2 diabetes had a blunted increase in ATP and blood flow, compared with non-diabetic individuals, when exposed to hypoxia (a potent stimulus for ATP release). The authors also found that, compared with the non-diabetic group, individuals with type 2 diabetes had lower venous plasma ATP levels and blood flow in the exercising leg during the one-legged knee-extensor exercise. In additional experiments, the individuals with type 2 diabetes had a lower vasodilatory response to exogenous ATP. Restoration of ATP release (e.g. by phosphodiesterase 3- or phosphodiesterase 5-inhibitors) could, therefore, be a novel treatment to help restore tissue perfusion in individuals with type 2 diabetes.
Matthias B. Schulze
Cardiovascular complications are commonly associated with obesity. However, a subgroup of obese individuals may not be at an increased risk for cardiovascular complications and evidence suggests that it might be possible to define this subgroup. In this issue, Matthias Schulze (https://doi.org/10.1007/s00125-018-4787-8) summarises recent evidence from prospective cohort studies that investigated long-term risk for subgroups defined according to the ‘metabolic health’ concept across different BMI groups. Comparison of metabolically healthy obese individuals with normal-weight individuals suggests an increased risk for cardiovascular complications; this is, however, substantially lower than that for metabolically unhealthy individuals. Investigation of the long-term stability of metabolic health has revealed that the metabolically healthy phenotype is a transient one for most. The use of repeated measures and the investigation of body-fat distribution patterns in cohorts promises to clarify the long-term relevance of the metabolic health concept and to point towards alternative anthropometric measures for clinical use. The figures from this review are available as a downloadable slideset.
Ana Luisa Perdigoto, Paula Preston-Hurlburt, Pamela Clark, S. Alice Long, Peter S. Linsley, Kristina M. Harris, Steven E. Gitelman, Carla J. Greenbaum, Peter A. Gottlieb, William Hagopian, Alyssa Woodwyk, James Dziura, Kevan C. Herold, the Immune Tolerance Network
In the short term, immune therapies for type 1 diabetes, such as Fc receptor (FcR) non-binding anti-CD3 monoclonal antibodies, can preserve C-peptide and improve glycaemic control, but long-term follow-up studies have been limited. In this issue, Perdigoto et al (https://doi.org/10.1007/s00125-018-4786-9) studied the long-term metabolic and immunological impact of anti-CD3 treatment on participants from the Autoimmunity-Blocking Antibody for Tolerance (AbATE) study. AbATE showed that treatment with the FcR non-binding antibody teplizumab improved C-peptide responses for 2 years after diagnosis. After a mean follow-up of 7 years, Perdigoto and colleagues found that participants previously identified as responders at year 1 retained improved C-peptide responses and lasting immunological changes compared with control and drug-treated non-responders. The authors identified features of T cell subsets that predicted maintenance of C-peptide levels at follow-up, namely, a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8+ T cells. This study highlights the long-lasting effects of immune therapy and how these can be predicted from short-term responses. The authors postulate that combination with other immune or metabolic therapies may further enhance the observed effects of anti-CD3 monoclonal antibody treatment. This article is the subject of a commentary by Lucienne Chatenoud.
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 (https://doi.org/10.1007/s00125-018-4772-2) 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 (https://doi.org/10.1007/s00125-018-4784-y), Diabetologia and Diabetes have adopted a modified version of Hart and Powers’ checklist, to be completed by authors on submission.
Christopher C. Patterson, Valma Harjutsalo, Joachim Rosenbauer, Andreas Neu, Ondrej Cinek, Torild Skrivarhaug, Birgit Rami-Merhar, Gyula Soltesz, Jannet Svensson, Roger C. Parslow, Conxa Castell, Eugen J. Schoenle, Polly J. Bingley, Gisela Dahlquist, Przemysława K. Jarosz-Chobot, Dalė Marčiulionytė, Edna F. Roche, Ulrike Rothe, Natasa Bratina, Constantin Ionescu-Tirgoviste, Ilse Weets, Mirjana Kocova, Valentino Cherubini, Natasa Rojnic Putarek, Carine E. deBeaufort, Mira Samardzic, Anders Green
Recent publications from Scandinavian countries have suggested that a previously increasing incidence of type 1 diabetes in children under 15 years old may now be stabilising. In this issue, Patterson et al (https://doi.org/10.1007/s00125-018-4763-3) report results from a pooled analysis of data from 26 registers in 22 European countries during the 25 year period 1989–2013. The average rate of increase across Europe during this period was estimated as 3.4% per annum, although different patterns were apparent in different countries. When estimates were obtained for 5 year subperiods, the rate of increase was lowest at 1.1% per annum in the 2004–2008 period but rose again to 2.7% per annum in the 2009–2013 period. Evidence of a 4 year periodicity in incidence was evident in four centres but there was no obvious explanation for this. These findings have implications for those involved in the planning and delivery of healthcare for children with type 1 diabetes.
Rachel Kadakia, Michael Nodzenski, Octavious Talbot, Alan Kuang, James R. Bain, Michael J. Muehlbauer, Robert D. Stevens, Olga R. Ilkayeva, Sara K. O’Neal, Lynn P. Lowe, Boyd E. Metzger, Christopher B. Newgard, Denise M. Scholtens, William L. Lowe Jr for the HAPO Study Cooperative Research Group
The maternal metabolome during pregnancy offers insight into the metabolic environment surrounding a developing fetus and may impact on newborn fat deposition and insulin sensitivity. In this issue, Kadakia et al (https://doi.org/10.1007/s00125-018-4781-1) investigated these associations in 1600 mothers and offspring who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Metabolomics assays were performed on maternal fasting and 1 h post glucose load serum samples. The authors identified several individual maternal fatty acid, lipid and amino acid metabolites at 1 h post glucose load that were associated with newborn sum of skinfolds, birthweight and cord C-peptide, a measure of fetal insulinaemia. These findings suggest that the maternal metabolomic response to a glucose load may have a greater impact on newborn size than the fasting state. In addition, maternal metabolites may mediate the well-known associations of maternal BMI and maternal glucose with newborn size. A unique maternal metabolomic signature may emerge as an early-life biomarker of offspring obesity risk.
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 (https://doi.org/10.1007/s00125-018-4769-x) 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.
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 (https://doi.org/10.1007/s00125-018-4777-x) 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.
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 (https://doi.org/10.1007/s00125-018-4767-z) 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.
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 (https://doi.org/10.1007/s00125-018-4759-z) 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.
Stuart I. Mannering, Anthony R. Di Carluccio, Colleen M. Elso
T cell responses against neoepitopes are emerging as important players in the development of autoimmune diseases. A variety of mechanisms result in post-translational modification of cellular proteins, leading to the generation of neoepitopes. Some of these ‘new’ epitopes are specific to peripheral tissues and provide a potential explanation for how self-protein-specific T cells can avoid thymic deletion. In this issue, Mannering et al (https://doi.org/10.1007/s00125-018-4760-6) outline recent advances in this field and challenges still to be overcome in the discovery of neoepitopes important in type 1 diabetes. Information about T cell responses to diabetogenic neoepitopes will support the development of antigen-specific therapies aimed at restoring immune tolerance in type 1 diabetes, as well as assays to monitor function and frequency of antigen-specific cells in the periphery. This may also contribute to the basic understanding of the initiation of autoimmune disease.
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 (https://doi.org/10.1007/s00125-018-4743-7) 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.
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 (https://doi.org/10.1007/s00125-018-4744-6) 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.
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 (https://doi.org/10.1007/s00125-018-4739-3) 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.
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 (https://doi.org/10.1007/s00125-018-4729-5) 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.
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 (https://doi.org/10.1007/s00125-018-4732-x) 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.
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 (https://doi.org/10.1007/s00125-018-4731-y) 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.
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 (https://doi.org/10.1007/s00125-018-4726-8) 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.
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 (https://doi.org/10.1007/s00125-018-4711-2) 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.
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 (https://doi.org/10.1007/s00125-018-4708-x) 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.
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 (https://doi.org/10.1007/s00125-018-4720-1) 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.
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 (https://doi.org/10.1007/s00125-018-4654-7) 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 (https://doi.org/10.1007/s00125-018-4656-5) 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 (https://doi.org/10.1007/s00125-018-4669-0), 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 (https://doi.org/10.1007/s00125-018-4670-7) 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 (https://doi.org/10.1007/s00125-018-4663-6) 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 (https://doi.org/10.1007/s00125-018-4671-6) 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 (https://doi.org/10.1007/s00125-018-4678-z) 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 (https://doi.org/10.1007/s00125-018-4673-4).
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 (https://doi.org/10.1007/s00125-018-4712-1) 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.
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 (https://doi.org/10.1007/s00125-018-4707-y) 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.
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 (https://doi.org/10.1007/s00125-018-4705-0) 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.
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 (https://doi.org/10.1007/s00125-018-4697-9) 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.
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 (https://doi.org/10.1007/s00125-018-4694-z) 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
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 (https://doi.org/10.1007/s00125-018-4685-0) 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.
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 (https://doi.org/10.1007/s00125-018-4692-1) 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.
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 (https://doi.org/10.1007/s00125-018-4664-5) 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.
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 (https://doi.org/10.1007/s00125-018-4688-x) 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.
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 (https://doi.org/10.1007/s00125-018-4677-0) 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.
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 (https://doi.org/10.1007/s00125-018-4680-5) 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.
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 (https://doi.org/10.1007/s00125-018-4657-4) 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.
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 (https://doi.org/10.1007/s00125-018-4658-3) 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.
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 (https://doi.org/10.1007/s00125-018-4642-y) 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.
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 (https://doi.org/10.1007/s00125-018-4641-z) 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.]
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 (https://doi.org/10.1007/s00125-018-4639-6), 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.
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 (https://doi.org/10.1007/s00125-018-4632-0) 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.
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 (https://doi.org/10.1007/s00125-018-4633-z) 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.]
Cardiovascular outcome trials (CVOTs) of glucose-lowering medications that have been completed in recent years have provided welcome pointers towards best use of these drugs in diabetes care. However, many questions and uncertainties remained. In this issue, Philip Home (https://doi.org/10.1007/s00125-018-4801-1) discusses studies in three major glucose-lowering drug classes, which were published and presented recently (October/November 2018). These studies help to confirm or clarify our understanding of how the three classes should be positioned clinically and whether there are within-class differences. For dipeptidyl peptidase-4 (DPP4) inhibitors, CARMELINA confirmed neutrality for cardiovascular outcomes, with no heart failure signal, albeit in a highly selected population. For GLP-1 receptor agonists, the Harmony Outcome study confirmed an early and continuing benefit for cardiovascular protection for this class, independent of glucose- or body-weight-lowering. For sodium–glucose cotransporter-2 (SGLT2) inhibitors, DECLARE-TIMI 58 confirmed strong renal protection and protection against heart failure, even in people without prior cardiovascular disease, but did not further clarify class issues around major cardiovascular outcomes. Studies in these three classes are now transforming guidelines for the use of glucose-lowering medications, notably extending them beyond glucose-lowering to managing the adverse vascular and renal manifestations of diabetes. The three studies discussed here drive guideline changes more firmly for the benefit of people with type 2 diabetes, and related studies due in the next 12 months will take that process further.