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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

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?

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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

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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])

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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

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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. [Text supplied by the authors.]

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. [Text supplied by the authors.]

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. [Text supplied by the authors.]

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.]