Competition for publication in Diabetologia continues to grow, and less than 20% of papers are accepted. Of all the high-quality papers that appear in this month’s issue I want to draw your attention to five articles that I think are particularly interesting. The articles are summarised here. Our publisher, Springer, has kindly made the full text of each of these papers freely available. I hope you enjoy reading them!

Sally M. Marshall, Editor

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Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction

Hannah R. Elliott, Gemma C. Sharp, Caroline L. Relton, Deborah A. Lawlor

Gestational diabetes (GDM) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. Epigenetic mechanisms have been hypothesised to mediate an effect of GDM on offspring adiposity and type 2 diabetes and therefore could provide a modifiable mechanism to reduce type 2 diabetes in future generations. Epigenetic mechanisms have also been proposed as useful clinical biomarkers for predicting future adverse outcomes, irrespective of their causal role in disease. In this issue, Elliott, Sharp et al (https://doi.org/10.1007/s00125-019-05011-8) summarise recent advances in the epigenetic epidemiology of GDM. They identify a nascent research area that is likely to benefit from triangulation of different methods for exploring causal effects of epigenetic mechanisms on disease. They also identify the need to determine the value of epigenetic markers measured in samples collected in early pregnancy as accurate predictors of GDM and associated adverse outcomes.

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The figures from this review are available as a downloadable slideset.

Extracellular vesicles in metabolic disease

Naveed Akbar, Valerio Azzimato, Robin P. Choudhury, Myriam Aouadi

Extracellular vesicles (EVs) are considered promising candidates for the diagnosis and treatment of metabolic diseases. EVs are membrane-enclosed lipid spheres that serve as messengers by transporting lipids, proteins, RNA and/or DNA from the parent cell of origin to other cells. EVs present a potential major advantage over current blood-borne diagnostic markers as they can provide new functional insights into the cells and tissues implicated in metabolic disease. Recent discoveries in clinical cohorts and animal models has led to a blossoming of publications, implicating EVs in the biology and development of metabolic diseases. In this this issue, Akbar et al (https://doi.org/10.1007/s00125-019-05014-5) discuss the role of platelet, endothelial, adipocyte, immune cell and gut-microbiome EVs in metabolic dysfunction, focusing on EV-dependent communication between adipocytes, the vasculature and immune cells in type 2 diabetes. They also explore potential issues associated with translating early biomarker discoveries into therapeutic targets.

The figures from this review are available as a downloadable slideset.

Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease

Johan Verhagen, Norkhairin Yusuf, Emma L. Smith, Emily M. Whettlock, Kerina Naran, Sefina Arif, Mark Peakman

The HLA-DR3-DQ2 haplotype represents a major risk factor for the development of type 1 diabetes. However, it is not fully established which antigen presented on these HLA molecules is important in disease development. In this issue, Verhagen and colleagues (https://doi.org/10.1007/s00125-019-04994-8) report a novel two-stage in vivo approach to identify these antigens. The authors first generated a new transgenic mouse model expressing HLA-DR3-DQ2 and found a high rate of spontaneous autoimmune diabetes. They then used adjuvanted priming with candidate antigens to demonstrate that only proinsulin is capable of further accelerating diabetes development. Moreover, this diabetogenicity maps to a 15-mer residue, with its core MHC-binding region in the N-terminal of C-peptide, which was not previously known to be disease relevant. The authors suggest that the identification of diabetogenic peptides in this way will provide new insights into the role of HLA in diabetes development, which could be relevant to human studies and therapies.

Metallothionein 1 negatively regulates glucose-stimulated insulin secretion and is differentially expressed in conditions of beta cell compensation and failure in mice and humans

Mohammed Bensellam, Yan-Chuan Shi, Jeng Yie Chan, D. Ross Laybutt, Heeyoung Chae, Michel Abou-Samra, Evan G. Pappas, Helen E. Thomas, Patrick Gilon, Jean-Christophe Jonas

The mechanisms of beta cell adaptation to insulin resistance in obesity and of beta cell failure in type 2 diabetes are poorly defined. Several metallothionein genes are upregulated in islets from type 2 diabetic donors, but their role in beta cells is unclear. In this issue, Bensellam et al (https://doi.org/10.1007/s00125-019-05008-3) report that beta cell compensation in murine models of obesity correlates with downregulation of islet metallothionein 1 (Mt1) and Mt2 gene expression, while beta cell failure correlates with their upregulation. They also confirm that MT1X expression is upregulated in islets isolated from type 2 diabetic donors. Combining in vivo, ex vivo and in vitro complementary approaches, the authors demonstrate that Mt1 inhibition enhances glucose-stimulated insulin secretion and improves glucose tolerance, whereas its overexpression attenuates the secretory response. They conclude that MT1 negatively regulates beta cell function and propose that MT1 inhibition may represent a potential strategy to enhance insulin secretion in (pre)diabetes.

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Ari V. Ahola-Olli, Linda Mustelin, Maria Kalimeri, Johannes Kettunen, Jari Jokelainen, Juha Auvinen, Katri Puukka, Aki S. Havulinna, Terho Lehtimäki, Mika Kähönen, Markus Juonala, Sirkka Keinänen-Kiukaanniemi, Veikko Salomaa, Markus Perola, Marjo-Riitta Järvelin, Mika Ala-Korpela, Olli Raitakari, Peter Würtz

Increased risk for type 2 diabetes is consistently associated with widespread metabolic aberrations in young adults from multiple cohorts with a mean age of 31–36 years at baseline. Among the strongest predictors of incident type 2 diabetes are circulating branched-chain amino acids, VLDL-particle measures and enrichment of triacylglycerol in all lipoprotein subclasses. Previous animal studies and Mendelian randomisation studies performed in humans have suggested causal relationships between increased concentrations of branched-chain amino acids and type 2 diabetes. In this issue, Ahola-Olli et al (https://doi.org/10.1007/s00125-019-05001-w) used NMR metabolomics to quantify 229 circulating metabolic measures in individuals from four Finnish observational cohorts (n = 11,896; baseline age 24–45 years) and tested associations with risk of developing diabetes, fasting glucose, 2 h glucose and HOMA-IR at follow-up (range 8–15 years). The authors explain that their results extend previously detected epidemiological associations (in middle-aged and older individuals) to young adults and demonstrate that branched-chain amino acids can predict the development of type 2 diabetes up to 15 years prior to disease onset. By summarising the information from multiple metabolic measures, the authors were able to derive and validate a multi-metabolite score identifying a subgroup of patients with a greatly increased risk for type 2 diabetes after adjusting for BMI and fasting glucose (OR 10.1 for individuals in upper vs lower fifth of the multi-metabolite score). They conclude that comprehensive metabolic profiling may eventually help target interventions for young people at increased risk for developing type 2 diabetes.

All text supplied by the authors.