Up front March 2016

Blood-based signatures in type 1 diabetes

Susanne M. Cabrera, Yi-Guang Chen, William A. Hagopian, Martin J. Hessner

Since the late 1990s there have been major developments in the fields of genetics, genomics, proteomics and computational biology. These advances have greatly enhanced our understanding of type 1 diabetes progression as well as non-progression among those with inherited risk. These tools also have the potential to inform the development of new biomarkers of disease risk and progression, as well as therapeutic responses. In this issue, Cabrera et al review blood-based signatures in type 1 diabetes, specifically summarising both direct transcriptomic analyses of whole blood and immunocyte subsets, and plasma/serum-induced transcriptional signatures. Proteomic analyses, microRNA assays and markers of beta cell death are also discussed. The findings of these blood-based profiling efforts are placed within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes.

Metformin and the gastrointestinal tract

Laura J. McCreight, Clifford J. Bailey, Ewan R. Pearson

Metformin, as the first-line agent in the medical management of type 2 diabetes, is extensively prescribed on a global scale. However, the mechanism of action of metformin has yet to be fully elucidated, and inter-individual variability in tolerance and response is poorly understood. Current understanding suggests that metformin exerts its glucose-lowering effects predominantly via a reduction in hepatic glucose production. Yet, evidence is mounting in support of the gastrointestinal tract playing an important role in metformin response and tolerance—metformin may even exert a pre-absorptive effect on glycaemia. In this issue, McCreight et al summarise the evidence regarding metformin’s complex relationship with the gastrointestinal tract (including its effect on incretin hormones, bile acids and the microbiome), and argue that further research into this relationship is key to our understanding of metformin.

Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study

Alaitz Poveda, Robert W. Koivula, Shafqat Ahmad, Inês Barroso, Göran Hallmans, Ingegerd Johansson, Frida Renström, Paul W. Franks

Type 2 diabetes is caused by unhealthy lifestyles set against the backdrop of genetic susceptibility. Diabetes prediction algorithms usually include intermediate biomarkers of diabetes that are consequences of poor lifestyle and genetic predisposition, but not the primordial risk factors themselves. In this issue, Poveda et al used a prospective study of a Swedish cohort to assess the predictive ability of genetic and self-reported lifestyle information for the development of type 2 diabetes 10 years later. They found that models including established common genetic variants and lifestyle risk factors, respectively, had similar predictive accuracy; the combined model was superior to either component model and yielded a clinically relevant level of predictive accuracy. These findings may be informative for the long-term prediction of type 2 diabetes for the purpose of preventive intervention, particularly when biochemical risk markers are unavailable.

Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets

Ionel Sandovici, Constanze M. Hammerle, Wendy N. Cooper, Noel H. Smith, L. Tarry-Adkins, Benjamin J. Dunmore, Julien Bauer, Simon R. Andrews, Giles S. H. Yeo, Susan E. Ozanne, Miguel Constância

Type 2 diabetes prevalence increases with age and is associated with progressive failure of pancreatic islets. The cellular and molecular mechanisms underlying this age-associated decline in islet function are poorly understood. In this issue, Sandovici et al provide evidence that islet ageing is associated with inflammation and cellular senescence. Using genome-wide technology, they compared mRNA expression in islets from young and aged rats and demonstrated that expression of genes related to inflammation and fibrosis increased with age. Some of these expression changes could be explained by alterations in DNA methylation. Consistent with these molecular signatures, aged animals displayed macrophage infiltration and altered endocrine cell ratios. These findings identify genetic, epigenetic and cellular signatures that may explain age-associated decline in islet function and consequently increased risk of type 2 diabetes. They point towards inflammation being a key triggering event and thus an important therapeutic target.

The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes

Polly J. Bingley, David C. Boulware, Jeffrey P. Krischer, the Type 1 Diabetes TrialNet Study Group

Islet autoantibodies are the best validated markers of an ongoing autoimmune process and allow accurate prediction of type 1 diabetes. The development of multiple islet autoantibodies seems to represent a ‘point of no return’ in the disease process. This generally occurs in early childhood, but some individuals with autoantibodies to a single antigen develop further autoantibodies after this age. The characteristics of this later progression are, however, unknown. In this issue, Bingley and colleagues report findings from a large cohort of single antibody positive relatives (median age 16 years). The cumulative risk of developing additional antibodies within 5 years was 22%, with high risk of subsequent diabetes. This progression of islet autoimmunity in late childhood/adulthood was associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. The authors conclude that this evidence of heterogeneity in the disease process has potentially important implications for type 1 diabetes prevention.

All text supplied by the authors.