Josephine M. Forbes, Amelia K. Fotheringham
The majority of the morbidity and mortality associated with diabetes is due to chronic complications, including kidney and cardiovascular disease. However, despite decades of research, the primary initiators remain elusive. In this issue, Forbes and Fotheringham (DOI https://doi.org/10.1007/s00125-017-4360-x) reflect on whether previous postulates for disease development, such as oxidative stress and heritability, have stood the test of time and shift focus to some alternative areas that may provide additional insight, such as metabolic flux and microbiota. They discuss how conventional therapies shape up in a world of evolving diabetes aetiology, where a return to natural history studies is increasing. Recent Phase III trials are also highlighted, where the pleiotropic effects of agents such as sodium−glucose cotransporter 2 (SGLT2) inhibitors were arguably as beneficial in achieving renal and cardiovascular endpoints as they were in lowering glucose. In a world of shrinking support for diabetes research, this review is also a reminder that concerted lobbying is part of the research effort to prevent, reverse and treat diabetes complications.
Manuela Battaglia, Mark S. Anderson, Jane H. Buckner, Susan M. Geyer, Peter A. Gottlieb, Thomas W. H. Kay, Åke Lernmark, Sarah Muller, Alberto Pugliese, Bart O. Roep, Carla J. Greenbaum, Mark Peakman
Type 1 diabetes is a disease that progresses sequentially, at variable rates, through identifiable stages prior to the onset of symptoms to clinical diagnosis. The ability to identify at-risk presymptomatic individuals has provided a setting in which type 1 diabetes prevention can be contemplated, as well as an unprecedented opportunity to study the evolution of the disease. In this issue, Battaglia et al (DOI https://doi.org/10.1007/s00125-017-4384-2) outline how Type 1 Diabetes TrialNet, an international consortium of clinical trial centres focused on intervention and prevention studies accompanied by deep longitudinal bio-sampling, is a key player in this area. The consortium’s power lies in its ability to integrate clinical trials and mechanistic studies, drawing in clinicians and scientists and developing partnerships with industry. This has provided TrialNet with an enviable and unique working model in the field of translational medicine. The authors highlight the ‘TrialNet model’ of conducting wide-ranging studies ancillary to trials and signpost examples of important advances in our understanding of this disease, which could only be realised using this type of ‘team science’ approach. They conclude that this approach has pushed the field forward in multiple directions, and has begun to reveal biomarkers and deliver the mechanistic understanding necessary to combat type 1 diabetes.
Lin Xu, Maria Carolina Borges, Gibran Hemani, Debbie A. Lawlor
As the average BMI is increasing globally, with a large number of people now obese and few effective and sustainable treatments (apart from bariatric surgery) for obesity, it is important to identify modifiable mediators of the impact of high BMI on disease outcomes. In this issue, Xu et al (DOI https://doi.org/10.1007/s00125-017-4396-y) sought to determine whether glycaemic/insulin and lipid traits were causal mediators of the effect of BMI on CHD. To test for mediation, the authors used Mendelian randomisation (MR), the use of genetic instruments to test causal effects, which is less prone to the biases of conventional multivariable regression. The MR results supported a positive effect of BMI on CHD risk that was mediated through triacylglycerols, HbA1c and type 2 diabetes. These findings indicate the extent to which acting on these risk factors might counteract the detrimental effects of obesity on CHD, and highlight the potential importance of using interventions that address these risk factors, specifically in those who are obese.
Felicia Gerst, Robert Wagner, Gabriele Kaiser, Madhura Panse, Martin Heni, Jürgen Machann, Malte N. Bongers, Tina Sartorius, Bence Sipos, Falko Fend, Christian Thiel, Silvio Nadalin, Alfred Königsrainer, Norbert Stefan, Andreas Fritsche, Hans-Ulrich Häring, Susanne Ullrich, Dorothea Siegel-Axel
Obesity is associated with fatty liver and fatty pancreas. However, the role of pancreatic steatosis in the development of type 2 diabetes is not understood. In this issue, Gerst et al (DOI https://doi.org/10.1007/s00125-017-4385-1) report that pancreatic pre-adipocytes and adipocytes have a proinflammatory potential that can be induced by palmitate and fetuin-A, a hepatokine secreted from the fatty liver. In human pancreatic resections, increased immune cell infiltration was detected in islets located in the vicinity of adipocytes. Furthermore, in human islets, fetuin-A increased cytokine production by resident immune cells and inhibited glucose-induced insulin secretion. The effect of fetuin-A on cytokine production was dependent on toll-like receptor 4 (TLR4), whereas the inhibition of insulin secretion occurred independently of TLR4. From these findings, Gerst and colleagues propose that a fetuin-A-mediated metabolic crosstalk between fatty liver and fatty pancreas exacerbates pancreatic inflammation and impairs insulin secretion, contributing to overt diabetes.
Cristina Hernández, Patricia Bogdanov, Cristina Solà-Adell, Joel Sampedro, Marta Valeri, Xavier Genís, Olga Simó-Servat, Marta García-Ramírez, Rafael Simó
Glucagon-like peptide 1 (GLP-1) and GLP-1 receptor (GLP-1R) are abundantly produced in the human retina, and the topical administration of GLP-1R agonists prevents retinal neurodegeneration in a mouse model of spontaneous type 2 diabetes (db/db mouse). GLP-1 is extremely susceptible to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV); consequently, the preservation of the GLP-1 retinal content by inhibiting its degradation could be a new strategy for treating the early stages of diabetic retinopathy. In this issue, Hernández, Bogdanov et al (DOI https://doi.org/10.1007/s00125-017-4388-y) report that administration of eye drops containing the DPP-IV inhibitors saxagliptin and sitagliptin prevents the neurodegenerative process, as well as vascular leakage, that occur in early stages of diabetic retinopathy. These effects can be attributed to the enhancement of the GLP-1 content of the retina, but other unrelated mechanisms cannot be ruled out. These findings could pave the way for clinical trials testing this new approach, alone or in combination with GLP-1R agonists, in the treatment of early stages of diabetic retinopathy.
All text supplied by the authors.