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Three large studies find screening reduces mortality for those with detectable type 2 diabetes but not for general population: 10.1007/s00125-017-4323-2, 10.1007/s00125-017-4299-y and 10.1007/s00125-017-4402-4

Read the accompanying commentaries by Professor David Simmons and Professor Jonathan Shaw

Current issue: November 2017

November 2017 cover

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The cover picture shows a high-resolution confocal laser scanning micrograph of albumin vascular permeability assessed by Evans Blue dye leakage (green/blue colour) in retinal whole mounts of an experimental model of diabetes (db/db mouse). Focal sites of leakage and diffusely distributed dye are found in the retina as a result of diabetes-induced disruption of the blood-retinal barrier. In the present issue of Diabetologia, Hernández et al report that topical administration of dipeptidyl peptidase IV (DPP-IV) inhibitors prevents not only neurodegeneration, but also vascular leakage in this experimental model of diabetes.

Cover credit: M. Valeri, Unit of High Technology, Vall d'Hebron Research Institute, Barcelona, Spain.

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Up front

Sally Marshall

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


Vascular complications in diabetes: old messages, new thoughts
by 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 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. [Text supplied by the authors.]

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Understanding and preventing type 1 diabetes through the unique working model of TrialNet
by 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 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. [Text supplied by the authors.]

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The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study
by 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 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. [Text supplied by the authors.]

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Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion
by 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 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. [Text supplied by the authors.]

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Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes
by 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 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. [Text supplied by the authors.]

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Inside this issue

Up front

Up front November 2017

Reviews

Vascular complications in diabetes: old messages, new thoughts
Josephine M. Forbes, Amelia K. Fotheringham

Understanding and preventing type 1 diabetes through the unique working model of TrialNet
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

Commentaries

Should we screen for type 2 diabetes among asymptomatic individuals? Yes
David Simmons, Janice C. Zgibor

Does the evidence support population-wide screening for type 2 diabetes? No
Jonathan E. Shaw

Articles

Clinical Science and Care

Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: a randomised controlled crossover trial
Klemen Dovc, Maddalena Macedoni, Natasa Bratina, Dusanka Lepej, Revital Nimri, Eran Atlas, Ido Muller, Olga Kordonouri, Torben Biester, Thomas Danne, Moshe Phillip, Tadej Battelino

Screening for neonatal diabetes at day 5 of life using dried blood spot glucose measurement
Timothy J. McDonald, Rachel E. Besser, Mandy Perry, Tarig Babiker, Bridget A. Knight, Maggie H. Shepherd, Sian Ellard, Sarah E. Flanagan, Andrew T. Hattersley

Individualised variable-interval risk-based screening for sight-threatening diabetic retinopathy: the Liverpool Risk Calculation Engine
Antonio Eleuteri, Anthony C. Fisher, Deborah M. Broadbent, Marta García-Fiñana, Christopher P. Cheyne, Amu Wang, Irene M. Stratton, Mark Gabbay, Daniel Seddon, Simon P. Harding, for the Individualised Screening for Diabetic Retinopathy (ISDR) Study Group

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Epidemiology

Effect of population screening for type 2 diabetes and cardiovascular risk factors on mortality rate and cardiovascular events: a controlled trial among 1,912,392 Danish adults
Rebecca K. Simmons, Simon J. Griffin, Daniel R. Witte, Knut Borch-Johnsen, Torsten Lauritzen, Annelli Sandbæk

Effect of screening for type 2 diabetes on risk of cardiovascular disease and mortality: a controlled trial among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009
Rebecca K. Simmons, Simon J. Griffin, Torsten Lauritzen, Annelli Sandbæk

Screening for type 2 diabetes: do screen-detected cases fare better?
Adina L. Feldman, Simon J. Griffin, Eva Fhärm, Margareta Norberg, Patrik Wennberg, Lars Weinehall, Olov Rolandsson

The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study
Lin Xu, Maria Carolina Borges, Gibran Hemani, Debbie A. Lawlor

Perceived racism and incident diabetes in the Black Women’s Health Study
Short Communication
Kathryn L. Bacon, Sherri O. Stuver, Yvette C. Cozier, Julie R. Palmer, Lynn Rosenberg, Edward A. Ruiz-Narváez

Immigration to Israel during childhood is associated with diabetes at adolescence: a study of 2.7 million adolescents
Short Communication
Alon Peled, Barak Gordon, Gilad Twig, Joseph Mendlovic, Estela Derazne, Michal Lisnyansky, Itamar Raz, Arnon Afek

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Genetics

Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes
Adem Y. Dawed, Ashfaq Ali, Kaixin Zhou, Ewan R. Pearson, Paul W. Franks

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Islet Studies

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion
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

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Immunology and Transplantation

Relapsing/remitting type 1 diabetes
Short Communication
Kayleigh M. van Megen, Matthew P. Spindler, Fleur M. Keij, Ineke Bosch, Fleur Sprangers, Annet van Royen-Kerkhof, Tatjana Nikolic, Bart O. Roep

The effect of interleukin-22 treatment on autoimmune diabetes in the NOD mouse
Danielle J. Borg, Ran Wang, Lydia Murray, Hui Tong, Raymond J. Steptoe, Michael A. McGuckin, Sumaira Z. Hasnain

Metabolism

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells
Gaia Botteri, Marta Montori, Anna Gumà, Javier Pizarro, Lídia Cedó, Joan Carles Escolà-Gil, Diana Li, Emma Barroso, Xavier Palomer, Alison B. Kohan, Manuel Vázquez-Carrera

FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes
Thomas Laeger, Christian Baumeier, Ilka Wilhelmi, Josefine Würfel, Anne Kamitz, Annette Schürmann

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Pathophysiology and Complications

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes
Cristina Hernández, Patricia Bogdanov, Cristina Solà-Adell, Joel Sampedro, Marta Valeri, Xavier Genís, Olga Simó-Servat, Marta García-Ramírez, Rafael Simó

Prolonged exposure of mouse and human podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor
Abigail C. Lay, Jenny A. Hurcombe, Virginie M. S. Betin, Fern Barrington, Ruth Rollason, Lan Ni, Lawrence Gillam, Grace M. E. Pearson, Mette V. Østergaard, Hellyeh Hamidi, Rachel Lennon, Gavin I. Welsh, Richard J. M. Coward

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Letters

Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy
Chinmay S. Marathe, Christopher K. Rayner, Karen L. Jones, Michael Horowitz

Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. Reply to Marathe CS, Rayner CK, Jones KL, et al [letter]
Adam D. Farmer, Anne Grave Pedersen, Birgitte Brock, Poul Erik Jakobsen, Jesper Karmisholt, Sahar D. Mohammed, S. Mark Scott, Asbjørn Mohr Drewes, Christina Brock

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