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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: October 2017

October 2017 cover

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The cover image is an original charcoal, coal and wax drawing depicting a growing fetus in utero, with lipoproteins of differing sizes superimposed electronically on surrounding maternal tissue. In the present issue of Diabetologia, following analysis of the metabolic profile of blood samples, White et al report multiple differences between obese pregnant women with gestational diabetes (GDM) and obese pregnant women without GDM, most of which are present at least 10 weeks prior to GDM diagnosis at the end of the second trimester. By identifying an insulin resistance signature in women with GDM, this study further fuels the debate about appropriate timing and modality of diagnosis of GDM, particularly in obese women.

Cover credit: Original drawing and overall image design by Sara Spizzichino (www.saraspizzichino.com), incorporating lipoproteins designed by Antti Kangas of Nightingale Health Ltd (www.nightingalehealth.com)

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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


Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it?
by Caroline M. Hull, Mark Peakman, Timothy I. M. Tree

Studies aiming to reduce or prevent T cell-mediated damage to pancreatic beta cells contribute to a major area of clinical trial activity in type 1 diabetes. Several of the strategies used are designed to increase immune regulation by targeting populations of regulatory T cells (Tregs). These strategies are, in part, based upon the principle that a defect in either the number or functional capacity of Tregs is highly germane to early pathogenic events and that correcting this may prevent or slow disease progression. In this issue, Hull et al (DOI 10.1007/s00125-017-4377-1) review the role Tregs play in the development of type 1 diabetes. They also discuss therapeutic strategies that may be harnessed to promote Treg function, including administration of low dose IL-2 and adoptive cell therapy with genetically enhanced Tregs. By correcting Treg defects, it is hoped that islet destruction may be prevented in a clinical setting. [Text supplied by the authors.]

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GLP-1/glucagon receptor co-agonism for treatment of obesity
by Miguel A. Sánchez-Garrido, Sara J. Brandt, Christoffer Clemmensen, Timo D. Müller, Richard D. DiMarchi, Matthias H. Tschöp

Obesity and its associated medical conditions impact millions of lives globally and current medications largely fail to restore full health. An emerging class of unimolecular, multifunctional peptides has demonstrated superior weight-loss and glucose-lowering efficacy compared with their mono-agonist constituents. In this issue, Sánchez-Garrido, Sara Brandt et al (DOI 10.1007/s00125-017-4354-8) review the historical context for the discovery of GLP-1/glucagon receptor co-agonists and the role they have played in pioneering the ongoing search for other multifunctional peptides. GLP-1/glucagon receptor co-agonists counterintuitively harness the catabolic and energy expenditure properties of glucagon in concert with the satiety-inducing and insulinotropic pharmacology of GLP-1 to achieve unprecedented improvements in body weight. Importantly, GLP-1 combats the hyperglycaemic liability of glucagon action to a point where improvements in glycaemic control are observed in multiple species, including obese monkeys, independent of weight loss. These multifunctional agonists represent a new pharmacological paradigm for treating metabolic disease, and multiple candidates are advancing in clinical studies. [Text supplied by the authors.]

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Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study
by Elina Isokuortti, You Zhou, Markku Peltonen, Elisabetta Bugianesi, Karine Clement, Dominique Bonnefont-Rousselot, Jean-Marc Lacorte, Amalia Gastaldelli, Detlef Schuppan, Jörn M. Schattenberg, Antti Hakkarainen, Nina Lundbom, Pekka Jousilahti, Satu Männistö, Sirkka Keinänen-Kiukaanniemi, Juha Saltevo, Quentin M. Anstee, Hannele Yki-Järvinen

Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) propose use of HOMA-IR (the product of fasting glucose and fasting insulin, divided by a constant) in the diagnosis of insulin resistance-associated NAFLD. There is, however, no agreement on a threshold defining insulin resistance using HOMA-IR. In this issue, Isokuortti et al (DOI 10.1007/s00125-017-4340-1) define the upper limits of normal HOMA-IR in healthy individuals in two large population-based cohorts, and analyse how HOMA-IR relates to accurately quantified liver fat content. The upper limits of HOMA-IR in the large cohorts were 1.9-2.0. A HOMA-IR of 2.0 corresponded to the upper limit of normal liver fat content of 5.56%. The inter-laboratory CV of HOMA-IR was high (25%) because of variation in insulin measurements. These data show that abnormal HOMA-IR closely corresponds to the threshold of NAFLD and may be a good surrogate for insulin resistance-related NAFLD. However, standardisation of insulin assays is first required to define normal values for HOMA-IR. [Text supplied by the authors.]

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Metabolic profiling of gestational diabetes in obese women during pregnancy
by Sara L. White, Dharmintra Pasupathy, Naveed Sattar, Scott M. Nelson, Debbie A. Lawlor, Annette L. Briley, Paul T. Seed, Paul Welsh, Lucilla Poston, on behalf of the UPBEAT Consortium

While obesity is a well-known risk factor for developing gestational diabetes mellitus (GDM), less than one-third of obese pregnant women are affected. However, the biochemical differences between obese women who do develop GDM and those who do not have not been previously explored. In this issue, White et al (DOI 10.1007/s00125-017-4380-6) used a targeted NMR metabolomic platform and conventional laboratory methods to compare metabolic profiles of obese pregnant women with or without GDM at approximately 17 gestational weeks and at the time of oral glucose tolerance testing (around 27 weeks' gestation). They observed differences in lipids and lipoprotein constituents, fatty acids, amino acids and other analytes, most of which were already evident 10 weeks prior to the diagnosis of GDM. The authors propose that this finding further fuels the debate about appropriate timing and modality of GDM diagnosis, particularly in obese women. [Text supplied by the authors.]

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The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study
by Ionut Bebu, Barbara H. Braffett, Rodica Pop-Busui, Trevor J. Orchard, David M. Nathan, John M. Lachin, the DCCT/EDIC Research Group

While chronic hyperglycaemia, as measured by HbA1c levels, has been shown in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) study to be a major risk factor for cardiovascular disease (CVD) in type 1 diabetes, the exact underlying mechanisms for this outcome and how it relates to traditional CVD risk factors remain unclear. In this issue, Bebu et al (DOI 10.1007/s00125-017-4374-4) describe how the effect of HbA1c on the risk of CVD is mediated through traditional risk factors (systolic BP, pulse rate, triacylglycerols and LDL-cholesterol) and how these mediation pathways change over time. The association of HbA1c with CVD outcomes was stable over time, while that of traditional risk factors increased. As participants aged, the predictive association of HbA1c on subsequent CVD events was increasingly mediated by its effect on standard risk factors. These findings reinforce the value of aggressive glycaemic management early in the course of diabetes, followed by aggressive management of other CVD risk factors as they become operant. [Text supplied by the authors.]

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Inside this issue

Up front

Up front October 2017

Reviews

Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it?
Caroline M. Hull, Mark Peakman, Timothy I. M. Tree

GLP-1/glucagon receptor co-agonism for treatment of obesity
Miguel A. Sánchez-Garrido, Sara J. Brandt, Christoffer Clemmensen, Timo D. Müller, Richard D. DiMarchi, Matthias H. Tschöp

Articles

Systematic Reviews/Meta-analyses

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials
Huilin Tang, Qi Dai, Weilong Shi, Suodi Zhai, Yiqing Song, Jiali Han

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Clinical Science and Care

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study
Elina Isokuortti, You Zhou, Markku Peltonen, Elisabetta Bugianesi, Karine Clement, Dominique Bonnefont-Rousselot, Jean-Marc Lacorte, Amalia Gastaldelli, Detlef Schuppan, Jörn M. Schattenberg, Antti Hakkarainen, Nina Lundbom, Pekka Jousilahti, Satu Männistö, Sirkka Keinänen-Kiukaanniemi, Juha Saltevo, Quentin M. Anstee, Hannele Yki-Järvinen

Toe–brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria
Emilie H. Zobel, Bernt Johan von Scholten, Henrik Reinhard, Frederik Persson, Tine W. Hansen, Hans-Henrik Parving, Peter K. Jacobsen, Peter Rossing

The advanced-DiaRem score improves prediction of diabetes remission 1 year post-Roux-en-Y gastric bypass
Judith Aron-Wisnewsky, Nataliya Sokolovska, Yuejun Liu, Doron S. Comaneshter, Shlomo Vinker, Tal Pecht, Christine Poitou, Jean-Michel Oppert, Jean-Luc Bouillot, Laurent Genser, Dror Dicker, Jean-Daniel Zucker, Assaf Rudich, Karine Clément

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Epidemiology

Metabolic profiling of gestational diabetes in obese women during pregnancy
Sara L. White, Dharmintra Pasupathy, Naveed Sattar, Scott M. Nelson, Debbie A. Lawlor, Annette L. Briley, Paul T. Seed, Paul Welsh, Lucilla Poston, on behalf of the UPBEAT Consortium

Epidemiology of gestational diabetes mellitus according to IADPSG/WHO 2013 criteria among obese pregnant women in Europe
Aoife M. Egan, Akke Vellinga, Jürgen Harreiter, David Simmons, Gernot Desoye, Rosa Corcoy, Juan M. Adelantado, Roland Devlieger, Andre Van Assche, Sander Galjaard, Peter Damm, Elisabeth R. Mathiesen, Dorte M. Jensen, Liselotte Andersen, Annuziata Lapolla, Maria G. Dalfrà, Alessandra Bertolotto, Urszula Mantaj, Ewa Wender-Ozegowska, Agnieszka Zawiejska, David Hill, Judith G. M. Jelsma, Frank J. Snoek, Christof Worda, Dagmar Bancher-Todesca, Mireille N. M. van Poppel, Alexandra Kautzky-Willer, Fidelma P. Dunne, on behalf of the DALI Core Investigator group

Serum adiponectin predicts fracture risk in individuals with type 2 diabetes: the Fukuoka Diabetes Registry
Yuji Komorita, Masanori Iwase, Hiroki Fujii, Toshiaki Ohkuma, Hitoshi Ide, Tamaki Jodai-Kitamura, Akiko Sumi, Masahito Yoshinari, Udai Nakamura, Dongchon Kang, Takanari Kitazono

Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study
Maria Lönnrot, Kristian F. Lynch, Helena Elding Larsson, Åke Lernmark, Marian J. Rewers, Carina Törn, Brant R. Burkhardt, Thomas Briese, William A. Hagopian, Jin-Xiong She, Olli G. Simell, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar, Jeffrey P. Krischer, Heikki Hyöty, on behalf of the TEDDY Study Group

Alcohol drinking patterns and risk of diabetes: a cohort study of 70,551 men and women from the general Danish population
Charlotte Holst, Ulrik Becker, Marit E. Jørgensen, Morten Grønbæk, Janne S. Tolstrup

Age at natural menopause and risk of type 2 diabetes: a prospective cohort study
Taulant Muka, Eralda Asllanaj, Naim Avazverdi, Loes Jaspers, Najada Stringa, Jelena Milic, Symen Ligthart, M. Arfan Ikram, Joop S. E. Laven, Maryam Kavousi, Abbas Dehghan, Oscar H. Franco

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Islet Studies

Transplantation sites for human and murine islets
Rebecca A. Stokes, Kim Cheng, Amit Lalwani, Michael M. Swarbrick, Helen E. Thomas, Thomas Loudovaris, Tom W. Kay, Wayne J. Hawthorne, Philip J. O’Connell, Jenny E. Gunton

Transplantation sites for porcine islets
Short Communication
Rebecca A. Stokes, Denbigh M. Simond, Heather Burns, Anita T. Patel, Philip J. O’Connell, Jenny E. Gunton, Wayne J. Hawthorne

PIWI-interacting RNAs as novel regulators of pancreatic beta cell function
Imène Sarah Henaoui, Cécile Jacovetti, Inês Guerra Mollet, Claudiane Guay, Jonathan Sobel, Lena Eliasson, Romano Regazzi

Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation
Miljan Kuljanin, Gillian I. Bell, Stephen E. Sherman, Gilles A. Lajoie, David A. Hess

ERK1 is dispensable for mouse pancreatic beta cell function but is necessary for glucose-induced full activation of MSK1 and CREB
Michele Leduc, Joy Richard, Safia Costes, Dany Muller, Annie Varrault, Vincent Compan, Julia Mathieu, Jean-François Tanti, Gilles Pagès, Jacques Pouyssegur, Gyslaine Bertrand, Stéphane Dalle, Magalie A. Ravier

MicroRNAs modulate core-clock gene expression in pancreatic islets during early postnatal life in rats
Cécile Jacovetti, Adriana Rodriguez-Trejo, Claudiane Guay, Jonathan Sobel, Sonia Gattesco, Volodymyr Petrenko, Camille Saini, Charna Dibner, Romano Regazzi

IKKβ inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents
Aleksandar Ivovic, Andrei I. Oprescu, Khajag Koulajian, Yusaku Mori, Judith A. Eversley, Liling Zhang, Rodolfo Nino-Fong, Gary F. Lewis, Marc Y. Donath, Michael Karin, Michael B. Wheeler, Jan Ehses, Allen Volchuk, Catherine B. Chan, Adria Giacca

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Immunology and Transplantation

Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice
Tine D. Hannibal, Anja Schmidt-Christensen, Julia Nilsson, Nina Fransén-Pettersson, Lisbeth Hansen, Dan Holmberg

Metabolism

Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes
Rikke Kruse, Sara G. Vienberg, Birgitte F. Vind, Birgitte Andersen, Kurt Højlund

Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance
Laura Formentini, Alexander J. Ryan, Manuel Gálvez-Santisteban, Leslie Carter, Pam Taub, John D. Lapek Jr., David J. Gonzalez, Francisco Villarreal, Theodore P. Ciaraldi, José M. Cuezva, Robert R. Henry

Why is it so difficult to measure glucagon-like peptide-1 in a mouse?
Johanne A. Windeløv, Nicolai J. Wewer Albrechtsen, Rune E. Kuhre, Sara L. Jepsen, Daniel Hornburg, Jens Pedersen, Elisa P. Jensen, Katrine D. Galsgaard, Marie Winther-Sørensen, Anne Ørgaard, Carolyn F. Deacon, Matthias Mann, Hannelouise Kissow, Bolette Hartmann, Jens J. Holst

Chronic administration of myristic acid improves hyperglycaemia in the Nagoya–Shibata–Yasuda mouse model of congenital type 2 diabetes
Tamae Takato, Kai Iwata, Chiaki Murakami, Yuko Wada, Fumio Sakane

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Pathophysiology and Complications

The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study
Ionut Bebu, Barbara H. Braffett, Rodica Pop-Busui, Trevor J. Orchard, David M. Nathan, John M. Lachin, the DCCT/EDIC Research Group

The association of depressive symptoms and diabetes distress with glycaemic control and diabetes complications over 2 years in newly diagnosed type 2 diabetes: a prospective cohort study
Khalida Ismail, Calum D. Moulton, Kirsty Winkley, John C. Pickup, Stephen M. Thomas, Roy A. Sherwood, Daniel Stahl, Stephanie A. Amiel

Innovative technology shows impact of glycaemic control on peripheral retinal vessels in adolescents with type 1 diabetes
Valli Velayutham, Paul Z. Benitez-Aguirre, Maria E. Craig, Gerald Liew, Tien Y. Wong, Alicia J. Jenkins, Kim C. Donaghue

Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes
Deoye Tonade, Haitao Liu, Krzysztof Palczewski, Timothy S. Kern

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Letters

Normoalbuminuric chronic kidney disease in type 1 diabetes: is it real and is it serious?
Vincent Rigalleau, Laurence Blanco, Laure Alexandre, Emilie Pupier, Catherine Lasseur, Nicole Barthe, Christian Combe

Normoalbuminuric chronic kidney disease in type 1 diabetes: is it real and is it serious? Reply to Rigalleau V, Blanco L, Alexandre L et al [letter]
Giuseppe Penno, Eleonora Russo, Monia Garofolo, Giuseppe Daniele, Daniela Lucchesi, Laura Giusti, Veronica Sancho Bornez, Cristina Bianchi, Angela Dardano, Roberto Miccoli, Stefano Del Prato

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