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Welcome to Diabetologia

Diabetologia publishes original clinical, translational and experimental research within the field of diabetes. We are interested in papers that convey new information or insight into any aspect of the condition, ranging from basic science to clinical applications. These are judged in terms of their scientific quality, novelty, relevance and interest to our broadly based readership.

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Precision Medicine Series

In the News

Study suggests omega-3 in mothers' diets may lower children's risk of type 1 diabetes

Read this new research by Dr Sari Niinistö at the National Institute of Health and Welfare, Helsinki, Finland and colleagues.
For further information contact Dr Niinistö (sari.niinisto@thl.fi).

Overweight/obese people with type 2 diabetes are at increased risk of abnormal brain structure and cognitive problems

Read this new research by Dr Sunjung Yoon and Dr In Kyoon Lyoo (Ewha Brain Institute, Ewha Womans University, Seoul, South Korea), Hanbyul Cho (The Brain Institute, University of Utah, Salt Lake City, UT, USA), and colleagues in Korea and the USA.
For further information contact Dr Lyoo (inkylyoo@gmail.com).

Current issue: June 2017

June 2017 cover

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Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases, but also from its inert metabolites, nitrite and nitrate. The cover shows coronary perivascular fibrosis (in blue) in a wild-type mouse that died suddenly in the course of a low nitrite/nitrate diet (Masson's trichrome staining). In the present issue of Diabetologia Kina-Tanada et al report that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and eventually cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications. The authors may have succeeded, for the first time, in identifying specific dietary ingredients that cause the metabolic syndrome even in the absence of excessive energy intake.


Cover credit: Masato Tsutsui, Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan


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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 five 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


The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities
by Louise Brunkwall, Marju Orho-Melander

The modifiable capacity of the gut microbiota is increasingly recognised as a promising target for improvements in glycaemic control and the treatment of type 2 diabetes. In this issue, Brunkwall and Orho-Melander (DOI 10.1007/s00125-017-4278-3) review the current human evidence and future possibilities and challenges of using the gut microbiota in the development of preventive and treatment strategies for type 2 diabetes. Several potential gut-targeting glucose-lowering therapies have emerged and show initial promise, but a better understanding of their mechanisms of action in humans is required. So far, human gut microbiota studies have been limited in size and large longitudinal and interventional studies are required. Amongst the great challenges for the future are the personalisation of nutrition to allow for individual dietary advice (taking into account the gut microbiota, genetics, drug use and other relevant environmental factors) and the integration of multi-omic human and microbiota data in large, longitudinal cohorts. For now, however, the potential for gut microbiota in the prevention and management of diabetes remains a hype, but a hype with plenty of hope. [Text supplied by the authors.]

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The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes
by Meghan F. Hogan, Rebecca L. Hull

The role of the islet endothelial cell in regulating islet beta cell growth and function under physiological conditions is now well established. An emerging literature demonstrates that islet microvascular abnormalities occur in type 2 diabetes and may contribute to the impaired beta cell function and survival that characterise this disease. In this issue, Hogan and Hull (DOI 10.1007/s00125-017-4272-9) review the current literature in this area. They review studies describing a number of endothelial-derived factors that stimulate beta cell growth, insulin production and release. Then, data showing abnormal islet capillary morphology in human type 2 diabetes are summarised and some important differences between humans and animal models are noted. Mechanisms underlying the induction of islet endothelial dysfunction in diabetes, their functional impact and potential therapeutic strategies are also discussed. Finally, caution is urged in extrapolating the beneficial effects of targeting the expansion of islet vasculature under normal conditions to metabolic disease. [Text supplied by the authors.]

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Human genetics as a model for target validation: finding new therapies for diabetes
by Soren K. Thomsen, Anna L. Gloyn

Conventional preclinical models have limited ability to predict safety and efficacy profiles of new treatments in humans. As a result, the vast majority of drug candidates fail to progress from clinical trials, driving the escalating costs of pharmaceutical research and development programmes. In this issue, Thomsen and Gloyn (DOI 10.1007/s00125-017-4270-y) review the role of human genetics as a complementary model for drug target validation. Naturally occurring genetic perturbations provide a window into causal human biology that can be used to predict both beneficial and adverse effects of drugs. The authors demonstrate how genetic discoveries over the past decades have confirmed drug mechanisms for existing type 2 diabetes treatments, including sulfonylureas, thiazolidinediones, glucokinase activators and sodium-glucose cotransporter 2 (SGLT2) inhibitors. To apply this strategy prospectively, experimental advances will be required to accelerate the translation of genetic findings into molecular mechanisms. Recent developments have provided promising solutions, paving the way for the future discovery of new diabetes therapies. [Text supplied by the authors.]

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Cognitive deficits associated with impaired awareness of hypoglycaemia in type 1 diabetes
by Tor I. Hansen, Sandra E. Olsen, Elise C. D. Haferstrom, Trond Sand, Brian M. Frier, Asta K. Håberg, Marit R. Bjørgaas

An association between impaired awareness of hypoglycaemia (IAH) and cognitive deficiency has previously been suggested but the putative role of impaired cognitive function in recurrent severe hypoglycaemia is unclear. In this issue, Hansen and colleagues (DOI 10.1007/s00125-017-4233-3) compare cognitive function in people with type 1 diabetes and established IAH with those in whom hypoglycaemia awareness is intact. They report that people with IAH had significant impairments in learning, memory and pattern separation, all of which rely on the integrity of the hippocampus. Participants followed standardised aural and written instructions and the frequency of severe hypoglycaemia correlated with the number of tests that had not been performed according to these instructions. The authors suggest that adults with IAH may have a reduced cognitive reserve, which may contribute to their increased risk of developing severe hypoglycaemia. Furthermore, the present results support a role for recurrent severe hypoglycaemia in the pathogenesis of IAH. These observations underline the value of including cognitive tests in intervention programmes to evaluate whether impaired cognitive ability may affect adherence to treatment and outcomes in type 1 diabetes. [Text supplied by the authors.]

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Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia Cohort Consortium
by Yu Chen, Fen Wu, Eiko Saito, Yingsong Lin, Minkyo Song, Hung N. Luu, Prakash C. Gupta, Norie Sawada, Akiko Tamakoshi, Xiao-Ou Shu, Woon-Puay Koh, Yong-Bing Xiang, Yasutake Tomata, Kemmyo Sugiyama, Sue K. Park, Keitaro Matsuo, Chisato Nagata, Yumi Sugawara, You-Lin Qiao, San-Lin You, Renwei Wang, Myung-Hee Shin, Wen-Harn Pan, Mangesh S. Pednekar, Shoichiro Tsugane, Hui Cai, Jian-Min Yuan, Yu-Tang Gao, Ichiro Tsuji, Seiki Kanemura, Hidemi Ito, Keiko Wada, Yoon-Ok Ahn, Keun-Young Yoo, Habibul Ahsan, Kee Seng Chia, Paolo Boffetta, Wei Zheng, Manami Inoue, Daehee Kang, John D. Potter

Emerging evidence is suggestive of a link between type 2 diabetes and an increased risk of developing cancer and death from cancer. However, the majority of studies in this area have been conducted in Western populations. In this issue, Chen et al (DOI 10.1007/s00125-017-4229-z) report whether Asian individuals with type 2 diabetes were more likely to die from cancer, using data from 771,000 individuals from the Asia Cohort Consortium. The authors found that having type 2 diabetes led to a 26% increase in the risk of dying from any form of cancer in Asians. More specifically, type 2 diabetes was related to the risk of death from cancers of the colorectum, liver, bile duct, gallbladder, pancreas, breast, endometrium, ovary, prostate, kidney and thyroid, and lymphoma. The strongest associations were observed for cancers of the liver, thyroid and kidney (approximately double the risk in each case), endometrium (2.7 times increased risk) and breast (1.7 times increased risk). These data suggest that the influence of type 2 diabetes on the risk of death from cancer is largely similar in Asian individuals and those from developed Western countries and that type 2 diabetes should be considered a risk factor for cancers in Asians. The authors conclude that the pattern of associations between type 2 diabetes and specific cancers (particularly liver cancer, which has a high incidence in Asian individuals) suggests the need for better control of the growing epidemic of diabetes in order to reduce cancer mortality rates. [Text supplied by the authors.]

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Inside this issue

Up front

Up front June 2017

Reviews

The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities
Louise Brunkwall, Marju Orho-Melander

The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes
Meghan F. Hogan, Rebecca L. Hull

Human genetics as a model for target validation: finding new therapies for diabetes
Soren K. Thomsen, Anna L. Gloyn

Articles

Clinical Science and Care

Cognitive deficits associated with impaired awareness of hypoglycaemia in type 1 diabetes
Tor I. Hansen, Sandra E. Olsen, Elise C. D. Haferstrom, Trond Sand, Brian M. Frier, Asta K. Håberg, Marit R. Bjørgaas

Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study
The Look AHEAD Research Group

Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes
Kirsten A. Berk, Reyhana Yahya, Adrie J. M. Verhoeven, Jeanette Touw, Frank P. Leijten, Elisabeth F. van Rossum, Vincent L. Wester, Mirjam A. Lips, Hanno Pijl, Reinier Timman, Gertraud Erhart, Florian Kronenberg, Jeanine E. Roeters van Lennep, Eric J. G. Sijbrands, Monique T. Mulder

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Epidemiology

Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY)
Brigitte I. Frohnert, Lisa Ide, Fran Dong, Anna E. Barón, Andrea K. Steck, Jill M. Norris, Marian J. Rewers

Predicting hospital stay, mortality and readmission in people admitted for hypoglycaemia: prognostic models derivation and validation
Francesco Zaccardi, David R. Webb, Melanie J. Davies, Nafeesa N. Dhalwani, Laura J. Gray, Sudesna Chatterjee, Gemma Housley, Dominick Shaw, James W. Hatton, Kamlesh Khunti

Does training of general practitioners for intensive treatment of people with screen-detected diabetes have a spillover effect on mortality and cardiovascular morbidity in ‘at risk’ individuals with normoglycaemia? Results from the ADDITION-Denmark cluster-randomised controlled trial
Short Communication
Rebecca K. Simmons, Niels H. Bruun, Daniel R. Witte, Knut Borch-Johnsen, Marit E. Jørgensen, Annelli Sandbæk, Torsten Lauritzen

Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia Cohort Consortium
Yu Chen, Fen Wu, Eiko Saito, Yingsong Lin, Minkyo Song, Hung N. Luu, Prakash C. Gupta, Norie Sawada, Akiko Tamakoshi, Xiao-Ou Shu, Woon-Puay Koh, Yong-Bing Xiang, Yasutake Tomata, Kemmyo Sugiyama, Sue K. Park, Keitaro Matsuo, Chisato Nagata, Yumi Sugawara, You-Lin Qiao, San-Lin You, Renwei Wang, Myung-Hee Shin, Wen-Harn Pan, Mangesh S. Pednekar, Shoichiro Tsugane, Hui Cai, Jian-Min Yuan, Yu-Tang Gao, Ichiro Tsuji, Seiki Kanemura, Hidemi Ito, Keiko Wada, Yoon-Ok Ahn, Keun-Young Yoo, Habibul Ahsan, Kee Seng Chia, Paolo Boffetta, Wei Zheng, Manami Inoue, Daehee Kang, John D. Potter

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Islet Studies

Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes
Allen L. Feng, Yun-Yan Xiang, Le Gui, Gesthika Kaltsidis, Qingping Feng, Wei-Yang Lu

Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice
Gabriela da Silva Xavier, Angeles Mondragon, Vishnou Mourougavelou, Céline Cruciani-Guglielmacci, Jessica Denom, Pedro Luis Herrera, Christophe Magnan, Guy A. Rutter

Conditional islet hypovascularisation does not preclude beta cell expansion during pregnancy in mice
Short Communication
Willem Staels, Yves Heremans, Gunter Leuckx, Naomi Van Gassen, Ciro Salinno, Sofie De Groef, Martine Cools, Eli Keshet, Yuval Dor, Harry Heimberg, Nico De Leu

MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells
Emily K. Sims, Alexander J. Lakhter, Emily Anderson-Baucum, Tatsuyoshi Kono, Xin Tong, Carmella Evans-Molina

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Metabolism

Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans
Mahesha H. Gangadhariah, Blake W. Dieckmann, Louise Lantier, Li Kang, David H. Wasserman, Manuel Chiusa, Charles F. Caskey, Jaime Dickerson, Pengcheng Luo, Jorge L. Gamboa, Jorge H. Capdevila, John D. Imig, Chang Yu, Ambra Pozzi, James M. Luther

Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice
Iliana López-Soldado, Rebeca Fuentes-Romero, Jordi Duran, Joan J. Guinovart

Ginsenoside Rg5 attenuates hepatic glucagon response via suppression of succinate-associated HIF-1α induction in HFD-fed mice
Na Xiao, Meng-Die Lou, Yi-Tong Lu, Le-Le Yang, Qun Liu, Baolin Liu, Lian-Wen Qi, Ping Li

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Pathophysiology and Complications

Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study
Shazli Azmi, Maryam Ferdousi, Uazman Alam, Ioannis N. Petropoulos, Georgios Ponirakis, Andrew Marshall, Omar Asghar, Hassan Fadavi, Wendy Jones, Mitra Tavakoli, Andrew J. M. Boulton, Maria Jeziorska, Handrean Soran, Nathan Efron, Rayaz A. Malik

Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus
Giuseppe Penno, Eleonora Russo, Monia Garofolo, Giuseppe Daniele, Daniela Lucchesi, Laura Giusti, Veronica Sancho Bornez, Cristina Bianchi, Angela Dardano, Roberto Miccoli, Stefano Del Prato

MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy
Cristina Zanchi, Daniela Macconi, Piera Trionfini, Susanna Tomasoni, Daniela Rottoli, Monica Locatelli, Michael Rudnicki, Jo Vandesompele, Pieter Mestdagh, Giuseppe Remuzzi, Ariela Benigni, Carlamaria Zoja

CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats
Zhen-Guo Ma, Yu-Pei Yuan, Si-Chi Xu, Wen-Ying Wei, Chun-Ru Xu, Xin Zhang, Qing-Qing Wu, Hai-Han Liao, Jian Ni, Qi-Zhu Tang

Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice
Mika Kina-Tanada, Mayuko Sakanashi, Akihide Tanimoto, Tadashi Kaname, Toshihiro Matsuzaki, Katsuhiko Noguchi, Taro Uchida, Junko Nakasone, Chisayo Kozuka, Masayoshi Ishida, Haruaki Kubota, Yuji Taira, Yuichi Totsuka, Shin-ichiro Kina, Hajime Sunakawa, Junichi Omura, Kimio Satoh, Hiroaki Shimokawa, Nobuyuki Yanagihara, Shiro Maeda, Yusuke Ohya, Masayuki Matsushita, Hiroaki Masuzaki, Akira Arasaki, Masato Tsutsui

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Research Letter

INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters
Elisabeth Kemter, Christian M. Cohrs, Matthias Schäfer, Marion Schuster, Klaus Steinmeyer, Lelia Wolf-van Buerck, Andrea Wolf, Annegret Wuensch, Mayuko Kurome, Barbara Kessler, Valeri Zakhartchenko, Matthias Loehn, Yuri Ivashchenko, Jochen Seissler, Anke M. Schulte, Stephan Speier, Eckhard Wolf

Letter

The Berlin Declaration: building upon St Vincent
Anne-Marie Felton, Sanjay Kalra


Erratum

Erratum to: Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration
Marko Škrtic, Gary K. Yang, Bruce A. Perkins, Nima Soleymanlou, Yuliya Lytvyn, Maximilian von Eynatten, Hans J. Woerle, Odd Erik Johansen, Uli C. Broedl, Thomas Hach, Melvin Silverman, David Z. I. Cherney

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