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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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In the News

Intensified and multifaceted treatment of patients with type 2 diabetes and known vascular damage extends life by around 8 years

Read this new research by Dr Peter Gaede and Dr Jens Oellgaard (Slagelse Hospital and University of Southern Denmark, Odense, Denmark) and colleagues.
For further information please contact Professor Pedersen (oluf@sund.ku.dk), Richard Steed (richard.steed@sund.ku.dk) or Andreas Westergaard (andreas.westergaard@sund.ku.dk).

Current issue: October 2016

October 2016 cover

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The cover picture shows an immunofluorescence micrograph of human pancreatic islet cells stained for insulin (green) and the two receptors for the TNF superfamily member LIGHT; lymphotoxin β receptor (LTβR; purple) and herpes virus entry mediator, HVEM (red). The lightning symbolises an inflammatory microenvironment. In the present issue of Diabetologia Halvorsen et al report that patients with type 2 diabetes have increased plasma LIGHT levels and suggest that LIGHT could be part of a pathogenic loop, promoting the progression of type 2 diabetes mellitus by impairing insulin secretion by islet cells and contributing to vascular inflammation.


Cover credit: The image was created by S. Abadpour and H. Scholz, Oslo University Hospital, Oslo, Norway

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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 quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds
by James D. Johnson

The promise of stem cell therapy for diabetes is exciting. The theoretical possibility of producing unlimited cells that could, once transplanted into a patient, respond immediately and physiologically to nutrients in a manner superior to any machine has driven intense research and development over the past 15 years. Recently, stem cell differentiation protocols have advanced to generate pancreatic islet beta-like cells that respond to glucose in vitro, although not yet in a manner similar to healthy beta cells. In this issue, James Johnson reviews progress in this field from the perspective of an islet biologist. Based on available evidence, he concludes that the field is yet to produce bona fide beta cells. The author urges researchers to raise the bar and employ more sensitive, robust and standardised assays to evaluate stem cell derived beta-like cells and to better understand the target of these cell engineering efforts, the healthy human beta cell. [Text supplied by the authors.]

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Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation
by Thomas O. Mundinger, Gerald J. Taborsky Jr

In type 1 diabetes, impairment of the glucagon response to hypoglycaemia is coupled with normal responses to other stimuli, suggesting a defect that is restricted to mechanisms specifically activated by hypoglycaemia. Alongside loss of pancreatic islet beta cells, a defect in the autonomic pathway that stimulates the alpha cell contributes to impaired glucagon responses. In this issue, Mundinger and Taborsky review research showing an early and marked loss of islet sympathetic nerves in animal models of autoimmune diabetes, which results in impaired glucagon responses to sympathetic activation. Importantly, they also summarise very recent work demonstrating a similar nerve loss in humans with type 1 diabetes, contrasted with retention of these nerves in patients with type 2 diabetes. These data suggest that a sympathetic defect within the islet may contribute to the impairment of the glucagon response to hypoglycaemia that is seen early in human type 1 diabetes, but not in type 2 diabetes. [Text supplied by the authors.]

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Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013
by Stephanie H. Read, Joannes J. Kerssens, David A. McAllister, Helen M. Colhoun, Colin M. Fischbacher, Robert S. Lindsay, Rory J. McCrimmon, John A. McKnight, John R. Petrie, Naveed Sattar, Sarah H. Wild, on behalf of the Scottish Diabetes Research Network Epidemiology Group

In recent decades, type 2 diabetes prevalence has increased considerably in Scotland. The extent to which this increase was related to increasing incidence or reduced mortality of patients was unknown. In this issue, Read et al report trends in type 2 diabetes incidence and mortality between 2004 and 2013 using data from the Scottish national diabetes register. The authors found that type 2 diabetes incidence remained stable during the study period, potentially reflecting a smaller pool of people with undiagnosed diabetes in the population or stable obesity prevalence rates in recent years. Trends in incidence rates varied by age and socioeconomic status, with incidence rates remaining stable or increasing in younger people, declining in older people and, after 2008, increasing in the most deprived groups. Over time, mortality rates declined but the excess risk of mortality in people with type 2 diabetes was 49% in women and 38% in men, compared with the non-diabetic population. It was concluded that the incidence of type 2 diabetes stabilised in recent years and, thus, declining mortality is likely to be responsible for the increase in prevalence. Nonetheless, prevention of type 2 diabetes remains important, specifically in socioeconomically deprived individuals. [Text supplied by the authors.]

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Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets
by Alice E. Adriaenssens, Berit Svendsen, Brian Y. H. Lam, Giles S. H. Yeo, Jens J. Holst, Frank Reimann, Fiona M. Gribble

Hormonal crosstalk between the gut and pancreatic islets plays a major role in regulating postprandial insulin secretion, but the factors regulating islet secretion in the fasting state are less well established. In this issue Adriaenssens, Svendsen, Lam et al employ an RNA sequencing approach to quantify genes expressed in purified murine alpha, beta and delta cells, identifying pancreatic cell-specific G-protein coupled receptors and signalling pathways. Examination of the delta cell transcriptome revealed high cell-selective expression of the ghrelin receptor, suggesting a previously unrealised role of ghrelin in the control of somatostatin secretion. By single delta cell imaging and hormonal measurements in perfused pancreases, the authors demonstrate that ghrelin suppresses insulin secretion via paracrine inhibition of beta cells by somatostatin. The transcriptomic profiles provide a molecular basis for understanding how islets are regulated by local and circulating signals and highlight the importance of gut-islet and intra-islet crosstalk in the regulation of glucose homeostasis. [Text supplied by the authors.]

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Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants
by Hong-wa Yung, Patji Alnæs-Katjavivi, Carolyn J. P. Jones, Tatiana El-Bacha, Michaela Golic, Anne-Cathrine Staff, Graham J. Burton

Gestational diabetes (GDM) is associated with an increased risk of complications of pregnancy, including pregnancy-induced hypertension, pre-eclampsia, stillbirth and fetal growth anomalies. Its incidence currently approaches 18% of all pregnancies. In this issue, Yung et al report evidence of endoplasmic reticulum (ER) stress in the trophoblast layer of the placenta. The trophoblast has a high metabolic rate because of its extensive endocrine activity and active transport functions, which are critical for normal fetal development. In response to this, the trophoblast produces lactate even under aerobic conditions. Culturing trophoblast cells in high glucose concentrations induced stress (similar to that observed in vivo), which was caused by acidification of the medium because of excessive lactate accumulation. The addition of vitamins C and E reduced acidification and prevented generation of ER stress, suggesting that these agents may have therapeutic benefits in GDM pregnancies, promoting placental health and, hence, fetal wellbeing. This article is the subject of a commentary in this issue by Alicia Jawerbaum. [Text supplied by the authors.]

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Inside this issue

Up front

Up front October 2016

Reviews

The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds
James D. Johnson

Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation
Thomas O. Mundinger, Gerald J. Taborsky Jr

Effects of exercise training on intrahepatic lipid content in humans
Bram Brouwers, Matthijs K. C. Hesselink, Patrick Schrauwen, Vera B. Schrauwen-Hinderling

Commentary

Placental endoplasmic reticulum stress and acidosis: relevant aspects in gestational diabetes
Alicia Jawerbaum

Articles

Clinical Science and Care

Risk of death following admission to a UK hospital with diabetic ketoacidosis
Fraser W. Gibb, Wei Leng Teoh, Joanne Graham, K. Ann Lockman

Effects of exercise training alone vs a combined exercise and nutritional lifestyle intervention on glucose homeostasis in prediabetic individuals: a randomised controlled trial
Cris A. Slentz, Lori A. Bateman, Leslie H. Willis, Esther O. Granville, Lucy W. Piner, Gregory P. Samsa, Tracy L. Setji, Michael J. Muehlbauer, Kim M. Huffman, Connie W. Bales, William E. Kraus

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Epidemiology

Maternal overweight and obesity and risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes
Martina Persson, Sven Cnattingius, Anna-Karin Wikström, Stefan Johansson

Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013
Stephanie H. Read, Joannes J. Kerssens, David A. McAllister, Helen M. Colhoun, Colin M. Fischbacher, Robert S. Lindsay, Rory J. McCrimmon, John A. McKnight, John R. Petrie, Naveed Sattar, Sarah H. Wild, On behalf of the Scottish Diabetes Research Network Epidemiology Group

Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes
Tove Fall, Samira Salihovic, Stefan Brandmaier, Christoph Nowak, Andrea Ganna, Stefan Gustafsson, Corey D. Broeckling, Jessica E. Prenni, Gabi Kastenmüller, Annette Peters, Patrik K. Magnusson, Rui Wang-Sattler, Vilmantas Giedraitis, Christian Berne, Christian Gieger, Nancy L. Pedersen, Erik Ingelsson, Lars Lind

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Islet Studies

Sensitivity profile of the human EndoC-βH1 beta cell line to proinflammatory cytokines
Ewa Gurgul-Convey, Ilir Mehmeti, Thomas Plötz, Anne Jörns, Sigurd Lenzen

LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro
Bente Halvorsen, Francesca Santilli, Hanne Scholz, Afaf Sahraoui, Hanne L. Gulseth, Cecilie Wium, Stefano Lattanzio, Gloria Formoso, Patrizia Di Fulvio, Kari Otterdal, Kjetil Retterstøl, Kirsten B. Holven, Ida Gregersen, Benedicte Stavik, Vigdis Bjerkeli, Annika E. Michelsen, Thor Ueland, Rossella Liani, Giovanni Davi, Pål Aukrust

The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets
Miwon Ahn, Stephanie M. Yoder, Zhanxiang Wang, Eunjin Oh, Latha Ramalingam, Ragadeepthi Tunduguru, Debbie C. Thurmond

Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets
Alice E. Adriaenssens, Berit Svendsen, Brian Y. H. Lam, Giles S. H. Yeo, Jens J. Holst, Frank Reimann, Fiona M. Gribble

The S20G substitution in hIAPP is more amyloidogenic and cytotoxic than wild-type hIAPP in mouse islets
Daniel T. Meier, Leon Entrup, Andrew T. Templin, Meghan F. Hogan, Mahnaz Mellati, Sakeneh Zraika, Rebecca L. Hull, Steven E. Kahn

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Immunology and Transplantation

A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children
David Endesfelder, Michael Hagen, Christiane Winkler, Florian Haupt, Stephanie Zillmer, Annette Knopff, Ezio Bonifacio, Anette-G. Ziegler, Wolfgang zu Castell, Peter Achenbach

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Metabolism

Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: a randomised controlled trial
Helen Vlassara, Weijing Cai, Elizabeth Tripp, Renata Pyzik, Kalle Yee, Laurie Goldberg, Laurie Tansman, Xue Chen, Venkatesh Mani, Zahi A. Fayad, Girish N. Nadkarni, Gary E. Striker, John C. He, Jaime Uribarri

Lactation is associated with altered metabolomic signatures in women with gestational diabetes
Daniela Much, Andreas Beyerlein, Alida Kindt, Jan Krumsiek, Ferdinand Stückler, Michaela Rossbauer, Anna Hofelich, David Wiesenäcker, Susanne Hivner, Melanie Herbst, Werner Römisch-Margl, Cornelia Prehn, Jerzy Adamski, Gabi Kastenmüller, Fabian Theis, Anette-G. Ziegler, Sandra Hummel

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes
Short Communication
Maria Apostolopoulou, Klaus Strassburger, Christian Herder, Birgit Knebel, Jörg Kotzka, Julia Szendroedi, Michael Roden, for the GDS group

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans
Aleix Gavaldà-Navarro, José M. Moreno-Navarrete, Tania Quesada-López, Montserrat Cairó, Marta Giralt, José M. Fernández-Real, Francesc Villarroya

Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages
Lei Zhang, Yi-Jing Han, Xian Zhang, Xin Wang, Bin Bao, Wei Qu, Jian Liu

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice
Ying Cui, Aijun Qiao, Tao Jiao, Huabing Zhang, Yuan Xue, Yongkang Zou, Anfang Cui, Fude Fang, Yongsheng Chang

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Pathophysiology and Complications

Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants
Hong-wa Yung, Patji Alnæs-Katjavivi, Carolyn J. P. Jones, Tatiana El-Bacha, Michaela Golic, Anne-Cathrine Staff, Graham J. Burton

Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy
Dongxu Fu, Jeremy Y. Yu, Shihe Yang, Mingyuan Wu, Samar M. Hammad, Anna R. Connell, Mei Du, Junping Chen, Timothy J. Lyons

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Research Letter

South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people
Shivani Misra, Beverley Shields, Kevin Colclough, Desmond G Johnston, Nick S Oliver, Sian Ellard, Andrew T Hattersley

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