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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.

Inside this issue Up front
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In the News

Interrupting sitting time improves blood sugar control in people with type 2 diabetes

Read this new research by Bernard Duvivier of the Department of Human Biology and Movement Science and NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, and colleagues.
For further information contact Bernard Duvivier (bernard.duvivier@maastrichtuniversity.nl) or Hans Savelberg (hans.savelberg@maastrichtuniversity.nl).

Current issue: January 2017

January 2017 cover

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The cover shows a computer illustration of amyloid plaques amongst neurons. Amyloid plaques are characteristic features of Alzheimer's disease and lead to degeneration of the affected neurons, which are destroyed through the activity of microglia. The neurons are embedded in a network of astrocytes. In the present issue of Diabetologia Davis et al investigated late-onset dementia in a type 2 diabetic cohort with matched controls. They found that the risk of dementia was attenuated when premature mortality was taken into account and suggest that the association between type 2 diabetes and dementia may be weaker than generally considered.


Cover credit: JUAN GAERTNER/SCIENCE PHOTO LIBRARY


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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


High-intensity interval training: a review of its impact on glucose control and cardiometabolic health
by Sophie Cassidy, Christian Thoma, David Houghton, Michael I. Trenell

High-intensity intermittent training (HIIT) has gained much attention over the past decade because of its ability to induce a large physiological response with reduced time commitment, compared with other forms of exercise training. For this reason, the use of HIIT is increasing among clinical populations. In this issue, Cassidy et al aim to explore whether the acclaim surrounding HIIT is justified, by reviewing the current evidence for its impact on glucose control and cardiovascular health. They also report its safety, tolerability and the practical considerations required when adopting this form of exercise in a clinical setting. They conclude that, for the optimal clinical benefit (including improved glycaemic control and cardiovascular function) the value of HIIT appears likely to be adjunct to energy restriction. [Text supplied by the authors.]

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Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes
by Morten A. Karsdal, Kim Henriksen, Federica Genovese, Diana J. Leeming, Mette J. Nielsen, Bente J. Riis, Claus Christiansen, Inger Byrjalsen, Detlef Schuppan

The extracellular matrix (ECM) is emerging to be more than just a passive scaffold: collagens are key structural components of the ECM, and during collagen degradation and processing, anti-angiogenic and anti-migratory cryptic fragments are released. The pro-peptide of type VI collagen is proteolytically spliced from the helical core during collagen maturation, with further cleavage of the pro-peptide resulting in endotrophin generation. Endotrophin has hormonal activities that are associated with insulin resistance and the metabolic syndrome. In this issue, Karsdal et al report that baseline endotrophin levels predicted the HbA1c- and glucose-lowering response to two insulin sensitisers (peroxisome proliferator-activated receptor gamma (PPARγ) agonists, balaglitazone and pioglitazone) in a phase III, type 2 diabetes study. Patients who had higher endotrophin levels, and thus responded better to these drugs, also had less severe side effects. These data indicate a need for a precision medicine approach to diabetes treatment and suggest that only a selected patient population may have a superior response with less adverse effects to PPARγ agonism. This article is the subject of a commentary in this issue by Sun et al. [Text supplied by the authors.]

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Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals
by Chloe Y. Y. Cheung, Clara S. Tang, Aimin Xu, Chi-Ho Lee, Ka-Wing Au, Lin Xu, Carol H. Y. Fong, Kelvin H. M. Kwok, Wing-Sun Chow, Yu-Cho Woo, Michele M. A. Yuen, JoJo S. H. Hai, Ya-Li Jin, Bernard M. Y. Cheung, Kathryn C. B. Tan, Stacey S. Cherny, Feng Zhu, Tong Zhu, G. Neil Thomas, Kar-Keung Cheng, Chao-Qiang Jiang, Tai-Hing Lam, Hung-Fat Tse, Pak-Chung Sham, Karen S. L. Lam

Conventional genome-wide association studies (GWAS) have identified a large number of common type 2 diabetes susceptibility variants that are predominately located at the intronic and intergenic regions. However, the functional consequences of such variants remain difficult to interpret. In this issue, Cheung, Tang et al conducted an exome-chip association analysis with a custom designed exome array, the Asian Exomechip. They report an association between type 2 diabetes and the Asian-specific missense variant (p.Arg192His) in PAX4. This variant may potentially decrease the transcription activity of PAX4, impacting pancreatic beta cell differentiation, proliferation and insulin production. The risk allele of p.Arg192His was also associated with younger age at diabetes diagnosis. These findings suggest that PAX4 is a possible effector gene of the 7q32 locus, which was previously identified by GWAS in Asians. They also provide supporting evidence for the role of PAX4, a known gene for MODY, in the pathogenesis of common type 2 diabetes. [Text supplied by the authors.]

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Immunogenicity of human embryonic stem cell-derived beta cells
by Cornelis R. van der Torren, Arnaud Zaldumbide, Gaby Duinkerken, Simone H. Brand-Schaaf, Mark Peakman, Geert Stangé, Laura Martinson, Evert Kroon, Eugene P. Brandon, Daniel Pipeleers, Bart O. Roep

The treatment of type 1 diabetes by transplantation with a donor pancreas or pancreatic islets can result in durable remission of diabetes, but donors are rare. Glucose-responsive, insulin-secreting cells can be cultured from pancreatic endoderm derived from human embryonic stem cells (hESC), for an alternative and unlimited source of beta cells. However, their implantation into type 1 diabetic recipients may result in reactivation of the autoimmune process that caused destruction of the patient's own beta cells, while their donor origin may induce allograft rejection. In this issue, van der Torren et al report the immune reactions against hESC-derived pancreatic progenitor cells and endocrine cells, which were retrieved after in vivo differentiation in capsules in mice. The progenitor cells proved to be hypoimmunogenic, but immunogenicity changed during inflammation or their differentiation into endocrine cells, resulting in immune attack by alloantibodies, and allo- and auto-reactive T cells. These data support the need for immune intervention or macro-encapsulation in the transplantation of hESC-derived pancreatic progenitor cells. [Text supplied by the authors.]

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Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus
by Danielle M. Osborne, Kelsey E. O'Leary, Dennis P. Fitzgerald, Alvin J. George, Michael M. Vidal, Brian M. Anderson, Ewan C. McNay

Recurrent hypoglycaemia is a common side effect of insulin therapy and its potential impact on the brain is a major obstacle to patient compliance with optimal insulin therapy. A marked impact of recurrent hypoglycaemia on subsequent hippocampal memory processing has been previously shown in a rat model. In this issue, Osborne et al use the same model to identify specific molecular changes in the hippocampus after recurrent hypoglycaemia. They demonstrate that both altered memory processing and molecular changes are largely mediated by increased hippocampal glucocorticoid signalling during hypoglycaemia, which boosts subsequent performance when euglycaemic. Molecular changes included alterations in glutamate signalling (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-D-aspartic acid [NMDA] receptors), serum/glucocorticoid-inducible kinase-1 (SGK1) and phosphorylated cyclic AMP response element binding (pCREB). The findings suggest that the impact of short-term recurrent hypoglycaemia on subsequent euglycaemic brain function may be beneficially adaptive. They also highlight a potential mechanism for alleviating diabetes-associated cognitive impairment. [Text supplied by the authors.]

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Inside this issue

Up front

Up front January 2017

Position statement

Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes

Review

High-intensity interval training: a review of its impact on glucose control and cardiometabolic health
Sophie Cassidy, Christian Thoma, David Houghton, Michael I. Trenell

Commentaries

Endotrophin, a multifaceted player in metabolic dysregulation and cancer progression, is a predictive biomarker for the response to PPARγ agonist treatment
Kai Sun, Jiyoung Park, Min Kim, Philipp E. Scherer

Depression: a common and burdensome complication of diabetes that warrants the continued attention of clinicians, researchers and healthcare policy makers
François Pouwer

For Debate

Rebranding asymptomatic type 1 diabetes: the case for autoimmune beta cell disorder as a pathological and diagnostic entity
Ezio Bonifacio, Chantal Mathieu, Gerald T. Nepom, Anette-G. Ziegler, Henry Anhalt, Michael J. Haller, Leonard C. Harrison, Matthias Hebrok, Jake A. Kushner, Jill M. Norris, Mark Peakman, Alvin C. Powers, John A. Todd, Mark A. Atkinson

Reclassification of asymptomatic beta cell autoimmunity: a critical perspective
Mikael Knip, Jenni Selvenius, Heli Siljander, Riitta Veijola

Articles

Systematic Reviews/Meta-analyses

GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis
Craig A. Beam, Colleen MacCallum, Kevan C. Herold, Diane K. Wherrett, Jerry Palmer, Johnny Ludvigsson, the Type 1 Diabetes TrialNet Study Group

Clinical Science and Care

Serum endotrophin identifies optimal responders to PPARγ agonists in type 2 diabetes
Morten A. Karsdal, Kim Henriksen, Federica Genovese, Diana J. Leeming, Mette J. Nielsen, Bente J. Riis, Claus Christiansen, Inger Byrjalsen, Detlef Schuppan

Trajectories of depression in adults with newly diagnosed type 1 diabetes: results from the German Multicenter Diabetes Cohort Study
Hanna Kampling, Frank Petrak, Erik Farin, Bernd Kulzer, Stephan Herpertz, Oskar Mittag

ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial
Anne M. Murray, Fang-Chi Hsu, Jeff D. Williamson, R. Nick Bryan, Hertzel C. Gerstein, Mark D. Sullivan, Michael E. Miller, Iris Leng, Laura L. Lovato, Lenore J. Launer, for the Action to Control Cardiovascular Risk in Diabetes Follow-On Memory in Diabetes (ACCORDION MIND) Investigators

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Epidemiology

Critical periods and growth patterns from fetal life onwards associated with childhood insulin levels
Ellis Voerman, Vincent W. V. Jaddoe, Oscar H. Franco, Eric A. P. Steegers, Romy Gaillard

Dementia onset, incidence and risk in type 2 diabetes: a matched cohort study with the Fremantle Diabetes Study Phase I
Wendy A. Davis, Renate R. Zilkens, Sergio E. Starkstein, Timothy M. E. Davis, David G. Bruce

Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study
Adela Brahimaj, Taulant Muka, Maryam Kavousi, Joop S. E. Laven, Abbas Dehghan, Oscar H. Franco

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Genetics

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals
Chloe Y. Y. Cheung, Clara S. Tang, Aimin Xu, Chi-Ho Lee, Ka-Wing Au, Lin Xu, Carol H. Y. Fong, Kelvin H. M. Kwok, Wing-Sun Chow, Yu-Cho Woo, Michele M. A. Yuen, JoJo S. H. Hai, Ya-Li Jin, Bernard M. Y. Cheung, Kathryn C. B. Tan, Stacey S. Cherny, Feng Zhu, Tong Zhu, G. Neil Thomas, Kar-Keung Cheng, Chao-Qiang Jiang, Tai-Hing Lam, Hung-Fat Tse, Pak-Chung Sham, Karen S. L. Lam

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Islet Studies

HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells
Mahboubeh Daneshpajooh, Karl Bacos, Madhusudhan Bysani, Annika Bagge, Emilia Ottosson Laakso, Petter Vikman, Lena Eliasson, Hindrik Mulder, Charlotte Ling

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Immunology and Transplantation

Immunogenicity of human embryonic stem cell-derived beta cells
Cornelis R. van der Torren, Arnaud Zaldumbide, Gaby Duinkerken, Simone H. Brand-Schaaf, Mark Peakman, Geert Stangé, Laura Martinson, Evert Kroon, Eugene P. Brandon, Daniel Pipeleers, Bart O. Roep

Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes
João Paulo M. C. M. Cunha, Gunter Leuckx, Peter Sterkendries, Hannelie Korf, Gabriela Bomfim-Ferreira, Lutgart Overbergh, Bart Vaes, Harry Heimberg, Conny Gysemans, Chantal Mathieu

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Metabolism

Effects of insulin-induced hypoglycaemia on lipolysis rate, lipid oxidation and adipose tissue signalling in human volunteers: a randomised clinical study
Thomas S. Voss, Mikkel H. Vendelbo, Ulla Kampmann, Steen B. Pedersen, Thomas S. Nielsen, Mogens Johannsen, Mads V. Svart, Niels Jessen, Niels Møller

Altered glucose profiles and risk for hypoglycaemia during oral glucose tolerance testing in pregnancies after gastric bypass surgery
Short Communication
Michael Feichtinger, Tina Stopp, Sandra Hofmann, Stephanie Springer, Sophie Pils, Alexandra Kautzky-Willer, Herbert Kiss, Wolfgang Eppel, Andrea Tura, Latife Bozkurt, Christian S. Göbl

Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver
Joana F. Sacramento, Maria J. Ribeiro, Tiago Rodrigues, Elena Olea, Bernardete F. Melo, Maria P. Guarino, Rui Fonseca-Pinto, Cristiana R. Ferreira, Joana Coelho, Ana Obeso, Raquel Seiça, Paulo Matafome, Sílvia V. Conde

Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins
Sini Heinonen, Maheswary Muniandy, Jana Buzkova, Adil Mardinoglu, Amaia Rodríguez, Gema Frühbeck, Antti Hakkarainen, Jesper Lundbom, Nina Lundbom, Jaakko Kaprio, Aila Rissanen, Kirsi H. Pietiläinen

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Pathophysiology and Complications

Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus
Danielle M. Osborne, Kelsey E. O’Leary, Dennis P. Fitzgerald, Alvin J. George, Michael M. Vidal, Brian M. Anderson, Ewan C. McNay

Impairments in microvascular function and skeletal muscle oxygenation in women with gestational diabetes mellitus: links to cardiovascular disease risk factors
Konstantina Dipla, Areti Triantafyllou, Iris Grigoriadou, Evangelia Kintiraki, Georgios A. Triantafyllou, Pavlos Poulios, Ioannis S. Vrabas, Andreas Zafeiridis, Stella Douma, Dimitrios G. Goulis

The TetO rat as a new translational model for type 2 diabetic retinopathy by inducible insulin receptor knockdown
Nadine Reichhart, Sergio Crespo-Garcia, Nadine Haase, Michaela Golic, Sergej Skosyrski, Anne Rübsam, Christina Herrspiegel, Norbert Kociok, Natalia Alenina, Michael Bader, Ralf Dechend, Olaf Strauss, Antonia M. Joussen

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