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In the News

New research reveals workplace bullying and violence are risk factors for type 2 diabetes

Read this new research by Tianwei Xu from the Department of Public Health, University of Copenhagen, Denmark and her collaborators from Denmark, Sweden and Finland.
For further information contact Dr Xu (tixu@sund.ku.dk).

Study shows that the consumption of antioxidant-rich foods is associated with a lower risk of type 2 diabetes

Read this new research by Inserm researchers in the 'Générations et Santé' team at the Centre de Recherche en Epidémiologie et Santé des populations (Inserm UMR 1018).
For further information contact Professor Guy Fagherazzi (guy.fagherazzi@gustaveroussy.fr) and Dr Francesca Romana Mancini (francesca.mancini@gustaveroussy.fr)..

Current issue: January

January 2018 cover

Click here to view this month's contents

Key to elucidating distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins. As shown on the cover, these include reader proteins that recognise chemical moieties (semi-circles: histone reader, turquoise; DNA reader, orange; RNA reader, white), writer proteins (pink hexagon) that deposit these and eraser proteins (blue hexagon) for their removal. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? In the present issue of Diabetologia, Keating et al hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. They also explore future strategies to expedite and refine the search for clinically relevant discoveries for the pharmacological control of epigenetic marks and consider the challenges associated with therapeutic strategies targeting epigenetic pathways.

Cover credit: Assam El-Osta, Central Clinical School, Monash University, Melbourne, VIC, Australia

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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


Epigenetics in diabetic nephropathy, immunity and metabolism
by Samuel T. Keating, Janna A. van Diepen, Niels P. Riksen, Assam El-Osta

To paraphrase Winston Churchill, if there was ever a time to 'never, never, never give up' on epigenetics then that time would be now. Diabetes is the disease of our time. It is clearly a complex disorder that has recently been shown to be associated with epigenetic changes. These changes were originally considered to be an epiphenomenon. However, the past several years have seen a surge in the discovery of epigenetic mechanisms associated with micro- and macrovascular complications. The tiniest of chemical marks that form the epigenome can make a big difference to gene function in metabolic disease. In this issue (https://doi.org/10.1007/s00125-017-4490-1), Keating et al review contemporary advances in the field of chromatin biology, drawing on state-of-the-art discoveries in diabetes, focussing on nephropathy, immunity and metabolism. The figures from this review are available as a downloadable slideset. [Text supplied by the authors.]

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Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease
by Guanghong Jia, Adam Whaley-Connell, James R. Sowers

Hyperglycaemia and insulin resistance cause diabetic cardiomyopathy. Cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by systolic dysfunction and clinical heart failure in the absence of hypertension, dyslipidaemia and coronary artery disease. In this issue (https://doi.org/10.1007/s00125-017-4390-4), Jia et al review the pathophysiological mechanisms that underlie the development of diabetic cardiomyopathy. They explain that systemic metabolic disorders, such as cardiac lipotoxicity, often contribute to cardiac insulin resistance and the development of diabetic cardiomyopathy. Other mechanisms include mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress, impaired calcium handling, cell death and dysregulation of coronary endothelial cells and exosomes. Together, these pathophysiological changes induce cardiac stiffness, interstitial fibrosis and consequent cardiac dysfunction and heart failure. The authors go on to discuss possible strategies for the prevention and treatment of diabetic cardiomyopathy. They conclude that further studies to improve understanding of the cellular and molecular mechanisms of diabetic cardiomyopathy will help to develop new therapeutic approaches. The figures from this review are available as a downloadable slideset. [Text supplied by the authors.]

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Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond
by Hans-Peter Hammes

Diabetic retinopathy is the most common diabetes complication and, although there are efforts to minimise blindness by effective screening and treatment, its prevalence is likely to increase as the prevalence of diabetes increases worldwide. The retina should be considered an efficient biomarker of vascular damage in diabetes. In a review by Hans-Peter Hammes in this issue (https://doi.org/10.1007/s00125-017-4435-8), the mechanisms directing the development of small vessels in the eye are discussed to revisit the incipience of microvessel damage. In particular, the author highlights that diabetes affects not only the (micro-)vasculature, but all cells that communicate with the vascular cells of the neurovascular unit in an intimate crosstalk. Beyond classical glucose toxicity hypotheses, novel disease transmitters and neurovascular response patterns are considered. The author also discusses normoglycaemic models for novel pathogenetic concepts and possible new treatments. Overall, the review is intended as a reminder that studying the retina remains crucial for understanding diabetes as a systemic disease. The figures from this review are available as a downloadable slideset.[Text supplied by the authors.]

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Human pancreatic neuro-insular network in health and fatty infiltration
by Shiue-Cheng Tang, Luc Baeyens, Chia-Ning Shen, Shih-Jung Peng, Hung-Jen Chien, David W. Scheel, Chester E. Chamberlain, Michael S. German

Because of the dispersed nature of neurovascular tissues, islets and their associations with the pancreatic blood vessels and nerves cannot easily be observed using standard two-dimensional (2D) histology. In this issue (https://doi.org/10.1007/s00125-017-4409-x), Tang et al report on their use of 3D panoramic histology with tissue clearing to investigate mouse and human pancreases, identifying the neuro-insular network in both species. Global visualisation of the pancreas reveals the intra-pancreatic ganglia (peri-lobular and intra-parenchymal ganglia in humans) and the islet-ganglionic association. The high-definition 3D images depict the islet sympathetic and parasympathetic innervation. Importantly, in humans, the pancreatic fatty infiltration appears to remodel the ganglionic microenvironment, in which the adipose-ganglionic complexes and enlargement of the ganglia are identified. The 3D image data provide insight into the mouse and human neuro-insular networks for comparison. They also demonstrate the use of a modern histological approach for characterisation of the previously unknown details of the pancreatic tissue network in health and disease. [Text supplied by the authors.]

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Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans
by Rebecca K. C. Loh, Melissa F. Formosa, Nina Eikelis, David A. Bertovic, Mitchell J. Anderson, Shane A. Barwood, Shane Nanayakkara, Neale D. Cohen, Andre La Gerche, Anne T. Reutens, Kenneth S. Yap, Thomas W. Barber, Gavin W. Lambert, Martin H. Cherk, Stephen J. Duffy, Bronwyn A. Kingwell, Andrew L. Carey

Obesity and associated comorbidities are major contributors to poor health and healthcare costs worldwide. Increasing brown adipose tissue (BAT) energy expenditure (thermogenesis) is a potential strategy to combat obesity. Thiazolidinediones are a class of glucose-lowering drugs widely prescribed to people with type 2 diabetes, and are also well known to induce browning of adipocytes in preclinical experimental models. However, their effect on the thermogenic capacity of human BAT is unknown. In this issue (https://doi.org/10.1007/s00125-017-4479-9), Loh et al report a reduction in cold-stimulated BAT glucose uptake (a surrogate measure of BAT activity) after chronic (28 days) pioglitazone administration to seven healthy young males. This inhibition of BAT function by pioglitazone is discordant with preclinical models and argues against the pursuit of related pathways for BAT-targeted therapeutics. These data may have implications for the treatment of type 2 diabetes, since pioglitazone-induced BAT dysfunction could contribute to weight gain in these individuals. [Text supplied by the authors.]

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Inside this issue

Up front

Up front January 2018

In Memoriam

Gian Franco Bottazzo, 1946–2017
Ezio Bonifacio, Emanuele Bosi, R. David Leslie

Reviews

Epigenetics in diabetic nephropathy, immunity and metabolism
Samuel T. Keating, Janna A. van Diepen, Niels P. Riksen, Assam El-Osta

Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease
Guanghong Jia, Adam Whaley-Connell, James R. Sowers

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond
Hans-Peter Hammes

Commentaries

When beta cells talk back
Heather C. Denroche, Dominika Nackiewicz, C. Bruce Verchere

Devoting attention to glucose variability and hypoglycaemia in type 2 diabetes
Martin K. Rutter

Articles

Clinical Science and Care

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)
Bernard Zinman, Steven P. Marso, Neil R. Poulter, Scott S. Emerson, Thomas R. Pieber, Richard E. Pratley, Martin Lange, Kirstine Brown-Frandsen, Alan Moses, Ann Marie Ocampo Francisco, Jesper Barner Lekdorf, Kajsa Kvist, John B. Buse, on behalf of the DEVOTE Study Group

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality
Thomas R. Pieber, Steven P. Marso, Darren K. McGuire, Bernard Zinman, Neil R. Poulter, Scott S. Emerson, Richard E. Pratley, Vincent Woo, Simon Heller, Martin Lange, Kirstine Brown-Frandsen, Alan Moses, Jesper Barner Lekdorf, Lucine Lehmann, Kajsa Kvist, John B. Buse, on behalf of the DEVOTE Study Group

Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia
Suzy V. Hope, Bridget A. Knight, Beverley M. Shields, Anita V. Hill, Pratik Choudhary, W. David Strain, Timothy J. McDonald, Angus G. Jones

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Epidemiology

Workplace bullying and violence as risk factors for type 2 diabetes: a multicohort study and meta-analysis
Tianwei Xu, Linda L. Magnusson Hanson, Theis Lange, Liis Starkopf, Hugo Westerlund, Ida E. H. Madsen, Reiner Rugulies, Jaana Pentti, Sari Stenholm, Jussi Vahtera, Åse M. Hansen, Mika Kivimäki, Naja H. Rod

The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes
Heba M. Ismail, Ping Xu, Ingrid M. Libman, Dorothy J. Becker, Jennifer B. Marks, Jay S. Skyler, Jerry P. Palmer, Jay M. Sosenko, Type 1 Diabetes TrialNet Study Group

Size and shape of the associations of glucose, HbA1c, insulin and HOMA-IR with incident type 2 diabetes: the Hoorn Study
Carolien Ruijgrok, Jacqueline M. Dekker, Joline W. Beulens, Ingeborg A. Brouwer, Veerle M. H. Coupé, Martijn W. Heymans, Femke P. C. Sijtsma, David J. Mela, Peter L. Zock, Margreet R. Olthof, Marjan Alssema

Glucose patterns during an oral glucose tolerance test and associations with future diabetes, cardiovascular disease and all-cause mortality rate
Short Communication
Adam Hulman, Dorte Vistisen, Charlotte Glümer, Michael Bergman, Daniel R. Witte, Kristine Færch

Type 2 diabetes, socioeconomic status and life expectancy in Scotland (2012–2014): a population-based observational study
Jeremy Walker, Helen Colhoun, Shona Livingstone, Rory McCrimmon, John Petrie, Naveed Sattar, Sarah Wild, on behalf of the Scottish Diabetes Research Network Epidemiology Group

Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study
Sophie Molnos, Simone Wahl, Mark Haid, E. Marelise W. Eekhoff, René Pool, Anna Floegel, Joris Deelen, Daniela Much, Cornelia Prehn, Michaela Breier, Harmen H. Draisma, Nienke van Leeuwen, Annemarie M. C. Simonis-Bik, Anna Jonsson, Gonneke Willemsen, Wolfgang Bernigau, Rui Wang-Sattler, Karsten Suhre, Annette Peters, Barbara Thorand, Christian Herder, Wolfgang Rathmann, Michael Roden, Christian Gieger, Mark H. H. Kramer, Diana van Heemst, Helle K. Pedersen, Valborg Gudmundsdottir, Matthias B. Schulze, Tobias Pischon, Eco J. C. de Geus, Heiner Boeing, Dorret I. Boomsma, Anette G. Ziegler, P. Eline Slagboom, Sandra Hummel, Marian Beekman, Harald Grallert, Søren Brunak, Mark I. McCarthy, Ramneek Gupta, Ewan R. Pearson, Jerzy Adamski, Leen M. ’t Hart

Maternal obesity as a risk factor for early childhood type 1 diabetes: a nationwide, prospective, population-based case–control study
Nina Lindell, Annelie Carlsson, Ann Josefsson, Ulf Samuelsson

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Genetics

HbA1c is associated with altered expression in blood of cell cycle- and immune response-related genes
Roderick C. Slieker, Amber A. W. A. van der Heijden, Nienke van Leeuwen, Hailiang Mei, Giel Nijpels, Joline W. J. Beulens, Leen M. ’t Hart

The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age
Jamie R. J. Inshaw, Neil M. Walker, Chris Wallace, Leonardo Bottolo, John A. Todd

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Islet Studies

Pancreatic neuro-insular network in young mice revealed by 3D panoramic histology
Shiue-Cheng Tang, Chia-Ning Shen, Pei-Yu Lin, Shih-Jung Peng, Hung-Jen Chien, Ya-Hsien Chou, Chester E. Chamberlain, Pankaj J. Pasricha

Human pancreatic neuro-insular network in health and fatty infiltration
Shiue-Cheng Tang, Luc Baeyens, Chia-Ning Shen, Shih-Jung Peng, Hung-Jen Chien, David W. Scheel, Chester E. Chamberlain, Michael S. German

Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity
Jonathan R. Weitz, Madina Makhmutova, Joana Almaça, Julia Stertmann, Kristie Aamodt, Marcela Brissova, Stephan Speier, Rayner Rodriguez-Diaz, Alejandro Caicedo

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Immunology and Transplantation

Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children
Helena Elding Larsson, Kristian F. Lynch, Maria Lönnrot, Michael J. Haller, Åke Lernmark, William A. Hagopian, Jin-Xiong She, Olli Simell, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar, Jeffrey P. Krischer, Marian J. Rewers, Heikki Hyöty, for the TEDDY Study Group

Live attenuated enterovirus vaccine (OPV) is not associated with islet autoimmunity in children with genetic susceptibility to type 1 diabetes: prospective cohort study
Hanna Viskari, Sami Oikarinen, Sanna Hoppu, Tytti Vuorinen, Heini Huhtala, Jorma Toppari, Riitta Veijola, Jorma Ilonen, Mikael Knip, Heikki Hyöty

Metabolism

Differential effects of age and sex on insulin sensitivity and body composition in adolescent offspring of women with type 1 diabetes: results from the EPICOM study
Zuzana Lohse, Sine Knorr, Birgitte Bytoft, Tine D. Clausen, Rikke B. Jensen, Peter Oturai, Henning Beck-Nielsen, Claus H. Gravholt, Peter Damm, Kurt Højlund, Dorte M. Jensen

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans
Rebecca K. C. Loh, Melissa F. Formosa, Nina Eikelis, David A. Bertovic, Mitchell J. Anderson, Shane A. Barwood, Shane Nanayakkara, Neale D. Cohen, Andre La Gerche, Anne T. Reutens, Kenneth S. Yap, Thomas W. Barber, Gavin W. Lambert, Martin H. Cherk, Stephen J. Duffy, Bronwyn A. Kingwell, Andrew L. Carey

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Pathophysiology and Complications

Biomarkers of inflammation and endothelial dysfunction as predictors of pulse pressure and incident hypertension in type 1 diabetes: a 20 year life-course study in an inception cohort
Isabel Ferreira, Peter Hovind, Casper G. Schalkwijk, Hans-Henrik Parving, Coen D. A. Stehouwer, Peter Rossing

Association of maternal exposures with adiposity at age 4/5 years in white British and Pakistani children: findings from the Born in Bradford study
Jane West, Gillian Santorelli, Peter H. Whincup, Lesley Smith, Naveed A. Sattar, Noel Cameron, Diane Farrar, Paul Collings, John Wright, Debbie A. Lawlor

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Retraction Note

Retraction Note to: L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity
P. O. Prada, S. M. Hirabara, C. T. de Souza, A. A. Schenka, H. G. Zecchin, J. Vassallo, L. A. Velloso, E. Carneiro, J. B. C. Carvalheira, R. Curi, M. J. Saad

Correction

Correction to: 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

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