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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

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: May 2017

May 2017 cover

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The cover picture shows a Flemish tapestry (circa 1510-1520), located in the Victoria and Albert Museum (London, UK) and entitled 'The Three Fates' (or 'The Triumph of Death'). This masterpiece depicts the three fates (personifications of destiny also known as the Moirai), standing over the body of Chastity. In Greek mythology, these fates controlled the span of human life; Klotho, standing on the right, spun the 'thread of life', Lachesis determined the length of it and Atropos cut the thread. In the present issue of Diabetologia, Maltese et al report that microalbuminuria in type 1 diabetes is associated with deficiency of the anti-ageing hormone Klotho, opening doors to new and exciting diagnostic, prognostic and therapeutic perspectives in diabetic nephropathy.


Cover credit: akg-images


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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


Precision diabetes: a realistic outlook on a promising approach
Editorial by: Sally M. Marshall
Reviews by: Andrew T. Hattersley, Kashyap A. Patel; Giles S. H. Yeo; Paul W. Franks, Alaitz Poveda; Mark I. McCarthy; Jose C. Florez

Precision medicine, the tailoring of healthcare based on an individual's genetics, lifestyle and environment, has been used with success in monogenic diabetes but several barriers have prevented its large-scale application throughout diabetes. In this issue, a series of reviews outline previous achievements, current limitations and future promises of precision diabetes: Hattersley and Patel (DOI 10.1007/s00125-017-4226-2) discuss its application in monogenic diabetes, including challenges faced when implementing this approach into clinical care. In terms of diabetes prevention, Giles Yeo (DOI 10.1007/s00125-016-4187-x) describes the use of precision medicine for the management of obesity, whilst Franks and Poveda (DOI 10.1007/s00125-017-4207-5) discuss its use to predict response to deleterious lifestyle factors and, conversely, to lifestyle interventions. Mark McCarthy (DOI 10.1007/s00125-017-4210-x) proposes a new model (the 'palette model') for precision diabetes that accounts for the multifactorial nature of diabetes and the impact of therapeutic agents on diabetes risk and progression. Finally, Jose Florez (DOI 10.1007/s00125-017-4227-1) explains how pharmacogenetics may be used to elucidate new drug targets, uncover pathophysiology, unravel disease heterogeneity and identify genes that contribute to diabetes risk. In summary, this precision medicine series suggests a new horizon in diabetes care but does not dismiss the enormous amount of work that remains necessary for large-scale application of this promising approach. This review set is accompanied by an editorial by Sally Marshall (DOI 10.1007/s00125-017-4244-0). [Text supplied by the authors.]

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Melatonin signalling and type 2 diabetes risk: is it a case of too little or too much?
by Commentaries by: Amélie Bonnefond, Philippe Froguel; Hindrik Mulder

Sweet dreams or nightmares? Human genetics provides a powerful tool for identifying causal pathways and relationships of disease risk. In the field, it is well recognised that genetic variation in and near MTNR1B influences type 2 diabetes risk but finding consensus on the molecular mechanisms that bring about this effect is still an area of hot debate and current research activity. In this issue, we feature a review by Forrestel et al (DOI 10.1007/s00125-016-4175-1; see below), summarising our current knowledge of melatonin in diabetes. In addition, because this is currently such a controversial field, we have commissioned two articles from laboratories that are leading research to understand the role of genetic variation in the melatonin receptor in diabetes risk: Bonnefond and Froguel (DOI 10.1007/s00125-017-4255-x) make a case for the detrimental impact of too little melatonin signalling on type 2 diabetes risk, whilst Hindrik Mulder (DOI 10.1007/s00125-017-4249-8) outlines evidence for the negative effect of both elevated and reduced melatonin signalling on diabetes risk. These authors present their opinions on the interpretation of the current landscape and thoughts on how the field might resolve them. [Text supplied by the authors.]

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Chronomedicine and type 2 diabetes: shining some light on melatonin
by Andrew C. Forrestel, Susanne U. Miedlich, Michael Yurcheshen, Steven D. Wittlin, Michael T. Sellix

Circadian timing systems are almost universally present in living organisms, from unicellular to mammalian species. In mammals (including humans), the timing system makes a sizeable contribution to insulin secretion and glucose metabolism processes. Pineal melatonin, known primarily for its role as a 'sleep hormone', is a principal mediator of human circadian rhythms. Disruption of this system is associated with obesity, dysglycaemia and other metabolic disturbances. In this issue, Forrestal et al (DOI 10.1007/s00125-016-4175-1) review the regulation of circadian rhythmicity, paying specific attention to the metabolic consequences of its disruption. Focus is placed on the impact of melatonin on metabolic processes, especially insulin secretion, and the consequences of melatonin receptor polymorphisms on glucose homeostasis and diabetes risk. Interestingly, melatonin levels are reduced in individuals with diabetes. In line with this, the authors provide a clinical perspective on the use of melatonin as a potential chronotherapy for the management of diabetes, discussing the pros and cons of melatonin therapy for glycaemic control. They conclude by highlighting the need for more dedicated study of chronopharmacological agents, such as melatonin, for the treatment of metabolic diseases. [Text supplied by the authors.]

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Prolonged sitting may increase diabetes risk in physically inactive individuals: an 11 year follow-up of the HUNT Study, Norway
by Bjørn O. Åsvold, Kristian Midthjell, Steinar Krokstad, Vegar Rangul, Adrian Bauman

Emerging evidence indicates that prolonged sitting may have adverse effects on blood glucose levels and insulin sensitivity, but few studies have examined the association between total daily sitting time and the risk of diabetes. In this issue, Åsvold et al (DOI 10.1007/s00125-016-4193-z) report the association between total sitting time and the risk of diabetes during an 11 year follow-up of the population-based Nord-Trøndelag Health Study (the HUNT Study). Total sitting time had little association with diabetes risk in the population as a whole. However, among physically inactive individuals, sitting ≥8 h/day was associated with a 30% increased risk of diabetes compared with sitting ≤4 h/day. The results suggest that prolonged sitting may contribute to increased risk of diabetes among physically inactive people. [Text supplied by the authors.]

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Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
by Yuvaraj Mahendran, Anna Jonsson, Christian T. Have, Kristine H. Allin, Daniel R. Witte, Marit E. Jørgensen, Niels Grarup, Oluf Pedersen, Tuomas O. Kilpeläinen, Torben Hansen

Fasting plasma levels of branched-chain amino acids (BCAA) are associated with peripheral insulin resistance. However, it is unclear whether this association is due to a causal link between BCAA levels and insulin resistance. In this issue, Mahendran et al (DOI 10.1007/s00125-017-4222-6) report that a genetically-determined increase in circulating BCAA levels does not lead to more severe insulin resistance. In contrast, a genetically-determined increase in the severity of insulin resistance resulted in elevated circulating BCAA levels. The authors conclude that the association between circulating BCAA levels and insulin resistance likely reflects a causal effect of insulin resistance on BCAA levels; this may be explained by the impact of insulin (a chief regulator of amino acid metabolism) on the rate of appearance and clearance of BCAA together with decreased activity of catabolic enzymes involved in BCAA metabolism. In summary, increased BCAA levels in individuals with insulin resistance appears to be a marker of impaired insulin action rather than a causative factor. [Text supplied by the authors.]

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Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats
by Valentine S. Moullé, Kevin Vivot, Caroline Tremblay, Bader Zarrouki, Julien Ghislain, Vincent Poitout

The mechanisms by which glucose homeostasis is maintained in the face of insulin resistance involve, at least in part, an increase in pancreatic beta cell mass via proliferation. Since failure of this compensatory response leads to type 2 diabetes, understanding its underlying mechanism is clinically relevant. In this issue, Moullé et al (DOI 10.1007/s00125-016-4197-8) report the effects of glucose and NEFA, alone or in combination, on beta cell proliferation. Using complementary in vivo studies in rats and ex vivo studies in isolated rat and human islets, the authors showed that glucose and NEFA synergistically and reversibly stimulated beta cell proliferation via several mechanisms, including via direct effect of these nutrients. Furthermore, nutrient-induced endogenous circulating factors released in response to insulin resistance potentiated beta cell proliferation. Importantly, nutrient-induced beta cell proliferation was independent from secreted insulin. These findings underscore the complexity of the beta cell response to nutrient excess in vivo. [Text supplied by the authors.]

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Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
by Stephen P. Gray, Jay C. Jha, Kit Kennedy, Erik van Bommel, Phyllis Chew, Cedric Szyndralewiez, Rhian M. Touyz, Harald H. H. W. Schmidt, Mark E. Cooper, Karin A. M. Jandeleit-Dahm

Oxidative stress derived from NADPH oxidase (NOX)1 and NOX4 has been reported to contribute to the development of diabetic complications, in particular diabetes-accelerated atherosclerosis and kidney disease. However, it has not yet been tested whether NOX-targeted drug intervention in established disease can prevent diabetes progression. In this issue, Gray et al (DOI 10.1007/s00125-017-4215-5) report that administration of a novel NOX inhibitor that prevents NOX1- and NOX4-derived oxidative stress halts the progression of kidney disease and the development of atherosclerosis. Tissue-specific and dose-dependent effects were evident in the response to NOX inhibition, particularly with regards to its impact on atherosclerosis progression. These studies highlight the importance of defining the optimal relative balance between NOX1 and NOX4 inhibition in the micro- and macrovasculature for the management of diabetes. [Text supplied by the authors.]

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Inside this issue

Up front

Up front May 2017

Editorial

Precision diabetes: a realistic outlook on a promising approach
Sally M. Marshall

Reviews

Precision diabetes: learning from monogenic diabetes
Andrew T. Hattersley, Kashyap A. Patel

Genetics of obesity: can an old dog teach us new tricks?
Giles S. H. Yeo

Lifestyle and precision diabetes medicine: will genomics help optimise the prediction, prevention and treatment of type 2 diabetes through lifestyle therapy?
Paul W Franks, Alaitz Poveda

Painting a new picture of personalised medicine for diabetes
Mark I. McCarthy

Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool?
Jose C. Florez

Chronomedicine and type 2 diabetes: shining some light on melatonin
Andrew C. Forrestel, Susanne U. Miedlich, Michael Yurcheshen, Steven D. Wittlin, Michael T. Sellix

Commentaries

The case for too little melatonin signalling in increased diabetes risk
Amélie Bonnefond, Philippe Froguel

Melatonin signalling and type 2 diabetes risk: too little, too much or just right?
Hindrik Mulder

Articles

Epidemiology

Prolonged sitting may increase diabetes risk in physically inactive individuals: an 11 year follow-up of the HUNT Study, Norway
Bjørn O. Åsvold, Kristian Midthjell, Steinar Krokstad, Vegar Rangul, Adrian Bauman

Season of birth and the risk of type 2 diabetes in adulthood: a prospective cohort study of 0.5 million Chinese adults
Jiahui Si, Canqing Yu, Yu Guo, Zheng Bian, Xia Li, Ling Yang, Yiping Chen, Huarong Sun, Bo Yu, Junshi Chen, Zhengming Chen, Jun Lv, Liming Li

Serum magnesium and the risk of prediabetes: a population-based cohort study
Brenda C. T. Kieboom, Symen Ligthart, Abbas Dehghan, Steef Kurstjens, Jeroen H. F. de Baaij, Oscar H. Franco, Albert Hofman, Robert Zietse, Bruno H. Stricker, Ewout J. Hoorn

Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals: findings from the RODAM study
Karlijn A. C. Meeks, Karien Stronks, Adebowale Adeyemo, Juliet Addo, Silver Bahendeka, Erik Beune, Ellis Owusu-Dabo, Ina Danquah, Cecilia Galbete, Peter Henneman, Kerstin Klipstein-Grobusch, Frank P. Mockenhaupt, Kwame Osei, Matthias B. Schulze, Joachim Spranger, Liam Smeeth, Charles Agyemang

Low muscle mass and risk of type 2 diabetes in middle-aged and older adults: findings from the KoGES
Jang Won Son, Seong Su Lee, Sung Rae Kim, Soon Jib Yoo, Bong Yun Cha, Ho Young Son, Nam H. Cho

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Genetics

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
Yuvaraj Mahendran, Anna Jonsson, Christian T. Have, Kristine H. Allin, Daniel R. Witte, Marit E. Jørgensen, Niels Grarup, Oluf Pedersen, Tuomas O. Kilpeläinen, Torben Hansen

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Islet Studies

Glucose and fatty acids synergistically and reversibly promote beta cell proliferation in rats
Valentine S. Moullé, Kevin Vivot, Caroline Tremblay, Bader Zarrouki, Julien Ghislain, Vincent Poitout

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Metabolism

Hedgehog signalling in myeloid cells impacts on body weight, adipose tissue inflammation and glucose metabolism
Julia Braune, Ulrike Weyer, Madlen Matz-Soja, Constance Hobusch, Matthias Kern, Anne Kunath, Nora Klöting, Susann Kralisch, Matthias Blüher, Rolf Gebhardt, Yana Zavros, Ingo Bechmann, Martin Gericke

c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice
Rong Wu, Jian-guang Sun, Ji-qiu Wang, Binhua Li, Qingsong Liu, Guang Ning, Wanzhu Jin, Zengqiang Yuan

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Pathophysiology and Complications

Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria
Short Communication
Giuseppe Maltese, Nikolaos Fountoulakis, Richard C. Siow, Luigi Gnudi, Janaka Karalliedde

HMOX1 as a marker of iron excess-induced adipose tissue dysfunction, affecting glucose uptake and respiratory capacity in human adipocytes
José María Moreno-Navarrete, Francisco Ortega, Amaia Rodríguez, Jèssica Latorre, Sara Becerril, Mònica Sabater-Masdeu, Wifredo Ricart, Gema Frühbeck, José Manuel Fernández-Real

Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease
Stephen P. Gray, Jay C. Jha, Kit Kennedy, Erik van Bommel, Phyllis Chew, Cedric Szyndralewiez, Rhian M. Touyz, Harald H. H. W. Schmidt, Mark E. Cooper, Karin A. M. Jandeleit-Dahm

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Letter

Metabolic brain adaptations to recurrent hypoglycaemia may explain the link between type 1 diabetes mellitus and epilepsy and point towards future study and treatment options
Domenico Tricò, Raimund I. Herzog

Erratum

Erratum to: Painting a new picture of personalised medicine for diabetes
Mark I. McCarthy

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