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People who drink 3 to 4 times per week less likely than those who never drink to develop diabetes
However women who drink spirits frequently linked with increased diabetes risk

Read this new research by Professor Janne Tolstrup and colleagues from the National Institute of Public Health of the University of Southern Denmark.
For further information contact Professor Tolstrup (jst@niph.dk).

Early menopause is independently linked to an increased risk of developing type 2 diabetes

Read this new research by Dr Taulant Muka and Dr Eralda Asllanaj of the Department of Epidemiology, Erasmus University Medical Centre, Netherlands, and colleagues.
For further information contact Dr Muka (t.muka@erasmusmc.nl) or Dr Asllanaj (e.asllanaj@erasmusmc.nl).

Current issue: September 2017

September 2017 cover

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The cover image shows Galega officinalis (also known as goat's rue, French lilac, Italian fitch, Spanish sainfoin or professor weed), the plant from which metformin is derived. In the present issue of Diabetologia, to mark the 60th anniversary of the first clinical use of metformin for diabetes, we have commissioned a series of articles on the many evolving (and somewhat controversial) aspects of use; the topics covered are shown surrounding the plant. This series aims not only to provide a critical review of the current evidence, but to look to the future and speculate where the metformin journey might take us.

Cover credit: 'Twig of blooming Galega officinalis on white background'. Picture Partners/Alamy Stock Photo

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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


60 years of metformin use: a glance at the past and a look to the future

To mark the 60th anniversary of the first clinical use of metformin for diabetes, Diabetologia has commissioned a series of articles on the many evolving (and controversial) aspects of metformin use. To begin, a historical overview is provided by Clifford Bailey (DOI 10.1007/s00125-017-4318-z), followed by an outline of the mechanisms of action by Rena et al (DOI 10.1007/s00125-017-4342-z). Sanchez-Rangel and Inzucchi (DOI 10.1007/s00125-017-4336-x) go on to present data for the efficacy and safety of metformin in type 2 diabetes, for which it is the first-line therapy. In contrast, Livingstone and colleagues (DOI 10.1007/s00125-017-4364-6) discuss its use in type 1 diabetes and Aroda et al (DOI 10.1007/s00125-017-4361-9) present findings for its potential use for diabetes prevention. Griffin et al (DOI 10.1007/s00125-017-4337-9) investigate the association between metformin and cardiovascular disease risk by conducting a meta-analysis, whilst Sam and Ehrmann (DOI 10.1007/s00125-017-4306-3) and Lindsay and Loeken (DOI 10.1007/s00125-017-4351-y) discuss its use in polycystic ovary syndrome and pregnancy, respectively. Metformin therapy in the ageing population is reviewed by Valencia et al (DOI 10.1007/s00125-017-4349-5), and Michael Pollak (DOI 10.1007/s00125-017-4352-x) confers the non-glycaemic effects of metformin, suggesting a role for the human microbiota/gut metabolome and the immune system. Another emerging area of interest, the impact of metformin on cancer incidence and mortality, is covered by Heckman-Stoddard et al (DOI 10.1007/s00125-017-4372-6). Finally, to address the heterogeneity in response to metformin therapy, Jose Florez (DOI 10.1007/s00125-017-4335-y) advises how a personalised approach may be achieved using genetic studies. In summary, this review series demonstrates how metformin shows promise in many conditions, but how long can this drug remain at the top spot? This review set is accompanied by an editorial by Sally Marshall (DOI 10.1007/s00125-017-4343-y). [Text supplied by the authors.]

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Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study
by Anna But, Marie L. De Bruin, Marloes T. Bazelier, Vidar Hjellvik, Morten Andersen, Anssi Auvinen, Jakob Starup-Linde, Marjanka K. Schmidt, Kari Furu, Frank de Vries, Øystein Karlstad, Nils Ekström, Jari Haukka

Several years after concerns were first raised regarding potential increased risk of cancer with exposure to certain types of insulin, study findings remain conflicting. Hence, But et al (DOI 10.1007/s00125-017-4312-5) conducted a large multi-country observational study to investigate long-term and time-dependent effects of different insulins on cancer risk, while addressing methodological shortcomings of previous studies. In this issue, these researchers from the Cancer Risk and Insulin Analogues (CARING) academic consortium report findings from their study, which used healthcare databases from five countries. They found no evidence for consistent differences between insulin glargine, insulin detemir and human insulin, when comparing the risk of cancer among individuals with diabetes. Even after long-term exposure (> 5 years), no persistent differences were observed for the ten most frequently occurring cancers. These findings suggest that concerns about cancer risk should not be a reason to withhold the use of the insulin analogues, insulin glargine and insulin detemir. [Text supplied by the authors.]

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Early metabolic markers identify potential targets for the prevention of type 2 diabetes
by Gopal Peddinti, Jeff Cobb, Loic Yengo, Philippe Froguel, Jasmina Kravi?, Beverley Balkau, Tiinamaija Tuomi, Tero Aittokallio, Leif Groop

Predictive biomarkers for the future risk of type 2 diabetes will help to develop prognostic and prevention strategies. In this issue, Peddinti et al (DOI 10.1007/s00125-017-4325-0) use mass spectrometry-based comprehensive metabolomic profiling and machine learning-based predictive modelling to identify a panel of seven metabolic markers that accurately predict type 2 diabetes; these markers significantly improved the ability to predict the risk of type 2 diabetes beyond commonly used clinical risk factors alone. Moreover, the predictive performance of these markers, which were derived based on a 10 year follow-up study involving Finnish individuals, generalised to an independent cohort of French individuals. In addition to improving prognostic prediction performance in type 2 diabetes, Peddinti and colleagues report how some of these metabolic markers may also provide insight into the possible mechanisms by which interventions, such as exercise, might contribute to the prevention of type 2 diabetes. In summary, this study provides a panel of novel metabolic markers for future efforts aimed at the prevention of type 2 diabetes. [Text supplied by the authors.]

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The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice
by Anne Ørgaard, Jens J. Holst

The failure of glucagon-like peptide-1 (GLP-1) to inhibit glucagon secretion during hypoglycaemia is thought to be owing to lack of stimulation of somatostatin secretion from the islet delta cells, which, like beta cells, are glucose-sensitive. In this issue, Ørgaard and Holst (DOI 10.1007/s00125-017-4315-2) use a perfused mouse pancreas model to show that, under various glucose concentrations (6.0, 1.5 and 0.5 mmol/l), GLP-1 stimulates somatostatin secretion with concurrent inhibition of glucagon secretion. However, the effect was reversed (glucagon secretion was increased) upon somatostatin blockade using a somatostatin receptor antagonist. Thus, in spite of the clear dependency of GLP-1's glucagon-lowering effect on somatostatin secretion in response to glucose levels, the paracrine inhibition of glucagon secretion was preserved during hypoglycaemia. [Text supplied by the authors.]

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Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study
by Helen R. Murphy, Ruth Bell, Cher Cartwright, Paula Curnow, Michael Maresh, Margery Morgan, Catherine Sylvester, Bob Young, Nick Lewis-Barned

Pregnant women with type 1 and type 2 diabetes experience high rates of perinatal mortality and morbidity. Guidance emphasises prepregnancy folic acid supplementation, and optimising glucose control before and during pregnancy. In this issue, Murphy et al (DOI 10.1007/s00125-017-4314-3) report on more than 3000 pregnancies from 155 maternity units participating in the National Pregnancy in Diabetes (NPID) audit in England and Wales (UK) in 2015. Stillbirth rates were significantly lower than in 2002/2003, with other adverse outcomes largely unchanged. Meanwhile, pregnancy preparation and glucose control remained suboptimal. Despite this, and the challenge it presents, the substantial variation between clinics in the uptake of folic acid supplementation and early glycaemic control suggests that there are opportunities to improve care through sharing successful practice. At the same time, the data generated by NPID can be used by local services to support quality improvement initiatives and track changes in outcome at a local, regional and national level. [Text supplied by the authors.]

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Inside this issue

Up front

Up front September 2017

Editorial

60 years of metformin use: a glance at the past and a look to the future
Sally M. Marshall

Commentary

Metformin: historical overview
Clifford J. Bailey

Reviews

The mechanisms of action of metformin
Graham Rena, D. Grahame Hardie, Ewan R. Pearson

Metformin: clinical use in type 2 diabetes
Elizabeth Sanchez-Rangel, Silvio E. Inzucchi

A new perspective on metformin therapy in type 1 diabetes
Rachel Livingstone, James G. Boyle, John R. Petrie

Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study
Vanita R. Aroda, William C. Knowler, Jill P. Crandall, Leigh Perreault, Sharon L. Edelstein, Susan L. Jeffries, Mark E. Molitch, Xavier Pi-Sunyer, Christine Darwin, Brandy M. Heckman-Stoddard, Marinella Temprosa, Steven E. Kahn, David M. Nathan, for the Diabetes Prevention Program Research Group

Metformin use in pregnancy: promises and uncertainties
Robert S. Lindsay, Mary R. Loeken

Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes
Simon J. Griffin, James K. Leaver, Greg J. Irving

Metformin and ageing: improving ageing outcomes beyond glycaemic control
Willy Marcos Valencia, Ana Palacio, Leonardo Tamariz, Hermes Florez

Repurposing metformin for the prevention of cancer and cancer recurrence
Brandy M. Heckman-Stoddard, Andrea DeCensi, Vikrant V. Sahasrabuddhe, Leslie G. Ford

The pharmacogenetics of metformin
Jose C. Florez

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome
Susan Sam, David A. Ehrmann

The effects of metformin on gut microbiota and the immune system as research frontiers
Michael Pollak

Articles

Clinical Science and Care

Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study
Helen R. Murphy, Ruth Bell, Cher Cartwright, Paula Curnow, Michael Maresh, Margery Morgan, Catherine Sylvester, Bob Young, Nick Lewis-Barned

Diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes-naive population with schizophrenia: a nationwide nested case–control study
Christoffer Polcwiartek, Kristian Kragholm, Christopher Rohde, Nasseh Hashemi, Torkel Vang, Jimmi Nielsen

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Epidemiology

Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study
Anna But, Marie L. De Bruin, Marloes T. Bazelier, Vidar Hjellvik, Morten Andersen, Anssi Auvinen, Jakob Starup-Linde, Marjanka K. Schmidt, Kari Furu, Frank de Vries, Øystein Karlstad, Nils Ekström, Jari Haukka

One-hour and two-hour postload plasma glucose concentrations are comparable predictors of type 2 diabetes mellitus in Southwestern Native Americans
Ethan Paddock, Maximilian G. Hohenadel, Paolo Piaggi, Pavithra Vijayakumar, Robert L. Hanson, William C. Knowler, Jonathan Krakoff, Douglas C. Chang

The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease
Eirik W. Rebnord, Elin Strand, Øivind Midttun, Gard F.T. Svingen, Monika H.E. Christensen, Per M. Ueland, Gunnar Mellgren, Pål R. Njølstad, Grethe S. Tell, Ottar K. Nygård, Eva R. Pedersen

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Genetics

Genetic risk scores in the prediction of plasma glucose, impaired insulin secretion, insulin resistance and incident type 2 diabetes in the METSIM study
Alena Stancáková, Teemu Kuulasmaa, Johanna Kuusisto, Karen L. Mohlke, Francis S. Collins, Michael Boehnke, Markku Laakso

Islet Studies

The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice
Anne Ørgaard, Jens J. Holst

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Metabolism

Early metabolic markers identify potential targets for the prevention of type 2 diabetes
Gopal Peddinti, Jeff Cobb, Loic Yengo, Philippe Froguel, Jasmina Kravic, Beverley Balkau, Tiinamaija Tuomi, Tero Aittokallio, Leif Groop

Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene
Simona S. Ghanem, Harrison T. Muturi, Anthony M. DeAngelis, Jiang Hu, Rohit N. Kulkarni, Garrett Heinrich, Sonia M. Najjar

Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice
Shogo Ida, Katsutaro Morino, Osamu Sekine, Natsuko Ohashi, Shinji Kume, Tokuhiro Chano, Kanako Iwasaki, Norio Harada, Nobuya Inagaki, Satoshi Ugi, Hiroshi Maegawa

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Pathophysiology and Complications

Retinal vascular geometry and 6 year incidence and progression of diabetic retinopathy
Carol Yim-lui Cheung, Charumathi Sabanayagam, Antony Kwan-pui Law, Neelam Kumari, Daniel Shu-wei Ting, Gavin Tan, Paul Mitchell, Ching Yu Cheng, Tien Yin Wong

Urinary liver-type fatty acid binding protein is an independent predictor of stroke and mortality in individuals with type 1 diabetes
Nicolae M. Panduru, Carol Forsblom, Markku Saraheimo, Lena M. Thorn, Daniel Gordin, Nina Elonen, Valma Harjusalo, Angelika Bierhaus, Per M. Humpert, Per-Henrik Groop, on behalf of the FinnDiane Study Group

High glucose increases the formation and pro-oxidative activity of endothelial microparticles
Dylan Burger, Maddison Turner, Fengxia Xiao, Mercedes N. Munkonda, Shareef Akbari, Kevin D. Burns

The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype
Ángela Vinué, Jorge Navarro, Andrea Herrero-Cervera, Marta García-Cubas, Irene Andrés-Blasco, Sergio Martínez-Hervás, José T. Real, Juan F. Ascaso, Herminia González-Navarro

The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes
Pascal Bus, Marion Scharpfenecker, Priscilla Van Der Wilk, Ron Wolterbeek, Jan A. Bruijn, Hans J. Baelde

Complement C5a induces mesenchymal stem cell apoptosis during the progression of chronic diabetic complications
Ming Zhu, Xiao He, Xiao-Hui Wang, Wei Qiu, Wei Xing, Wei Guo, Tian-Chen An, Luo-Quan Ao, Xue-Ting Hu, Zhan Li, Xiao-Ping Liu, Nan Xiao, Jian Yu, Hong Huang, Xiang Xu

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Research Letters

Autoantibody binding in liquid phase to IL-2 in human sera is not type 1 diabetes specific
Ilaria Marzinotto, Daniela Liberati, Cristina Brigatti, Riccardo Bonfanti, Angela Stabilini, Paolo Monti, Emanuele Bosi, Lorenzo Piemonti, Vito Lampasona

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