Diabetologia

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Welcome to Diabetologia

Diabetologia publishes original clinical 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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The cover picture shows an illustration of a macrophage (top) engulfing a bacterium. Macrophages are central to innate immunity, and to the pathology of tissue injury and inflammation. The importance of increased inflammatory activity in obesity and type 2 diabetes has been recognised. In the present issue of Diabetologia (55: 273–278) Fernández-Real and Pickup review the development of this concept and the current evidence linking the pathophysiology of these disorders to several components of innate immunity. A framework is proposed in which the response to injury, with inflammation as the consequence, is used as a model to identify new therapeutic targets for type 2 diabetes.

Cover credit: DAVID GOODSELL/SCIENCE PHOTO LIBRARY

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Remembering our classics: then and now
by J. R. Zierath

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Each month the Editor will choose five articles of particular interest.

Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss
by S. H. Shah, D. R. Crosslin, C. S. Haynes, S. Nelson, C. B. Turer, R. D. Stevens, M. J. Muehlbauer, B. R. Wenner, J. R. Bain, B. Laferrere, P. Gorroochurn, J. Teixeira, P. J. Brantley, V. J. Stevens, J. F. Hollis, L. J. Appel, L. F. Lien, B. Batch, C. B. Newgard, L. P. Svetkey

Obesity is associated with the development of insulin resistance (IR) and type 2 diabetes mellitus. In fact, many of the adverse cardiovascular consequences of obesity are mediated through IR. IR is reversible with weight loss, but this response shows substantial variability. In a study reported this issue, Shah et al used a novel technology, metabolomics, to measure levels of 65 small molecules, present at low concentrations in the blood, that reflect diverse cellular processes. In individuals enrolled in the Weight Loss Maintenance (WLM) clinical trial, the authors showed that baseline blood levels of a set of metabolites reporting on branched chain amino acid catabolism predict the extent of improvement in IR with subsequent weight loss, independently of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.

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Common genetic variants differentially influence the transition between clinically defined states of fasting glucose metabolism
by G. A. Walford, T. Green, B. Neale, T. Isakova, J. I. Rotter, S. F. A. Grant, C. S. Fox, J. S. Pankow, J. G. Wilson, J. B. Meigs, D. S. Siscovick, D. W. Bowden, M. J. Daly, J. C. Florez

Multiple commonly occurring genetic variants have been unequivocally associated with type 2 diabetes. Understanding the relative contribution of these variants to transitions between the clinically-defined states of normal fasting glucose (NFG), impaired fasting glucose (IFG) and diabetes may provide insight into their mechanisms of action. In this issue, Walford et al provide evidence that four genetic loci (MTNR1B, encoding melatonin receptor 1B; GCK, encoding glucokinase; GCKR, encoding the glucokinase receptor; and SLC30A8, encoding the solute carrier family 30 [zinc transporter], member 8) are more strongly associated with the NFG to IFG transition; a variant at the IGF2BP2 locus (encoding insulin-like growth factor 2 mRNA binding protein 2) is more strongly associated with the IFG to diabetes transition; and the well-known TCF7L2 variant is associated with both transitions. These findings suggest that a subset of common genetic variants may increase the risk of type 2 diabetes primarily by promoting fasting hyperglycaemia, while others do so through different mechanisms.

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Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice
by W. Quan, K. Y. Hur, Y. Lim, S. H. Oh, J.-C. Lee, K. H. Kim, G. H. Kim, S.-W. Kim, H. L. Kim, M.-K. Lee, K.-W. Kim, J. Kim, M. Komatsu, M.-S. Lee

Autophagy is a catabolic process involving the rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to lysosomes for subsequent degradation and recycling. In this issue, Quan et al. determined the relationship between autophagy and diabetes by assessing the unfolded protein response (UPR) of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to endoplasmic reticulum (ER) stressors. Production of UPR machinery was reduced in autophagy-deficient beta cells, concomitant and increased susceptible to ER stressors and reductions in non-catalytic subunits of phosphoinositide 3-kinase. Accumulation of reactive oxygen species, beta cell death and severe diabetes was observed in beta cell specific autophagy deficient ob/ob mice. The authors provide evidence that beta cell autophagy is necessary for appropriate UPR machinery constitutively and in response to ER stress. Autophagy deficiency in pancreatic beta cells may be a factor in the progression from obesity to diabetes.

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An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age
by I. Vermeulen, I. Weets, O. Costa, M. Asanghanwa, K. Verhaeghen, K. Decochez, J. Ruige, K. Casteels, J. Wenzlau, J.C. Hutton, D. G. Pipeleers, F.K. Gorus, the Belgian Diabetes Registry

Immuno-interventions in recent-onset type 1 diabetes were found to suppress disease progress. This has raised interest in prevention trials in high-risk groups as identified by autoantibody-positivity in first-degree relatives. Since these trials will probably first enrol adolescents and adults, screening strategies face the question of whether conversion to autoantibody positivity can occur in these age categories. In this issue, Vermeulen et al have investigated age dependency of seroconversion by following a large representative group of initially antibody-negative first-degree relatives, aged 0-39 years. Conversion to persistent autoantibody positivity developed regardless of age. Characteristics and progression rates were similar to those in age-matched initially antibody-positive relatives. Those who underwent seroconversion after the age of 10 years progressed more slowly to diabetes but represent a quantitatively important fraction of potential trial candidates. These data warrant continued monitoring of autoantibody status in risk groups up to at least the age of 40 years when planning secondary prevention trials.

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A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus
by D. P. K. Ng, A. Salim, Y. Liu, L. Zou, F. G. Xu, S. Huang, H. Leong, C. N. Ong

Some diabetic patients have a low estimated GFR even in the absence of proteinuria, yet little is known about the risk factors or mechanisms associated with this phenotype. In this issue, Ng et al applied metabolic approaches to gained biological insight into the clinical phenotype in patients with type 2 diabetes. At the same time, several candidate biomarkers were positively identified that might prove useful for the detection and monitoring of chronic kidney disease even in the early stages of diabetes. These new biomarkers for low estimated GFR extended beyond the conventional uraemic toxins such as indoxyl sulphate, and displayed excellent discriminatory power for disease classification.

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Then and Now

Innate immunity, insulin resistance and type 2 diabetes
J. M. Fernández-Real and J. C. Pickup

Commentary

The importance of beta cell characterisation: generating human beta cells by differentiating human embryonic stem cells
G. S. Korbutt, T. Y. Yeung and C. E. Ellis

Articles

• Clinical Science and Care
• Epidemiology
• Genetics
• Islet Studies
• Immunology and Transplantation
• Metabolism
• Pathophysiology and Complications

Clinical Science and Care

Pathophysiology of postprandial hyperglycaemia in women with type 1 diabetes during pregnancy
H. R. Murphy, D. Elleri, J. M. Allen, J. Harris and D. Simmons, et al.

Epidemiology

Causes of death among diabetic patients in Denmark
M. B. Hansen, M. L. Jensen and B. Carstensen

Five-year follow-up of a cohort of people with their first diabetic foot ulcer: the persistent effect of depression on mortality
K. Winkley, H. Sallis, D. Kariyawasam, L. H. Leelarathna and T. Chalder, et al.

Early adulthood television viewing and cardiometabolic risk profiles in early middle age: results from a population, prospective cohort study
E. Stamatakis, M. Hamer and G. D. Mishra

Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss
S. H. Shah, D. R. Crosslin, C. S. Haynes, S. Nelson and C. B. Turer, et al.

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Genetics

Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism
G. A. Walford, T. Green, B. Neale, T. Isakova and J. I. Rotter, et al.

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes
L. S. Snogdal, M. Wod, N. Grarup, M. Vestmar and T. Sparsø, et al.

Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs
V. Gupta, D. G. Vinay, S. Rafiq, M. V. Kranthikumar and C. S. Janipalli, et al.

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Islet Studies

The functional and molecular characterisation of human embryonic stem cell-derived insulin-positive cells compared with adult pancreatic beta cells
C. L. Basford, K. J. Prentice, A. B. Hardy, F. Sarangi and S. J. Micallef, et al.

Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas
M. J. Riedel, A. Asadi, R. Wang, Z. Ao and G. L. Warnock, et al.

Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2^C95S)
S. Kautz, L. van Bürck, M. Schuster, E. Wolf and R. Wanke, et al.

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice
W. Quan, K. Y. Hur, Y. Lim, S. H. Oh and J.-C. Lee, et al.

Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice
Y. Takeda, Y. Fujita, J. Honjo, T. Yanagimachi and H. Sakagami, et al.

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Immunology and Transplantation

An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age
I. Vermeulen, I. Weets, O. Costa, M. Asanghanwa and K. Verhaeghen, et al.

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Metabolism

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?
A. Othman, M. F. Rütti, D. Ernst, C. H. Saely and P. Rein, et al.

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study
C. Beysen, E. J. Murphy, K. Deines, M. Chan and E. Tsang, et al.

Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration
S. Larsen, R. Rabøl, C. N. Hansen, S. Madsbad and J. W. Helge, et al.

Insulin entry into muscle involves a saturable process in the vascular endothelium
S. Majumdar, A. J. Genders, A. C. Inyard, V. Frison and E. J. Barrett

Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilisation and glucose transport dysfunction in skeletal muscle
K. M. Habegger, B. A. Penque, W. Sealls, L. Tackett and L. N. Bell, et al.

T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice
K. Loh, T. L. Merry, S. Galic, B. J. Wu and M. J. Watt, et al.

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat
J. S. V. Lally, L. A. Snook, X. X. Han, A. Chabowski and A. Bonen, et al.



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Pathophysiology and Complications

Diabetes is associated with impairment of uterine contractility and high Caesarean section rate
S. Al-Qahtani, A. Heath, S. Quenby, F. Dawood and R. Floyd, et al.

A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus
D. P. K. Ng, A. Salim, Y. Liu, L. Zou and F. G. Xu, et al.

Kidney-targeting Smad7 gene transfer inhibits renal TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice
S. M. Ka, Y. C. Yeh, X. R. Huang, T. K. Chao and Y. J. Hung, et al.

Coupling factor 6-induced activation of ecto-F₁F_o complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice
T. Osanai, M. Tanaka, K. Magota, H. Tomita and K. Okumura

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Research Letter

Impact of circulating vaspin levels on metabolic variables in elderly twins
K. Hida, P. Poulsen, S. Teshigawara, E. Nilsson and M. Friedrichsen, et al.

Retraction Note

Retraction Note: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells
Y. Hattori, T. Jojima, A. Tomizawa, H. Satoh and S. Hattori, et al.

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Erratum

Erratum to: Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4
M. N. Pham, M. I. Hawa, C. Pfleger, M. Roden and G. Schernthaner, et al.

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