Bonner C.,European Genomic Institute for Diabetes |
Bonner C.,French Institute of Health and Medical Research |
Bonner C.,Lille University Hospital Center |
Kerr-Conte J.,European Genomic Institute for Diabetes |
And 38 more authors.
Nature Medicine | Year: 2015
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through K ATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue. © 2015 Nature America, Inc. All rights reserved.
Vaxillaire M.,European Genomic Institute for Diabetes |
Vaxillaire M.,French National Center for Scientific Research |
Vaxillaire M.,Lille 2 University of Health and Law |
Yengo L.,European Genomic Institute for Diabetes |
And 23 more authors.
Diabetologia | Year: 2014
Aims/hypothesis: Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. Methods: Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. Results: The two most inclusive GRS were significantly associated with increased FPG (β=0.0011 mmol/l per year per risk allele, p GRS-1 =8.2×10-5 and p GRS-2 =6.0×10-6), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p=4.3×10 -9 and HR GRS-2 1.04, p=1.0×10-16), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p=1.9×10-14 for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p=7.8×10-25, for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p=6.6×10 -7; NRI GRS-2 17.6%, p=4.2×10-7; NRI GRS-3 13.1%, p=1.7×10-4). Conclusions/ interpretation: Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population. © 2014 Springer-Verlag.
Bonnefond A.,European Genomic Institute for Diabetes |
Bonnefond A.,French National Center for Scientific Research |
Bonnefond A.,Lille 2 University of Health and Law |
Bonnefond A.,Qatar Biomedical Research Institute |
And 38 more authors.
Diabetes Care | Year: 2014
OBJECTIVE Accurate etiological diagnosis of monogenic forms of diabetes and obesity is useful as it can lead to marked improvements in patient care and genetic counseling. Currently, molecular diagnosis based on Sanger sequencing is restricted to only a few genes, as this technology is expensive, time-consuming, and laborintensive. High-throughput next-generation sequencing (NGS) provides an opportunity to develop innovative cost-efficient methods for sensitive diabetes and obesity multigene screening. RESEARCH DESIGN AND METHODS We assessed a new method based on PCR enrichment in microdroplets (Rain- Dance Technologies) and NGS using the Illumina HiSeq2000 for the molecular diagnosis of 43 forms of monogenic diabetes or obesity. Forty patients carrying a known causal mutation for those subtypes according to diagnostic laboratories were blindly reanalyzed. RESULTS Except for one variant, we reidentified all causal mutations in each patient associated with an almost-perfect sequencing of the targets (mean of 98.6%). We failed to call one highly complex indel, although we identified a dramatic drop of coverage at this locus. In three patients, we detected other mutations with a putatively deleterious effect in addition to those reported by the genetic diagnostic laboratories. CONCLUSIONS Our NGS approach provides an efficient means of highly sensitive screening for mutations in genes associated with monogenic forms of diabetes and obesity. As cost and time to deliver results have been key barriers to uncovering a molecular cause in the many undiagnosed cases likely to exist, the present methodology should be considered in patients displaying features of monogenic diabetes or obesity. © 2014 by the American Diabetes Association.
Julia V.,French National Center for Scientific Research |
Julia V.,French Institute of Health and Medical Research |
Julia V.,University of Nice Sophia Antipolis |
Macia L.,Monash University |
And 4 more authors.
Nature Reviews Immunology | Year: 2015
The incidence of allergic diseases is increasing, both in developed and developing countries, concomitantly with the rise in living standards and the adoption of a 'western lifestyle'. For two decades, the hygiene hypothesis-which proposes that the lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases in later life-provided the conceptual framework for unravelling the mechanisms that could account for the increased incidence of allergic diseases. In this Review, we discuss recent evidence that highlights the role of diet as a key factor influencing immune homeostasis and the development of allergic diseases through a complex interplay between nutrients, their metabolites and immune cell populations. Although further investigations are still required to understand these complex relationships, recent data have established a possible connection between metabolic homeostasis and allergic diseases.
Molica F.,University of Geneva |
Burger F.,University of Geneva |
Thomas A.,University of Geneva |
Staub C.,University of Geneva |
And 16 more authors.
Journal of Lipid Research | Year: 2013
Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an infl ammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of FA amide hydrolase (FAAH) defi- ciency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apoE knockout (apoE -/- ) and apoE -/- FAAH -/- mice. Anandamide levels were systemically elevated in apoE -/- mice after balloon injury. ApoE -/- FAAH -/- mice had significantly higher baseline anandamide levels and enhanced neointima formation compared with apoE -/- controls. The latter effect was inhibited by treatment with CB 1 antagonist AM281. Similarly, apoE -/- mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth-muscle cell (SMC) content, and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB 1 -/- SMCs or when treating apoE -/- or apoE -/- FAAH -/- SMCs with AM281. Macrophage in vitro adhesion and migration were marginally affected by CB 1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB 1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.
Pawlak M.,European Genomic Institute for Diabetes |
Pawlak M.,French Institute of Health and Medical Research |
Pawlak M.,Lille 2 University of Health and Law |
Pawlak M.,Institute Pasteur Of Lille |
And 23 more authors.
Hepatology | Year: 2014
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. Conclusion: The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression. (Hepatology 2014;60:1593-1606). © 2014 by the American Association for the Study of Liver Diseases.
Woldt E.,Institute Pasteur Of Lille |
Woldt E.,Institute National Of La Sante Et Of La Recherche Medicale Unite Mixte Of Recherche 1011 Nuclear Receptors |
Woldt E.,University of Lille Nord de France |
Woldt E.,University Du Droit Et Of La Sante Of Lille |
And 52 more authors.
Nature Medicine | Year: 2013
The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1- Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function. © 2013 Nature America, Inc. All rights reserved.
Allen R.E.,Texas A&M University |
Allen R.E.,Texas A&M University at Qatar |
Hughes T.D.,Texas A&M University |
Ng J.L.,Texas A&M University |
And 10 more authors.
Theoretical Biology and Medical Modelling | Year: 2013
Background: The most common bariatric surgery, Roux-en-Y gastric bypass, leads to glycemia normalization in most patients long before there is any appreciable weight loss. This effect is too large to be attributed purely to caloric restriction, so a number of other mechanisms have been proposed. The most popular hypothesis is enhanced production of an incretin, active glucagon-like peptide-1 (GLP-1), in the lower intestine. We therefore set out to test this hypothesis with a model which is simple enough to be robust and credible. Method. Our method involves (1) setting up a set of time-dependent equations for the concentrations of the most relevant species, (2) considering an "adiabatic" (or quasi-equilibrium) state in which the concentrations are slowly varying compared to reaction rates (and which in the present case is a postprandial state), and (3) solving for the dependent concentrations (of e.g. insulin and glucose) as an independent concentration (of e.g. GLP-1) is varied. Results: Even in the most favorable scenario, with maximal values for (i) the increase in active GLP-1 concentration and (ii) the effect of GLP-1 on insulin production, enhancement of GLP-1 alone cannot account for the observations. I.e., the largest possible decrease in glucose predicted by the model is smaller than reported decreases, and the model predicts no decrease whatsoever in glucose ×insulin, in contrast to large observed decreases in homeostatic model assessment insulin resistance (HOMA-IR). On the other hand, both effects can be accounted for if the surgery leads to a substantial increase in some substance that opens an alternative insulin-independent pathway for glucose transport into muscle cells, which perhaps uses the same intracellular pool of GLUT-4 that is employed in an established insulin-independent pathway stimulated by muscle contraction during exercise. Conclusions: Glycemia normalization following Roux-en-Y gastric bypass is undoubtedly caused by a variety of mechanisms, which may include caloric restriction, enhanced GLP-1, and perhaps others proposed in earlier papers on this subject. However, the present results suggest that another possible mechanism should be added to the list of candidates: enhanced production in the lower intestine of a substance which opens an alternative insulin-independent pathway for glucose transport. © 2013 Allen et al.; licensee BioMed Central Ltd.
Tailleux A.,European Genomic Institute for Diabetes |
Tailleux A.,French Institute of Health and Medical Research |
Tailleux A.,Lille University of Science and Technology |
Tailleux A.,Institute Pasteur Of Lille |
And 7 more authors.
Current Opinion in Lipidology | Year: 2015
Purpose of review To summarize recent epidemiological, preclinical and clinical studies on the effects of Roux-en-Y-gastric bypass (RYGBP) surgery on cardiovascular risk factors and the underlying mechanisms. Recent findings Although RYGBP has mechanical effects on the gastrointestinal tract, the reduced gastric pouch and intestinal calorie absorption cannot fully explain the metabolic improvements. Summary Obesity predisposes to cardiovascular risk factors such as dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and hypertension. In contrast to the limited success of pharmacological and lifestyle interventions, RYGBP induces sustained weight loss, metabolic improvements and decreases morbidity/mortality. In line, RYGBP reduces cardiovascular risk factors. Although the mechanisms are not entirely understood, RYGBP induces complex changes in the gut affecting other organs through endocrine and metabolic signals from the intestine to all key metabolic organs, which can link RYGBP and decreased cardiovascular risk. Here, we discuss the roles of changes in lipid absorption and metabolism, bile acid metabolism, gut hormones and the microbiote as potential mechanisms in the decreased cardiovascular risk and metabolic improvement after RYGBP. © 2015 Wolters Kluwer Health, Inc.