ABSTRACT
Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Insulin/metabolism , Polymorphism, Single Nucleotide/genetics , Receptor, Melatonin, MT2/genetics , Receptors, Melatonin/genetics , Aged , Animals , Cohort Studies , Female , Gene Expression Regulation , Humans , Insulin Secretion , Islets of Langerhans/metabolism , Islets of Langerhans/pathology , Male , Mice , Middle Aged , Protein Transport , Rats , Receptor, Melatonin, MT2/metabolism , Receptors, Melatonin/metabolismABSTRACT
BACKGROUND: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. METHODS: We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. RESULTS: Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0x10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. CONCLUSIONS: As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Genotype , Polymorphism, Single Nucleotide , Proteins/genetics , Adult , Blood Glucose/metabolism , Blood Pressure , Body Mass Index , Female , Finland , Follow-Up Studies , Humans , Insulin/metabolism , Insulin Secretion , Logistic Models , Male , Middle Aged , Odds Ratio , ROC Curve , Risk Factors , Smoking/adverse effects , Sweden , Transaminases/bloodABSTRACT
Sulfonylureas are still largely used for treatment of type 2 diabetic patients, and they still occupy a central position in many international therapy guidelines. More recently concern has been raised with respect to possible adverse effects associated with the use of these agents. Sulfonylureas are, indeed, believed to favor the development of hypoglycemia, to accelerate beta cell apoptosis and beta-cell exhaustion, and to impair endothelial function with increased risk for ischemic complications. However, because of the intrinsic pathogenetic heterogeneity of type 2 diabetes, sulfonylureas are likely to remain a therapeutic option. Careful choice of a specific sulfonylurea should be made on the basis of efficacy, safety, convenience, tissue specificity, and neutrality with respect to the beta cell. In this review the advantage:disadvantage ratio of available sulfonylureas is analyzed with the purpose of providing a critical clinical appraisal of the role of sulfonylureas in the modern treatment of type 2 diabetes.
