Association of a variant in exon 31 of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus in French Caucasians

Abstract

The sulfonylurea receptor (SUR1) of the pancreatic beta-cell ATP-sensitive potassium channel plays a key role in glucose-induced insulin secretion. The A-allele of a single nucleotide polymorphism (SNP) in exon 31 of the SUR1 gene (AGG-->AGA; Arg1273Arg) has previously been shown to be associated with hyperinsulinemia in nondiabetic Mexican-American subjects. Here, we have investigated the association of this SNP with type 2 diabetes mellitus (T2DM) in French Caucasian subjects. We have observed an increased frequency of the A allele (37.1% vs 27.6%, P=0.0048; odds ratio 1.54), of the AA genotype (15.7% vs 9.8%; P=0.025), and of the combined AA/AG genotypes (58.5% vs 45.5%, P=0.0098; odds ratio 1.69) in patients compared with controls. This association is stronger in the subgroup of patients with age of diagnosis of diabetes equal to or less than 45 years: A allele 43.2% (P=0.0003 compared with controls; odds ratio 1.99), AA genotype 21.4% (P=0.0032), and combined AA/AG genotypes 65.1% (P=0.0022; odds ratio 2.23). Unexpectedly, the G allele is strongly associated with arterial hypertension in obese diabetic subjects (GG vs AA odds ratio 19.97). In conclusion, we have observed an association of an SNP in exon 31 of the SUR1 gene with T2DM. These data reinforce the hypothesis that insulin secretion defects in T2DM might be at least partially related to allelic variations in the SUR1 gene.

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…In support of this, a variant in SUR1 resulting in elevated fasting and glucose-induced plasma insulin concentrations has been described in non-diabetic Mexican Americans, an ethnic group with a high incidence of type 2 diabetes [4]. A follow-up study showed that this same allelic variation in SUR1 was associated with type 2 diabetes in French white individuals [5], which may further support the notion of a causal link between insulin hypersecretion and the development of diabetes. Importantly, a study in Pima Indians, who have the highest incidence of diabetes of any ethnic group in the world, showed that fasting hyperinsulinaemia was a significant predictor of the disease, with individuals demonstrating fasting plasma insulin levels above the 90th percentile having a sixfold higher risk of developing diabetes compared with individuals in the lowest 10th percentile, independent of insulin resistance [6].…”

Physical activity modifies the effect of SNPs in theSLC2A2(GLUT2) andABCC8(SUR1) genes on the risk of developing type 2 diabetes

“…Recently, the association of the T110I polymorphism in SLC2A2 with the risk of type 2 diabetes among Finnish subjects was replicated (50). The results of other case control studies with respect to SNPs in SLC2A2 and ABCC8 and risk of type 2 diabetes have, however, been inconsistent (1,2,13,15,32,34,36,39,40,43,47), whereas a meta-analysis confirmed the association of the K allele of the E23K polymorphism in KCNJ11with an increased risk of type 2 diabetes among Caucasians (47). The prospective DPP, however, unexpectedly found a lower risk of conversion from IGT to type 2 diabetes in the carriers of the K allele (14).…”

Association Studies of Variants in the Genes Involved in Pancreatic β-Cell Function in Type 2 Diabetes in Japanese Subjects

“…Mutations in the genes (ABCC8 and KCNJ11) can cause familial persistent hyperinsulinemic hypoglycemia of infancy (5) and permanent neonatal diabetes (6). Several polymorphisms in these genes also have been reported to be associated with type 2 diabetes in populations with distinct ethnic backgrounds (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, a large-scale association study of these genes has not been performed in type 2 diabetes in the Japanese population.…”