The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

Sesti, Giorgio; Laratta, Emanuela; Cardellini, Marina; Andreozzi, Francesco; Guerra, S Del; Irace, Concetta; Gnasso, Agostino; Grupillo, Maria; Lauro, Renato; Hribal, Marta Letizia; Perticone, Francesco; Marchetti, Piero

doi:10.1210/jc.2005-2323

Cited by 151 publications

(102 citation statements)

References 34 publications

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“…Numerous polymorphisms of these genes are reported in association with susceptibility to type 2 diabetes and diabetic phenotypes (5,6,7). These polymorphisms may lead to a loss of activity of potassium channel and to uncontrolled over secretion of insulin (2), as well as modulated response to sulfonylurea therapy (8,9).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Control in Type 2 Diabetes Is Associated with Sulfonylurea Receptor-1 (SUR-1) but Not with KCNJ11 Polymorphisms

Nikolac

Šimundić

Katalinić³

et al. 2009

Archives of Medical Research

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Section: Introductionmentioning

confidence: 99%

Metabolic Control in Type 2 Diabetes Is Associated with Sulfonylurea Receptor-1 (SUR-1) but Not with KCNJ11 Polymorphisms

Nikolac

Šimundić

Katalinić³

et al. 2009

Archives of Medical Research

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“…Gloyn et al (3) studied 364 subjects randomized to sulfonylurea therapy in the UK Prospective Diabetes Study (UKPDS) and determined that the presence of the lysine allele did not predict failure to treatment with sulfonylureas at 1 year. Recently, Sesti et al (15) reported a higher proportion of lysine carriers among 208 subjects who failed sulfonylurea-metformin combination therapy (defined as a rise in fasting plasma glucose Ͼ300 mg/dl); interestingly, islets isolated from lysine carriers showed a diminished insulin response to glyburide.…”

mentioning

confidence: 99%

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

et al. 2007

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The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over ϳ3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-todiabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation. Diabetes 56: 531-536, 2007

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“…Literature on the impact of the KCNJ11 risk variant E23K on treatment response to sulfonylureas is similarly controversial. Whereas E23K associated with an increased risk of secondary failure to sulfonylureas in patients with type 2 diabetes [95], a lack of protection by metformin [96], and diminished repaglinide efficacy [97], in another study, the KCNJ11 risk variant did not affect response to sulfonylurea therapy [98]. Data on the association between SNPs in TCF7L2 and treatment outcome appears to be more consistent.…”

Section: Discussionmentioning

confidence: 97%

Genetic variants affecting incretin sensitivity and incretin secretion

et al. 2010

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Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The majority of these type 2 diabetes risk variants confer impaired pancreatic beta cell function. Though the molecular mechanisms by which common genetic variation within these loci affects beta cell function are not completely understood, risk variants may alter glucose-stimulated insulin secretion, proinsulin conversion, and incretin signals. In humans, the incretin effect is mediated by the secretion and insulinotropic action of two peptide hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. This review article aims to give an overview of the type 2 diabetes risk loci that were found to associate with incretin secretion or incretin action, paying special attention to the potential underlying mechanisms.

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The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes

Abstract: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.

Cited by 151 publications

References 34 publications

Metabolic Control in Type 2 Diabetes Is Associated with Sulfonylurea Receptor-1 (SUR-1) but Not with KCNJ11 Polymorphisms

Metabolic Control in Type 2 Diabetes Is Associated with Sulfonylurea Receptor-1 (SUR-1) but Not with KCNJ11 Polymorphisms

Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program

Genetic variants affecting incretin sensitivity and incretin secretion

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