title: Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
abstract: 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 approximately 3 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-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
authors.affiliation: Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852, USA. dppmail@biostat.bsc.gwu.edu
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.forename: Dana
authors.initials: D
authors.lastname: Dabelea
authors.forename: Richard F
authors.initials: RF
authors.lastname: Hamman
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: David M
authors.initials: DM
authors.lastname: Nathan
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000628:therapy; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008239:Lysine / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D016016:Proportional Hazards Models; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D016896:Treatment Outcome; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D007328:Insulin; D008239:Lysine; D008687:Metformin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel