Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.

• 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 ∼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.

Nyckelord

ATP-Binding Cassette Transporters/*genetics

Alleles

Diabetes Mellitus; Type 2/*genetics/therapy

Disease Progression

Female

Genetic Predisposition to Disease

Genotype

Glucose Intolerance/*genetics

Humans

Hypoglycemic Agents/therapeutic use

Insulin/secretion

Lysine/*genetics

Male

Metformin/therapeutic use

Middle Aged

Mutation; Missense

Polymorphism; Genetic

Potassium Channels/*genetics

Potassium Channels; Inwardly Rectifying/*genetics

Proportional Hazards Models

Receptors; Drug/*genetics

Treatment Outcome

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)