Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants.

Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.

Investigators
Abbreviation
Diabetes
Publication Date
2015-11-02
Volume
65
Issue
2
Page Numbers
520-6
Pubmed ID
26525880
Medium
Print-Electronic
Full Title
Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants.
Authors
Hivert MF, Christophi CA, Franks PW, Jablonski KA, Ehrmann DA, Kahn SE, Horton ES, Pollin TI, Mather KJ, Perreault L, Barrett-Connor E, Knowler WC, Florez JC,