Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in diabetes prevention program participants

Marie France Hivert, Costas A. Christophi, Paul W. Franks, Kathleen A. Jablonski, David A. Ehrmann, Steven E. Kahn, Edward S. Horton, Toni I. Pollin, Kieren Mather, Leigh Perreault, Elizabeth Barrett-Connor, William C. Knowler, Jose C. Florez

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Abstract

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 = 20.754 [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 = 20.520 [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.

Original languageEnglish (US)
Pages (from-to)520-526
Number of pages7
JournalDiabetes
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2016

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Metformin
Insulin Resistance
Life Style
Genome-Wide Association Study
Waist Circumference

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in diabetes prevention program participants. / Hivert, Marie France; Christophi, Costas A.; Franks, Paul W.; Jablonski, Kathleen A.; Ehrmann, David A.; Kahn, Steven E.; Horton, Edward S.; Pollin, Toni I.; Mather, Kieren; Perreault, Leigh; Barrett-Connor, Elizabeth; Knowler, William C.; Florez, Jose C.

In: Diabetes, Vol. 65, No. 2, 01.02.2016, p. 520-526.

Research output: Contribution to journalArticle

Hivert, MF, Christophi, CA, Franks, PW, Jablonski, KA, Ehrmann, DA, Kahn, SE, Horton, ES, Pollin, TI, Mather, K, Perreault, L, Barrett-Connor, E, Knowler, WC & Florez, JC 2016, 'Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in diabetes prevention program participants', Diabetes, vol. 65, no. 2, pp. 520-526. https://doi.org/10.2337/db15-0950
Hivert, Marie France ; Christophi, Costas A. ; Franks, Paul W. ; Jablonski, Kathleen A. ; Ehrmann, David A. ; Kahn, Steven E. ; Horton, Edward S. ; Pollin, Toni I. ; Mather, Kieren ; Perreault, Leigh ; Barrett-Connor, Elizabeth ; Knowler, William C. ; Florez, Jose C. / Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in diabetes prevention program participants. In: Diabetes. 2016 ; Vol. 65, No. 2. pp. 520-526.
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