Lifestyle and metformin ameliorate insulin sensitivity independently of the genetic burden of established insulin resistance variants in Diabetes Prevention Program participants.

Research output: Contribution to journalArticle


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 if people with genetic enrichment for these IR-variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score based on 17 established IR-variants and their 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 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 IR-GRS on change in ISI; higher IR-GRS was associated with 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 improved ISI, regardless of the genetic burden of IR-variants.


  • Marie-France Hivert
  • Costas A Christophi
  • Paul Franks
  • Kathleen A Jablonski
  • David A Ehrmann
  • Steven E Kahn
  • Edward S Horton
  • Toni I Pollin
  • Kieren J Mather
  • Leigh Perreault
  • Elizabeth Barrett-Connor
  • William C Knowler
  • Jose C Florez
External organisations
  • Harvard University
  • Université de Sherbrooke
  • George Washington University
  • University of Chicago
  • University of Washington
  • Joslin Diabetes Center
  • University of Maryland
  • Indiana University
  • University of Colorado
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)520-526
Issue number2
Publication statusPublished - 2016 Feb
Publication categoryResearch