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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.

  • 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
Publishing year: 2016-02
Language: English
Pages: 520-526
Publication/Series: Diabetes
Volume: 65
Issue: 2
Document type: Journal article
Publisher: American Diabetes Association Inc.

Abstract english

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.


  • Endocrinology and Diabetes


  • Genetic and Molecular Epidemiology
  • ISSN: 1939-327X
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49



Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00