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Diabetes DOI:10.2337/db15-0950

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

Publication TypeJournal Article
Year of Publication2016
AuthorsHivert, M-F, 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
Corporate AuthorsDiabetes Prevention Program Research Group
JournalDiabetes
Volume65
Issue2
Pages520-6
Date Published2016 Feb
ISSN1939-327X
KeywordsAdult, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Middle Aged, Risk Assessment, Risk Factors, Risk Reduction Behavior, United States
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 = -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.

URLhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26525880
DOI10.2337/db15-0950
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26525880?dopt=Abstract

Alternate JournalDiabetes
PubMed ID26525880
PubMed Central IDPMC4747453
Grant ListU01 DK048437 / DK / NIDDK NIH HHS / United States
U01 DK048406 / DK / NIDDK NIH HHS / United States
U01 DK048407 / DK / NIDDK NIH HHS / United States
U01 DK048412 / DK / NIDDK NIH HHS / United States
U01 DK048375 / DK / NIDDK NIH HHS / United States
U01 DK048434 / DK / NIDDK NIH HHS / United States
U01 DK048413 / DK / NIDDK NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
R01 DK072041 / DK / NIDDK NIH HHS / United States
P30 DK097512 / DK / NIDDK NIH HHS / United States
U01 DK048397 / DK / NIDDK NIH HHS / United States
U01 DK048381 / DK / NIDDK NIH HHS / United States
U01 DK048339 / DK / NIDDK NIH HHS / United States
U01 DK048514 / DK / NIDDK NIH HHS / United States
U01 DK048485 / DK / NIDDK NIH HHS / United States
U01 DK048411 / DK / NIDDK NIH HHS / United States
U01 DK048380 / DK / NIDDK NIH HHS / United States
U01 DK048400 / DK / NIDDK NIH HHS / United States
U01 DK048468 / DK / NIDDK NIH HHS / United States
U01 DK048387 / DK / NIDDK NIH HHS / United States
U01 DK048404 / DK / NIDDK NIH HHS / United States
DK-48489 / DK / NIDDK NIH HHS / United States
U01 DK048489 / DK / NIDDK NIH HHS / United States
U01 DK048349 / DK / NIDDK NIH HHS / United States
U01 DK048377 / DK / NIDDK NIH HHS / United States
P30 DK017047 / DK / NIDDK NIH HHS / United States