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DOI: 10.2337/db05-1331
© 2006 by the American Diabetes Association
A Functional Tyr1306Cys Variant in LARG Is Associated With Increased Insulin Action in Vivo
1 Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
2 Medical Department III, University of Leipzig, Leipzig, Germany
Address correspondence and reprint requests to Leslie J. Baier, PhD, Diabetes Molecular Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th St., Phoenix, AZ 85004. E-mail: lbaier{at}phx.niddk.nih.gov
Abbreviations:
GEF, guanine nucleotide exchange factor; LARG, leukemia-associated Rho guanine nucleotide exchange factor; LD, linkage disequilibrium; LPA, lysophosphatidic acid; PDZ, postsynaptic density disc-large zo-1; SNP, single nucleotide polymorphism; SRE, serum response element; TCF, ternary complex factor; UTR, untranslated region
Diminished insulin sensitivity is a characteristic feature of type 2 diabetes. Inhibition of insulin action, resulting in reduced skeletal muscle glucose uptake, is mediated in part through stimulation of RhoA activity. One regulator of RhoA activity is leukemia-associated Rho guanine nucleotide exchange factor (LARG). The LARG gene maps to a region on chromosome 11q23-24 that shows genetic linkage to BMI and type 2 diabetes in Pima Indians. Because of its role in RhoA activation, the LARG gene was analyzed as a positional candidate gene for this linkage. Sequencing of the LARG gene and genotyping of variants identified several polymorphisms that were associated with in vivo rates of insulin-mediated glucose uptake, at both physiological and maximally stimulating insulin concentrations, among 322 nondiabetic Pima Indians who had undergone a hyperinsulinemic-euglycemic clamp. The strongest association with rate of glucose uptake was found with a Tyr1306Cys polymorphism (P < 0.0001, adjusted for age, sex, percent body fat, and nuclear family membership). In transient transfection studies in NIH3T3 cells, the LARG(Cys1306) protein had reduced activity compared with LARG(Tyr1306) protein (P < 0.05). We propose that the Tyr1306Cys substitution in LARG, through its differential activation of RhoA, increases insulin sensitivity in nondiabetic Pima Indians.
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