PT  - JOURNAL ARTICLE
AU  - Kovacs, Peter
AU  - Stumvoll, Michael
AU  - Bogardus, Clifton
AU  - Hanson, Robert L.
AU  - Baier, Leslie J.
TI  - A Functional Tyr1306Cys Variant in LARG Is Associated With Increased Insulin Action in Vivo
AID  - 10.2337/db05-1331
DP  - 2006 May 01
TA  - Diabetes
PG  - 1497--1503
VI  - 55
IP  - 5
4099  - http://diabetes.diabetesjournals.org/content/55/5/1497.short
4100  - http://diabetes.diabetesjournals.org/content/55/5/1497.full
SO  - Diabetes2006 May 01; 55
AB  - 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.