A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo.
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.
Kovacs
Peter
P
Diabetes Molecular Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ 85004, USA.
Stumvoll
Michael
M
Bogardus
Clifton
C
Hanson
Robert L
RL
Baier
Leslie J
LJ
D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D001130:Arizona; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005006:Ethnicity; D014644:Genetic Variation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007198:Indians, North American; D007328:Insulin / Q000502:physiology*; D008137:Longitudinal Studies; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D064067:Rho Guanine Nucleotide Exchange Factors; D014162:Transfection
C577222:ARHGEF12 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D064067:Rho Guanine Nucleotide Exchange Factors