A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo

Diabetes
Peter KovacsLeslie J Baier

Abstract

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 s...Continue Reading

References

Sep 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·C FrommJ S Gutkind
Oct 6, 1997·Genes & Development·L Van Aelst, C D'Souza-Schorey
Apr 29, 1998·American Journal of Human Genetics·R A NormanE Ravussin
Jun 26, 1998·Science·T KozasaP C Sternweis
Apr 23, 1999·The Journal of Biological Chemistry·I N FlemingJ H Exton
Feb 19, 2000·Proceedings of the National Academy of Sciences of the United States of America·P J KourlasM A Caligiuri
Oct 6, 2000·The Journal of Clinical Investigation·L J BaierC Bogardus
Oct 31, 2000·Genetic Epidemiology·J R O'Connell
Jul 27, 2001·Diabetes Technology & Therapeutics·S C Elbein
Apr 12, 2002·Gene·Benjamin Boettner, Linda Van Aelst
May 25, 2002·Molecular and Cellular Biology·Michelle A BoodenChanning J Der
Aug 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jennifer AurandtKun-Liang Guan
Jan 8, 2003·Proceedings of the National Academy of Sciences of the United States of America·Nobuchika SuzukiTohru Kozasa
Mar 6, 2003·Molecular Genetics and Metabolism·Johanna K WolfordRobert L Hanson
May 29, 2003·The Journal of Biological Chemistry·Stephan VogtStefan Offermanns
Apr 10, 2004·American Journal of Physiology. Heart and Circulatory Physiology·James R Sowers

❮ Previous
Next ❯

Citations

May 29, 2007·Nucleic Acids Research·Yana Bromberg, Burkhard Rost
Oct 31, 2007·Circulation Research·Maritza J RomeroRobert W Caldwell
Apr 15, 2015·Hypertension·Maria Luigia CarboneGervaise Loirand
Apr 25, 2007·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Robert KisilevskySuzana Petanceska
May 16, 2019·Journal of Diabetes Research·Matthew P JohnsonSarah Williams-Blangero
Oct 18, 2007·Current Opinion in Endocrinology, Diabetes, and Obesity

❮ Previous
Next ❯

Related Concepts

Related Feeds

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.