Occurrence of GRB10 (+11275G > A) polymorphism in Hungarian population and its relationship to glucose metabolism

Abstract

In our backstage experiment with differential display method among the differentially expressed genes we found the gene of GRB10 (Growth factor Receptor-Bound protein 10). The GRB10 protein binds to insulin and insulin-like growth factor receptors and acts as a negative regulatory protein. Besides, GRB10 gene polymorphisms are connected to the development of type 2 diabetes mellitus. In this experiment we investigated the allele frequency of RS 2237457, +11275G > A polymorphism in Hungarian healthy and type 2 diabetic populations (healthy: n = 77, diabetics: n = 85). We also searched for the connections between the genotype and glucose homeostasis measured by hyperinsulinemic - normoglycemic clamps in healthy volunteers (n = 88), glucose intolerant (IFG n = 15; IGT n = 29) and non-treated type 2 diabetic patients (n = 9). We did not find significant differences in allele frequencies between the Hungarian healthy and diabetic populations (healthy: g vs. a: 62% vs. 38%; 2DM g vs. a: 70% vs. 30%). In case of females, glucose utilization did not depend on GRB10 gene polymorphisms. Insulin production after oral glucose load was increased among males with gg alleles, and not after iv. glucose administration. The glucose disposal in muscle tissue was lower and the metabolic clearance rate was also lower calculated either for total body or muscle tissue in this group. In both genders gg alleles were associated with a disadvantageous lipid profile of decreased levels of large, buoyant LDL molecules and HDL levels in females. Metabolic changes related to the polymorphism of GRB10 gene support a gender specific role of this gene in insulin sensitivity and insulin signal transduction. It may be hypothesized on the basis of the differences in insulin release after oral and iv. glucose loads that GRB10 is involved in incretin signaling pathway.