Hepatic glucokinase promoter polymorphism is associated with hepatic insulin resistance in Asian Indians.

We identified 38 GG, 24 GA, and one AA subjects. The AA subject was pooled with the GA subjects during the analysis. No difference was noted in the demographic features between the two genotypic groups (GG vs. GA/AA). Compared to the GG group, the GA/AA group had a lower ISIH (p=0.002), a lower ISIM (p=0.009), a higher %B (p=0.014), and a higher dI/dG (p=0.030). Multivariate analysis revealed that this polymorphism is an independent determinant for ISIH (p=0.019) and along with age, waist-hip ratio, gender, and diastolic blood pressure accounted for 51.5% of the variation of ISIH. However, this polymorphism was a weak, but independent determinant for ISIM (p=0.089) and %B (p=0.083). Furthermore, it had no independent effect on dI/dG (p=0.135).These data suggest that the G-to-A polymorphism in the hepatic GCK promoter is associated with hepatic insulin resistance in Asian Indians.Glucokinase (GCK) was originally proposed to be a glucose sensor and metabolic signal generator in pancreatic beta cells and hepatocytes [1]. The discoveries of a linkage and subsequent identification of mutated GCK genes [2,3] in families with maturity-onset diabetes of the young (MODY) provide the strongest evidence for a crucial role of GCK in the pathogenesis of MODY [1]. However, the structural mutations (missense, nonsense mutation, or mutations affecting the splicing mechanism) of GCK were only found in less than 1% of patients with type 2 diabetes [4]. Thus, the mutated GCKs do not play a key role in the pathogenesis of most forms of diabetes.Nonetheless, some studies suggest that defective liver GCK may play a role in the pathogenesis of insulin resistance and type 2 diabetes [5]. In patients with type 2 diabetes who underwent elective cholecystectomy, hepatic GCK activity was decreased by about 50% in obese diabetic subjects compared to lean controls and obese controls [5]. Hyperglycemia in animals has been shown to decrease hepatic GCK activity, which can be reversed by treatment