Human evidence for the involvement of insulin-induced gene 1 in the regulation of plasma glucose concentration

Insulin-induced gene 1 (INSIG1) is a protein that blocks proteolytic activation of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate genes regulating cholesterol and fatty acid metabolism and possibly genes involved in glucose homeostasis. In search of genetic regulation of these processes we examined human INSIG1 for common polymorphisms and analysed their associations with biochemical parameters related to lipid and glucose metabolism. Associations between common polymorphisms in INSIG1 and several biochemical parameters were analysed in a group of 618 healthy, 50-year-old men. A replication analysis was performed in a cohort of 472 healthy, middle-aged men. The impact of one promoter polymorphism on oral glucose tolerance was analysed in a subset of 181 subjects. Small interfering RNA (siRNA) inhibition was used to test the significance of INSIG1 for gene expression in human Huh7 hepatoma cells. A potentially functional polymorphism, a C to T substitution at position -169, was discovered in a highly conserved section of the promoter. Significant relationships between the -169C > T polymorphism and plasma glucose concentration were found in two cohorts of healthy, middle-aged men (p < 0.01 and p < 0.02, respectively). The -169T allele was associated with significantly lower post-load plasma glucose concentrations. A significant (Ce=0.02) reduction in expression of phosphoenolpyruvate carboxykinase (PCK2) was observed following siRNA inhibition of INSIG1 in human Huh7 hepatoma cells. Population studies demonstrate that INSIG1 plays a role in glucose homeostasis. Experiments with siRNA suggest that this action of INSIG1 is related to SREBP-mediated regulation of PCK2.