Genetics of glucose homeostasis: implications for insulin resistance and metabolic syndrome

Abstract

This review summarizes the current understanding of the genetic basis of glucose homeostasis through genome-wide association scans and candidate gene studies of case-control and family-based designs. We highlight the implications of phenotype-direct (euglycemic clamp or frequently sampled intravenous glucose tolerance test) and indirect (fasting insulin and fasting glucose) measures on the determinants of insulin resistance and β-cell response that precede and contribute to the development of type 2 diabetes mellitus (T2DM) and the metabolic syndrome. Finally, we examine future approaches that may aid in understanding the biology of insulin resistance and T2DM. Over the past 2 decades, the prevalence of insulin resistance, the metabolic syndrome, and T2DM has increased. Ethnic differences in T2DM and insulin resistance are evident, with nonwhite populations having the greatest risk. There continue to be significant gaps in our knowledge regarding the metabolic, behavioral, and genetic determinants of these conditions. Understanding the genetic basis of glucose homeostasis, insulin resistance, and T2DM should provide insight on known and novel metabolic pathways that identify potential therapeutic targets and mechanisms for intervention.

Figure 1

Genetic and epidemiological basis of glucose homeostasis, insulin resistance, and the metabolic syndrome.

Figure 2

Changes of insulin sensitivity (S_i) and acute-phase insulin response (AIR) from baseline (arrow base) to follow-up (arrow top) in populations stratified by baseline and follow-up glucose tolerance status. IGT indicates impaired glucose tolerance; DM, diabetes mellitus.