Heritability of Insulin Secretion, Peripheral and Hepatic Insulin Action, and Intracellular Glucose Partitioning in Young and Old Danish Twins

Abstract

The etiology of type 2 diabetes is multifactorial, including genetic as well as pre- and postnatal factors that influence several different defects of glucose homeostasis, primarily in muscle, beta-cells, and liver. In the present twin study, we report heritability estimates (h(2)) for measures of insulin secretion, insulin resistance, hepatic glucose production (HGP), and intracellular glucose partitioning using gold standard methods (euglycemic-hyperinsulinemic clamp technique, tritiated glucose infusion, indirect calorimetry, and intravenous glucose tolerance testing) among 110 younger (22-31 years of age) and 86 older (57-66 years of age) twins. To obtain a valid estimate of beta-cell function, insulin secretion was adjusted for the individual degree of insulin action (disposition index). In both age-groups there was a major genetic component in the etiology of insulin secretion that was statistically significantly higher among older twins (young h(2) = 0.75 [0.55-0.86] and old h(2) = 0.84 [0.69-0.92], P < 0.05). The heritability estimates for peripheral insulin sensitivity (young h(2) = 0.53 [0.28-0.71] and old h(2) = 0.55 [0.20-0.76]) and nonoxidative glucose metabolism (young h(2) = 0.50 [0.32-0.64] and old h(2) = 0.48 [0.04-0.72]) were similar in younger and older twins, supporting the notion of both genetic and environmental etiological factors in the control of insulin action and nonoxidative glucose metabolism. The results suggested that HGP was predominantly controlled by nongenetic factors in both young and old twins. In conclusion, we provide further evidence for a role of genes in controlling insulin secretion, insulin action, and nonoxidative glucose metabolism. The relative contribution of genes versus environment on in vivo insulin secretion exhibited an age dependency with a slightly greater relative impact of genes among older as compared with younger twins.