Heritability of pancreatic beta-cell function among nondiabetic members ofCaucasian familial type 2 diabetic kindreds

Both defective insulin secretion and insulin resistance have been reported in relatives of type 2 diabetic subjects. We tested 120 members of 26 famil ies with a type 2 diabetic sibling pair with a tolbutamide-modified, freque ntly sampled iv glucose tolerance test to determine the insulin sensitivity index (S-I) and acute insulin response to glucose (AIR(glucose)). A measur e of beta-cell compensation for insulin sensitivity was calculated as the p roduct S-I x AIR(glucose), based on the demonstrated hyperbolic relationshi p between insulin sensitivity and insulin secretion. A percentile score for this compensation was assigned based on published values. Of the 120 famil y members, 26 had previously diagnosed impaired glucose tolerance on oral t esting, and 94 had normal glucose tolerance tests. As a group, family membe rs showed a significantly lower S-I x AIR(glucose) than a similar, previous ly reported, control population, even when impaired glucose tolerance membe rs were excluded. Ne performed a multivariate analysis of diabetes status, S-I, AIR(glucose), and to estimate the heritability of each trait and the g enetic and environmental correlations between traits. We estimated the heri tability of S-I x AIR(glucose) to be 67 +/- 3% when all members were includ ed and 70 +/- 4% when only normal glucose tolerance members were considered . Both AIR(glucose) and S-I were also familial, albeit with lower heritabil ities (38 +/- 1% and 38 +/- 2%, respectively, for all family members). Both S-I x AIR(glucose) and S-I showed strong negative genetic correlations wit h diabetes (-85 +/- 3% and -87 +/- 2%, respectively. all family members), w hereas AIR(glucose) did not correlate with diabetes. We conclude that insul in secretion, as measured by S-I x AIR(glucose), is decreased in nondiabeti c members of familial type 2 diabetic kindreds, that S-I x AIR(glucose) in these high risk families is highly heritable, and that the same polygenes m ay determine diabetes status and a low S-I x AIR(glucose). Our data suggest that insulin secretion, when expressed as an index normalized for insulin sensitivity, is more familial than either insulin sensitivity or first phas e insulin secretion alone and may be a very useful trait for identifying ge netic predisposition to type 2 diabetes.