Familiality of Quantitative Metabolic Traits in Finnish Families with Non-Insulin-Dependent Diabetes mellitus

Abstract

Type 2 diabetes mellitus (NIDDM) is a complex disorder encompassing multiple metabolic defects. There exists strong evidence for a genetic component to NIDDM; however, to date there have been few reports of linkage between genetic markers along the genome and NIDDM or NIDDM-related quantitative traits. We sought to determine whether individual quantitative traits which determine glucose tolerance exhibit familiality in Finnish families with at least one NIDDM-affected sibling pair. Tolbutamide-modified frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on unaffected offspring (n = 431) and spouses (n = 154) of affected sibling pairs sampled for the Finland-United States Investigation of NIDDM Genetics (FUSION) study. FSIGT data were analyzed using the Minimal Model to obtain quantitative measures of insulin sensitivity (S_I), glucose effectiveness (S_G), and insulin secretion assessed as the acute insulin response to glucose (AIR). The disposition index (DI), a measure of insulin resistance-corrected β-cell function, was also derived as the product of S_I and AIR. Variance components analysis was used to determine for each trait, the heritability (h²), the proportion of the total trait variance accounted for by additive genes. After adjustment for age, gender, and body mass index, h² estimates were: S_G: 18 ± 9%, S_I: 28 ± 8%, AIR: 35 ± 8%, and DI: 23 ± 8%. We conclude that there is strong evidence for modest heritability of Minimal-Model-derived NIDDM-related quantitative traits in unaffected spouses and offspring of Finnish affected sibling pairs.