Introduction

The genetic nature of diabetes has been well documented by studies of familial aggregation, concordance in identical twins and, for insulin-dependent diabetes, HLA analysis in sib pairs (Rotter & Rimoin, 1981). For insulin-dependent (Type 1) diabetes mellitus (IDDM), autoimmune pancreatic destruction clearly occurs and appears to be mediated in part by genetic susceptibility in the HLA class II genes. None the less, considerable evidence suggests involvement of other loci, including the insulin gene (Rotter & Rimoin, 1981; Bell et al., 1984). For non-insulin-dependent diabetes mellitus (Type 2, NIDDM), concordance in identical twins approaches 100%; the familial nature is well documented (Rotter & Rimoin, 1981; Kobberling & Tillil, 1982). The physiological defect remains controversial, but elements of insulin resistance, increased hepatic glucose output, and relative insulin deficiency are all present in the fully developed phenotype (Weir, 1982; Truglia et al., 1985; Ward et al., 1984). Although defects in insulin production could account for part of this spectrum, a role for insulin gene defects has been described only in a few pedigrees with mild glucose intolerance or diabetes and hyperinsulinemia or hyperproinsulinemia (see below).

Insulin gene structure

The cloning of the human insulin gene (Bell et al., 1980; Ullrich et al., 1980) permitted a new approach to the role of insulin gene mutations in IDDM and NIDDM. Insulin is encoded by a single gene of 1430 base pairs (bp). Both somatic cell hybrids (Owerbach et al., 1980) and in situ hybridization (Zabel et al., 1985) have localized the gene to the short arm of chromosome 11(11p).