Insulin Gene in Diabetes Analysis Through RFLP

Abstract

Insulin deficiency is a prominent feature of non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus that could result from defects in the insulin gene. Cloning of this gene has permitted molecular-genetic studies including the definition of multiple-DNA-sequence polymorphisms detected with restriction endonucleases, or restriction-fragment-length polymorphisms (RFLPs), and the mapping of the insulin gene to the short arm of chromosome 11 adjacent to the insulinlike growth factor II (IGF-II) and tyrosine hydroxylase genes. The combined RFLPs for the insulin, IGF-II, and tyrosine hydroxylase genes make this a highly informative locus for genetic studies of the insulin gene in diabetes. Early studies of an RFLP consisting of variable-number tandem repeats (VNTR) of DNA near the insulin gene suggested an association of certain alleles with approximately 170 copies of the repeat unit with NIDDM. Although subsequent studies in NIDDM did not confirm this association, an association of different alleles defined by approximately 40 copies of the repeat unit in this VNTR region with IDDM has been demonstrated in multiple studies. This VNTR region and the multiple other RFLPs for this region have been used in linkage analysis to study the segregation of insulin genes in families. These studies have failed to demonstrate a major significant role for insulin-gene defects in NIDDM, maturity-onset diabetes of the young, or IDDM in American Blacks and Whites and under various models of inheritance. Several pedigrees with diabetes and defects of the insulin gene have been described, however, and a minor role for this gene in NIDDM cannot be eliminated from available studies. Similarly, the association studies of the insulin gene and IDDM suggest a minor modifying role undetectable in pedigree studies. The role of defects in or near the insulin gene in a small subset of NIDDM or in IDDM must await direct investigation of the insulin gene in diabetic individuals with the most recent methods for gene amplification and sequence analysis.

A variant insulin promoter in non-insulin-dependent diabetes mellitus.

“…Previous studies of the insulin gene in populations of subjects and in families with NIDDM led to the conclusion that this locus did not contribute in a major way to the inherited risk for NIDDM in any racial group (4,5,7,8). The results of the current study at least partially explain failure to find an association of this locus with NIDDM in American Blacks.…”

“…Initial reports of a positive association of a large class 3 allele with NIDDM were not confirmed in later studies oflarger racially uniform populations (see reference 4 for review). Linkage analysis in families with maturity onset diabetes ofthe young (5,6), the autosomal dominant subtype of NIDDM, and in more typical Northern European Caucasian (7) and American Black (8) NIDDM families, concluded that there was no linkage ofthe insulin gene and NIDDM, and that insulin gene defects are not a major factor predisposing to NIDDM.…”

Types of Diabetes According to National Diabetes Data Group Classification: Limited Applicability and Need to Revisit

“…1. Mutations in the insulin-receptor gene have been described in Whites (12)(13)(14). In contrast, however, studies indicate that in Native Americans with NIDDM there are normal DNA insulin-receptor sequences (15,16).…”

“…Some data suggest that a subgroup of patients labeled as type II NIDDM really represent a late-onset (or a slow-onset) autoimmune type I IDDM (12)(13)(14)(15)(16). In one study, up to 26% of those with oral agent failure had autoimmune markers (14). Data also show that 15% of patients clinically labeled as type II have evidence of islet cell autoimmunity and within several years will become insulin dependent (10).…”

“…Hence, it is essential that any classification embraces current knowledge of heterogeneity. Some data suggest that a subgroup of patients labeled as type II NIDDM really represent a late-onset (or a slow-onset) autoimmune type I IDDM (12)(13)(14)(15)(16). In one study, up to 26% of those with oral agent failure had autoimmune markers (14).…”