Lessons Learned From Molecular Biology of Insulin-Gene Mutations

Abstract

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Dominant Negative Pathogenesis by Mutant Proinsulin in the Akita Diabetic Mouse

“…These findings suggest that a portion of nascent wild-type proinsulin is misfolded, and that ␤-cells are continuously in a situation close to ER "overload." Several point mutations that result in amino acid substitutions within the proinsulin molecules are known in humans, although those involving disulfide bonds have not been reported (23). Minor conformational changes of these human mutant proinsulins may induce ␤-cell dysfunction in the long term.…”

Sorting and processing of secretory proteins

“…More specifically, mutation of the dibasic residues [294] and the use of active-site-directed peptides [296] has shown that type 1 (PC 1) and type 2 (PC2) enzymes require the presence of pairs of basic residues at their respective proinsulin cleavage sites. Finally, it has been shown that in some patients with familial hyperproinsulinaemia in which one of the basic amino acids at one of the cleavage sites has been altered, a partially cleaved proinsulin conversion intermediate is found in the circulation [297]. The cleavage specificity of proinsulin by PCI and PC2 has been analysed in more detail by co-transfection of rat insulin I into COS cells with human PCl and mouse PC2 [249].…”

Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients.

“…Abnormalities associated with NIDDM have been identified in insulin (2,3), insulin receptor (4,5), glucokinase ( MODY2 ) (6, 7), HNF-4 ␣ ( MODY1 ) (8), HNF-1 ␣ ( MODY3 ) (9), and mitochondrial genes (10,11). However, these abnormalities seem to be rare in the common form of NIDDM, and the major causes of NIDDM remain elusive.…”