A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse

The mouse autosomal dominant mutation Mody develops hyperglycemia with nota ble pancreatic beta-cell dysfunction. This study demonstrates that one of t he alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between t he A and B chains and can induce a drastic conformational change of this mo lecule. Although there was no gross defect in the transcription from the wi ld-type insulin 2 allele or two alleles of insulin 1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, sugg esting that the number of wild-type (pro)insulin molecules was also decreas ed. Electron microscopy revealed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proin sulin was processed to insulin, but high molecular weight forms of proinsul in existed with concomitant overexpression of BiP, a molecular chaperone in the endoplasmic reticulum. Furthermore, mutant proinsulin expressed in Chi nese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findi ngs indicate that mutant proinsulin was trapped and accumulated in the endo plasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation.