Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth

Abstract

Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene. Not all mutations in the INS gene cause the autosomal dominant Mutant INS-gene Induced Diabetes of Youth (MIDY) syndrome, but most missense mutations affecting proinsulin folding produce MIDY. MIDY patients are heterozygotes, with the expressed mutant proinsulins exerting dominant-negative (toxic gain of function) behavior in pancreatic beta cells. Here we focus primarily on proinsulin folding in the endoplasmic reticulum, providing insight into perturbations of this folding pathway in MIDY. Accumulated evidence indicates that, in the molecular pathogenesis of the disease, misfolded proinsulin exerts dominant effects that initially inhibit insulin production, progressing to beta cell demise with diabetes.

Figure 1

Proposed molecular mechanisms of beta cell failure caused by misfolded (pre)proinsulin. When WT (blue) and mutant (red) proinsulin are co-expressed in beta cells, the mutant proinsulin promotes WT proinsulin retention in the ER, decreasing insulin production, and forcing beta cells to use up insulin secretory granules from their progressively depleted insulin storage pool. The insufficiency of insulin increases blood glucose that initially stimulates even more production of wild-type and mutant preproinsulins, exacerbating ER stress induced by misfolded proinsulin-containing protein complexes. Inexorable progression of insulin insufficiency leads to frank diabetes, further ER stress, and beta cell demise.