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.