Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy

Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of beta cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of beta cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on beta cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in beta cell mass, which was due to limited beta cell proliferation and enhanced beta cell apoptosis. Importantly, expression of hIAPP in mice with a beta cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance beta cell dysfunction and progression of T2DM.