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

ABSTRACT: Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of ? 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 ? 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 ? cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in ? cell mass, which was due to limited ? cell proliferation and enhanced ? cell apoptosis. Importantly, expression of hIAPP in mice with a ? 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 ? cell dysfunction and progression of T2DM.

SUBMITTER: Shigihara N 

PROVIDER: S-EPMC4109539 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature