[HTML][HTML] Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagy

N Shigihara, A Fukunaka, A Hara… - The Journal of …, 2014 - Am Soc Clin Investig
N Shigihara, A Fukunaka, A Hara, K Komiya, A Honda, T Uchida, H Abe, Y Toyofuku…
The Journal of clinical investigation, 2014Am Soc Clin Investig
Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of
β 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 β cells to the cytotoxic effects of hIAPP.
Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation …
Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β 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 β 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 β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet–induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β 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 β cell dysfunction and progression of T2DM.
The Journal of Clinical Investigation