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

• Published in: The Journal of clinical investigation 2014-08, Vol.124 (8), p.3634-3644
• Main Authors: Shigihara, Nayumi, Fukunaka, Ayako, Hara, Akemi, Komiya, Koji, Honda, Akira, Uchida, Toyoyoshi, Abe, Hiroko, Toyofuku, Yukiko, Tamaki, Motoyuki, Ogihara, Takeshi, Miyatsuka, Takeshi, Hiddinga, Henry J, Sakagashira, Setsuya, Koike, Masato, Uchiyama, Yasuo, Yoshimori, Tamotsu, Eberhardt, Norman L, Fujitani, Yoshio, Watada, Hirotaka
• Format: Article
• Language: English
• Subjects: Animals; Autophagy (Cytology); Autophagy - physiology; Autophagy-Related Protein 7; Cell Cycle; Cell Line; Cell Survival; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; Glycoproteins; Humans; Insulin Resistance - physiology; Insulin-Secreting Cells - pathology; Insulin-Secreting Cells - physiology; Islet Amyloid Polypeptide - genetics; Islet Amyloid Polypeptide - physiology; Islet Amyloid Polypeptide - toxicity; Mice; Mice, Knockout; Mice, Transgenic; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - genetics; Pancreatic beta cells; Physiological aspects; Recombinant Proteins - genetics; Recombinant Proteins - toxicity
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI69866

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.