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

Nayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Henry J. Hiddinga, Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Norman L. Eberhardt, Yoshio Fujitani, Hirotaka Watada

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3634-3644
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

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Islet Amyloid Polypeptide
Autophagy
Poisons
Type 2 Diabetes Mellitus
Amyloid Plaques
High Fat Diet
Islets of Langerhans
Insulin Resistance
Cell Death
Cell Proliferation
Apoptosis
Diet
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shigihara, N., Fukunaka, A., Hara, A., Komiya, K., Honda, A., Uchida, T., ... Watada, H. (2014). Human IAPP-induced Pancreatic β cell toxicity and its regulation by autophagy. Journal of Clinical Investigation, 124(8), 3634-3644. https://doi.org/10.1172/JCI69866

Human IAPP-induced Pancreatic β cell toxicity and its regulation by autophagy. / 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.

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3634-3644.

Research output: Contribution to journalArticle

Shigihara, N, Fukunaka, A, Hara, A, Komiya, K, Honda, A, Uchida, T, Abe, H, Toyofuku, Y, Tamaki, M, Ogihara, T, Miyatsuka, T, Hiddinga, HJ, Sakagashira, S, Koike, M, Uchiyama, Y, Yoshimori, T, Eberhardt, NL, Fujitani, Y & Watada, H 2014, 'Human IAPP-induced Pancreatic β cell toxicity and its regulation by autophagy', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3634-3644. https://doi.org/10.1172/JCI69866
Shigihara N, Fukunaka A, Hara A, Komiya K, Honda A, Uchida T et al. Human IAPP-induced Pancreatic β cell toxicity and its regulation by autophagy. Journal of Clinical Investigation. 2014 Aug 1;124(8):3634-3644. https://doi.org/10.1172/JCI69866
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. / Human IAPP-induced Pancreatic β cell toxicity and its regulation by autophagy. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3634-3644.
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