title: Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy.
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.
authors.forename: Nayumi
authors.initials: N
authors.lastname: Shigihara
authors.forename: Ayako
authors.initials: A
authors.lastname: Fukunaka
authors.forename: Akemi
authors.initials: A
authors.lastname: Hara
authors.forename: Koji
authors.initials: K
authors.lastname: Komiya
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Toyoyoshi
authors.initials: T
authors.lastname: Uchida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Abe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Toyofuku
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Tamaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyatsuka
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Hiddinga
authors.forename: Setsuya
authors.initials: S
authors.lastname: Sakagashira
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Norman L
authors.initials: NL
authors.lastname: Eberhardt
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watada
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology*; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000633:toxicity
chemical_list: C502661:Atg7 protein, mouse; D058228:Islet Amyloid Polypeptide; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D000071193:Autophagy-Related Protein 7