title: Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes.
abstract: Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with β cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with β cell-specific expression of hIAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing hIAPP alone or lacking autophagy alone. Furthermore, lack of autophagy in hIAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of β cells. Expression of hIAPP in purified monkey islet cells or a murine β cell line resulted in pro-hIAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mIAPP or nonfibrillar mutant hIAPP. In autophagy-deficient cells, accumulation of pro-hIAPP dimers increased markedly, and pro-hIAPP trimers were detected in the detergent-insoluble fraction. Enhancement of autophagy improved the metabolic profile of hIAPP-expressing mice fed a high-fat diet. These results suggest that autophagy promotes clearance of amyloidogenic hIAPP, autophagy deficiency exacerbates pathogenesis of human T2D, and autophagy enhancers have therapeutic potential for islet amyloid accumulation-associated human T2D.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Hwanju
authors.initials: H
authors.lastname: Cheon
authors.forename: Yeon Taek
authors.initials: YT
authors.lastname: Jeong
authors.forename: Wenying
authors.initials: W
authors.lastname: Quan
authors.forename: Kook Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Cho
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Lim
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Oh
authors.forename: Sang-Man
authors.initials: SM
authors.lastname: Jin
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Kim
authors.forename: Moon-Kyu
authors.initials: MK
authors.lastname: Lee
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014199:Trehalose / Q000494:pharmacology
chemical_list: C502661:Atg7 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D014199:Trehalose; D000071193:Autophagy-Related Protein 7