2162-P: Autophagy Deficiency Cumulatively Causes ß-Cell Failure in Mice
Authors: SUZUKI LUKA , MIYATSUKA TAKESHI , HIMURO MIWA , MIURA MASAKI , KATAHIRA TAKEHIRO , KOMIYA KOJI , FUJITANI YOSHIO , NISHIDA YUYA , WATADA HIROTAKA 
Published: June 2019

Autophagy is known to play a pivotal role in intracellular quality control through the degradation of damaged organelles and components. We previously reported that β-cell specific autophagy deficient mice (βAtg7KO), which lack Atg7 in β cells throughout their lives after birth, exhibited impaired glucose tolerance accompanied by decreased β-cell mass. Since the phenotypes in βAtg7KO mice result from life-long autophagic failure, it remains unclear as to when and how autophagy deficiency affects β-cell homeostasis. To address these questions, we have generated the inducible β-cell-specific Atg7-knockout mice (iβAtg7KO), by crossing mice carrying floxed Atg7 allele with MIP-Cre/ERT mice that induce Cre-mediated recombination in a tamoxifen-inducible manner under the control of mouse Ins1 promoter. When the autophagy deficiency was induced for 2 weeks (between 10 and 12 weeks of age), the iβAtg7KO2W mice exhibited normal glucose tolerance during IPGTT. On the other hand, the prolonged autophagy deficiency for 6 weeks (between 6 and 12 weeks of age) in iβAtg7KO6W mice caused glucose intolerance with significantly impaired insulin secretion. Thus, the short-term Atg7 deficiency in iβAtg7KO2W mice did not apparently deteriorate β-cell function, whereas the long-term Atg7 deficiency for 6 weeks in iβAtg7KO6W mice caused β-cell failure. In order to investigate the underlying molecular mechanisms by which the autophagy deficiency links to β-cell failure, RNA-sequencing was performed with the isolated islets from iβAtg7KO2w, iβAtg7KO6w mice and control littermates. Among more than 13,000 genes expressed in the islets, we identified a gene that was expressed &gt;50-fold higher in iβAtg7KO2W and iβAtg7KO6w mice than in the control littermates, and that are highly expressed in diabetic db/db mice. Taken together, these findings suggest that the autophagy failure cumulatively leads to β-cell failure after a certain interval, accompanied by stepwise alteration of gene expression patterns.

Disclosure
L. Suzuki: None. T. Miyatsuka: None. M. Himuro: None. M. Miura: None. T. Katahira: None. K. Komiya: None. Y. Fujitani: Research Support; Self; Takeda Pharmaceutical Company Limited. Y. Nishida: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

Funding
Japan Society for the Promotion of Science