Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation.
There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1(+/-) mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1(+/-) mice to Becn1(+/-) mice. After 1 week on a high fat diet, 4-week-old Pdx1(+/-) Becn1(+/-) mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1(+/-) mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention.
Fujimoto
Kei
K
Division of Endocrinology, Metabolism and Lipid Research, Department of Internal Medicine, Washington University School of Medicine/Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Hanson
Piia T
PT
Tran
Hung
H
Ford
Eric L
EL
Han
Zhiqiang
Z
Johnson
James D
JD
Schmidt
Robert E
RE
Green
Karen G
KG
Wice
Burton M
BM
Polonsky
Kenneth S
KS
D000596:Amino Acids / Q000172:deficiency / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D013217:Starvation; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D003470:Culture Media; D018398:Homeodomain Proteins; D008869:Microtubule-Associated Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein