Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia.
Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic beta cells and glucose homeostasis has not been described. We produced mice with beta cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. beta cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of beta cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient beta cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in beta cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic beta cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea.
Hye Seung
HS
Jung
Kun Wook
KW
Chung
Jeong
J
Won Kim
Jin
J
Kim
Masaaki
M
Komatsu
Keiji
K
Tanaka
Yen Hoang
YH
Nguyen
Tong Mook
TM
Kang
Kun-Ho
KH
Yoon
Ji-Won
JW
Kim
Yeon Taek
YT
Jeong
Myoung Sook
MS
Han
Moon-Kyu
MK
Lee
Kwang-Won
KW
Kim
Jaekyoon
J
Shin
Myung-Shik
MS
Lee
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
C502661:Atg7 protein, mouse; D007328:Insulin; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin; D000071193:Autophagy-Related Protein 7; D005947:Glucose