Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes.
Overload of pancreatic beta cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to beta cell exhaustion and type 2 diabetes. Because beta cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills beta cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced beta cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress-associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 beta cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8-10 weeks. We conclude that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.
Oyadomari
Seiichi
S
Department of Molecular Genetics, Kumamoto University School of Medicine, Kumamoto, Japan.
Koizumi
Akio
A
Takeda
Kiyoshi
K
Gotoh
Tomomi
T
Akira
Shizuo
S
Araki
Eiichi
E
Mori
Masataka
M
D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D018832:Molecular Chaperones; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP