The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes.
Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.
Leibowitz
G
G
Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. gleib@hadassah.org.il
Cerasi
E
E
Ketzinel-Gilad
M
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases