title: Rapamycin-induced glucose intolerance: hunger or starvation diabetes.
abstract: Rapamycin prolongs healthy lifespan in yeast, flies and mammals and delays age-related diseases, including cancer and atherosclerosis. Rapamycin is considered for prevention of diabetic complications, such as retinopathy and nephropathy, and acute treatment with rapamycin decreases insulin resistance. However, under certain conditions, chronic administration of rapamycin may cause glucose intolerance and even provoke type II diabetes. This does not fit logically with its potential effects against diabetic complications. This also seems puzzling, because calorie restriction (CR) can prevent type II diabetes and its complications, and rapamycin mimics CR. It was somehow forgotten that almost two centuries ago, Claude Bernard discovered "starvation diabetes," as shown later, characterized by glucose intolerance, decreased insulin, increased lipoproteins and ketones, gluconeogenesis and hepatic resistance to insulin. This reversible condition is not true diabetes: it does not lead to diabetic complications, and CR extends healthy lifespan. If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce "hunger diabetes." But will rapamycin prevent true type II diabetes? Here are some answers.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA. blagosklonny@oncotarget.com
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
mesh_terms: D031204:Caloric Restriction; D048909:Diabetes Complications / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000378:metabolism*; D018149:Glucose Intolerance / Q000139:chemically induced*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008954:Models, Biological; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus