mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes.
OBJECTIVE
Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.


METHODS
Normoglycemic and diabetic P. obesus were treated with 0.2 mg x kg(-1) x day(-1) i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.


RESULTS
Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3beta activity. In diabetic animals, rapamycin reduced beta-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH(2)-terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and beta-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.


CONCLUSIONS
Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing beta-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating beta-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
Fraenkel
Merav
M
Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel.
Ketzinel-Gilad
Mali
M
Ariav
Yafa
Y
Pappo
Orit
O
Karaca
Melis
M
Castel
Julien
J
Berthault
Marie-France
MF
Magnan
Christophe
C
Cerasi
Erol
E
Kaiser
Nurit
N
Leibowitz
Gil
G
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D005849:Gerbillinae; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000633:toxicity*; D058570:TOR Serine-Threonine Kinases
D007328:Insulin; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus