TY - JOUR
T1 - mTOR inhibition by rapamycin prevents β-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes
AU - Fraenkel, Merav
AU - Ketzinel-Gilad, Mali
AU - Ariav, Yafa
AU - Pappo, Orit
AU - Karaca, Melis
AU - Castel, Julien
AU - Berthault, Marie France
AU - Magnan, Christophe
AU - Cerasi, Erol
AU - Kaiser, Nurit
AU - Leibowitz, Gil
PY - 2008/4
Y1 - 2008/4
N2 - 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. RESEARCH DESIGN AND METHODS-Normoglycemic and diabetic P. obesus were treated with 0.2 mg · kg -1 · 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 normoglyce-mic 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 3β activity. In diabetic animals, rapamycin reduced β-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 β-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 β-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating β-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
AB - 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. RESEARCH DESIGN AND METHODS-Normoglycemic and diabetic P. obesus were treated with 0.2 mg · kg -1 · 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 normoglyce-mic 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 3β activity. In diabetic animals, rapamycin reduced β-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 β-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 β-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating β-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes.
UR - http://www.scopus.com/inward/record.url?scp=42449104351&partnerID=8YFLogxK
U2 - 10.2337/db07-0922
DO - 10.2337/db07-0922
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C2 - 18174523
AN - SCOPUS:42449104351
SN - 0012-1797
VL - 57
SP - 945
EP - 957
JO - Diabetes
JF - Diabetes
IS - 4
ER -
