mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes
Merav Fraenkel 1 ,
Mali Ketzinel-Gilad 1 ,
Yafa Ariav 1 ,
Orit Pappo 2 ,
Melis Karaca 3 ,
Julien Castel 3 ,
Marie-France Berthault 3 ,
Christophe Magnan 3 ,
Erol Cerasi 1 ,
Nurit Kaiser 1 and
Gil Leibowitz 1
1 Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2 Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3 Laboratoire de Physiopathologie de la Nutrition, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Universiteì
Paris, Paris, France
Address correspondence and reprint requests to Gil Leibowitz, MD, Endocrinology and Metabolism Service, Department of Medicine,
Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120. E-mail: gleib{at}hadassah.org.il
Abstract
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 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 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.
FFA, free fatty acid
IRS, insulin receptor substrate
JNK, c-Jun NH2-terminal kinase
KRBH, Krebs-Ringer bicarbonate HEPES buffer
mTOR, mammalian target of rapamycin
S6K1, S6 kinase 1
SAPK, stress-activated protein kinase
TORC1, rapamycin-sensitive complex with the regulatory-associated protein of mTOR (raptor)
TORC2, rapamycin-resistant complex with rapamycin-insensitive companion of mTOR (rictor)
TUNEL, transferase-mediated dUTP nick-end labeling
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 3 January 2008. DOI: 10.2337/db07-0922.
M.F. and M.K.-G. contributed equally to this article.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0922 .
The costs of publication of this article were defrayed in...

mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes

10.2337/db07-0922