HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-0922v1 57/4/945    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fraenkel, M. Articles by Leibowitz, G. Search for Related Content PubMed PubMed Citation Articles by Fraenkel, M. Articles by Leibowitz, G. Social Bookmarking                What's this?

mTOR inhibition by rapamycin prevents β-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes

¹Endocrinology and Metabolism Service, Department of Medicine, and
²Department of Pathology, Hadassah - Hebrew University Medical Center, Jerusalem, 91120 Israel
³Laboratoire de Physiopathologie de la Nutrition, CNRS UMR 7059, Universiteì Paris 7, 75251 Paris, Cedex 05, France

Objective: mTOR and its downstream target S6K1 mediate nutrient-induced insulin resistance by downregulating IRS 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/day i.p. rapamycin or vehicle and the effects on insulin signaling in muscle, liver and islets and on different metabolic parameters 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 to 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 GSK3β activity. In diabetic animals rapamycin reduced β-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive JNK 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.

Conclusion: 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?