Rapamycin Treatment Exacerbates Nutrition-Induced Diabetes in Psammomys obesus.

Fraenkel, Merav; Gilad, Mali Ketzinel; Karaca, Melis; Castel, Julien; Magnan, Christophe; Ceraci, Erol; Kaiser, Nurit; Leibowitz, Gil

mTOR is a serine threonine kinase regulated by nutrients and growth factors. Acivation of mTOR/S6K1 results in downregulation of IRS1 and IRS2 with subsequent reduced Akt phosphorylation, hence insulin resistance. It was suggested that inhibition of mTOR/6SK1 could become a therapeutic target in insulin resistant states, such as obesity and Type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of diet-induced Type 2 diabetes using the mTOR/S6K1 inhibitor rapamycin. Diabetic P. obesus fed the high-energy (HE) diet were treated with 0.2 mg/kg/day (IP) rapamycin or vehicle for 14 days. Rapamycin therapy accelerated diabetes in P. obesus. At 2 weeks, blood glucose of the rapamycin treated animals was 436±26 mg/dl vs 303.3±55.6 mg/dl in the control group (p<0.001). This was accompanied by weight loss. Body weight of the rapamycin-treated animals was 174.4±4.7 gr vs 200.3±4.4 gr that of control animals (p<0.001). Hyperglycemia in diabetic P. obesus was accompanied by a 10-fold increase of serum insulin compared to normoglycemic controls, while rapamycin therapy completely abolished this increase. The hypoinsulinemia in the rapamycin treated P. obesus was accompanied by a 55-, 12- and 23-fold increase in serum triglycerides, FFAs and ketone bodies, respectively (p<0.001). Rapamycin completely abolished S6 kinase and reduced IRS1 serine 636/639 phosphorylation. However, this was associated with reduced total IRS1 levels and Akt phosphorylation at serine 473 in muscle, fat and liver. In line with this observation, intraperitoneal insulin tolerance test revealed a lower insulin sensitivity of the rapamycin-treated P. obesus compared to controls. In the islets, rapamycin therapy increased IRS2 expression in vivo and in vitro. However, this was not associated with increased Akt phosphorylation. Moreover, rapamycin therapy resulted in a 3-fold decrease in β-cell mass and impaired glucose-stimulated insulin secretion and proinsulin biosynthesis. We conclude that treatment of diabetic P. obesus with rapamycin generates a fulminant form of diabetes characterized by excessive hyperglycemia, weight loss, hyperlipidemia and hypoinsulinemia. Exacerbation of diabetes results from both increased insulin resistance, reduced β-cell mass and impairment of β-cell function. These findings make it unlikely that mTOR/S6K1 inhibition is an adequate therapeutic approach to insulin- resistant diabetes.

RAPAMYCIN; TYPE 2 diabetes; SERINE; GROWTH factors; PHOSPHORYLATION; OBESITY; HYPERGLYCEMIA; HYPERLIPIDEMIA

Diabetes, 2007, Vol 56, pA514

0012-1797

Academic Journal