Chronic mTOR Inhibition By Rapamycin Induces Muscle Insulin Resistance Despite Weight Loss In Rats

Research Summary

An experimental study in rats and in cultured muscle cells asking why chronic rapamycin (sirolimus) treatment produces diabetes-like metabolic changes even though it lowers body weight and fat mass.

Who Or What Was Studied?

Male Wistar rats fed either a standard diet or a 45% high-fat diet and given sirolimus 2 mg/kg/day by intraperitoneal injection for 21 days, alongside pair-fed and vehicle-treated controls; whole-blood sirolimus reached about 15.6 ug/L, the therapeutic range used in patients. Insulin sensitivity was assessed by glucose tolerance tests and euglycaemic hyperinsulinaemic clamps, and the mechanisms were followed up in cultured rat L6 myotubes exposed to rapamycin for 48 hours.

What Did The Research Show?

• Sirolimus reduced food intake, body-weight gain and fat mass; the loss of fat mass was independent of the change in food intake, and lean mass as a share of body weight rose.
• Despite the weight loss, sirolimus-treated rats were glucose intolerant, hyperinsulinaemic and hyperglycaemic: fasting insulinaemia roughly doubled (1.4 to 3.5 ng/mL) and HOMA-IR rose from 8.4 to 28.0.
• Euglycaemic hyperinsulinaemic clamps identified skeletal muscle as a major site of insulin resistance, with a strongly reduced insulin-stimulated glucose utilisation index in red and white muscles.
• In muscle, chronic sirolimus blocked phosphorylation of S6 (confirming mTORC1 inhibition) and completely prevented insulin-induced Akt phosphorylation at Ser473 (an mTORC2 site), reduced phosphorylation of the Akt substrates AS160 and GSK3, and lowered GLUT1 and GLUT4 expression and insulin-stimulated GLUT4 translocation.
• In high-fat-fed rats, sirolimus prevented weight gain and hepatic steatosis and normalised plasma triglycerides, but worsened glucose intolerance and raised HOMA-IR from 17.4 to 67.0.

Limitations And Interpretation

• Animal and cell data, not human: the findings describe a rat and L6-muscle-cell mechanism and do not establish the same effects or doses in people.
• A fixed dose (2 mg/kg/day) was used and whole-blood levels sat at the upper end of the therapeutic range; effects could differ at lower or intermittent doses.
• Skeletal muscle alone does not explain the whole picture – the authors note that effects in the liver and on pancreatic beta-cell function may also contribute.