Fasting And Rapamycin: Diabetes Versus Benevolent Glucose Intolerance

Research Summary

An opinion review about a puzzle in the rapamycin literature: the same drug is reported both to improve insulin sensitivity and to cause glucose intolerance, and the review asks whether the second effect is harmful.

Who Or What Was Studied?

No new experiment is reported. The review draws on mouse and rat studies of rapamycin and mTOR signalling, human studies of fasting and very low-calorie diets, and clinical data from transplant patients, cancer patients and generally healthy elderly people treated with rapamycin or everolimus.

What Did The Research Show?

• Rapamycin and its analog everolimus inhibit mTORC1, the same nutrient-sensing pathway that fasting and severe calorie restriction switch off.
• In mice, prolonged rapamycin treatment has been reported to cause glucose intolerance and insulin resistance that travel together with a longer, not shorter, lifespan.
• In transplant patients the weak link between rapamycin and diabetes is largely explained by co-administration with tacrolimus, a diabetogenic calcineurin inhibitor; in one series switching patients away from calcineurin inhibitors resolved diabetes in 80% of cases.
• In cancer patients, hyperglycaemia attributed to rapamycin, everolimus or temsirolimus is usually mild (grade 1-2) and reversible; a meta-analysis put the risk between 3% in breast cancer and 27% in renal cell carcinoma.
• In generally healthy elderly people, low daily doses (1 mg/day of rapamycin for 8 weeks, or everolimus for 6 weeks) were not reported to raise blood glucose.

Limitations And Interpretation

• This is an argumentative review by a single author, not a trial; the central idea, that rapamycin-induced glucose intolerance is a benevolent pseudo-diabetes, remains a hypothesis.
• Much of the supporting evidence is from mice and rats; human data come from transplant, cancer and small healthy-volunteer studies rather than dedicated metabolic trials.
• The closing suggestion — intermittent rapamycin combined with carbohydrate restriction, exercise and metformin for anti-ageing use — is a proposal, not a tested regimen.