Fasting and rapamycin: diabetes versus benevolent glucose intolerance

Abstract

Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.

Fig. 1. mTOR in glucose and lipid metabolism.

Overactivated by nutrients and insulin, mTOR causes noticeable metabolic effects that are reversible by starvation or rapamycin (or everolimus)

Fig. 2. Comparison of starvation- and rapamycin-induced benevolent pseudo-diabetes.

Common alterations caused by prolonged fasting/starvation or chronic treatment with rapamycin (or everolimus). Green arrow—upregulation; red arrow—downregulation

Fig. 3. From glucose intolerance to hyperglycemia.

a Starvation causes glucose intolerance, but levels of blood glucose are low due to glucose deprivation. Resuming carbohydrate feeding causes hyperglycemia associated with glycosuria, which has been termed “starvation pseudo-diabetes.” b Chronic rapamycin treatment is accompanied by constant feeding, so glucose intolerance is associated with mild hyperglycemia, reversible by rapamycin discontinuation

Fig. 4. Biphasic effects of mTOR on beta cells.

mTOR initially stimulates beta cell growth and function, thereby enhancing insulin production. Chronic activation of mTOR leads to beta cell hyperfunction and eventually to their exhaustion (loss of function)