Rapamycin impairs HPD-induced beneficial effects on glucose homeostasis

Br J Pharmacol. 2015 Aug;172(15):3793-804. doi: 10.1111/bph.13168. Epub 2015 Jun 12.


Background and purpose: Rapamycin, which is used clinically to treat graft rejection, has also been proposed to have an effect on metabolic syndrome; however, very little information is available on its effects in lean animals/humans. The purpose of this study was to characterize further the effects of the continuous use of rapamycin on glucose homeostasis in lean C57BL6/J mice.

Experimental approach: Mice were fed a high-protein diet (HPD) for 12 weeks to develop a lean model and then were treated daily with rapamycin for 5 weeks while remaining on a HPD. Metabolic parameters, endocrine profiles, glucose tolerance tests, insulin sensitivity index, the expression of the glucose transporter GLUT4 and chromium distribution were measured in vivo.

Key results: Lower body weight gain as well as a decreased caloric intake, fat pads, fatty liver scores, adipocyte size and glucose tolerance test values were observed in HPD-fed mice compared with mice fed a high-fat or standard diet. Despite these beneficial effects, rapamycin-treated lean mice showed greater glucose intolerance, reduced insulin sensitivity, lower muscle GLUT4 expression and changes in chromium levels in tissues even with high insulin levels.

Conclusion and implications: Our findings demonstrate that continuous rapamycin administration may lead to the development of diabetes syndrome, as it was found to induce hyperglycaemia and glucose intolerance in a lean animal model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipose Tissue / drug effects
  • Animals
  • Body Weight / drug effects
  • Chromium / metabolism
  • Dietary Fats / pharmacology
  • Dietary Proteins / pharmacology*
  • Energy Intake / drug effects
  • Fatty Liver / metabolism
  • Glucose / metabolism*
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Glucose Transporter Type 4 / biosynthesis
  • Homeostasis / drug effects*
  • Insulin / metabolism
  • Insulin Resistance
  • Male
  • Mice
  • Sirolimus / pharmacology*


  • Dietary Fats
  • Dietary Proteins
  • Glucose Transporter Type 4
  • Insulin
  • Chromium
  • Glucose
  • Sirolimus