GHRP-6
Growth Hormone Releasing Peptide-6, Growth hormone-releasing hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
Ghrelin contributes to derangements of glucose metabolism induced by rapamycin in mice.
Xu. G G; Wang. Z Z; Li. Y Y; Li. Z Z; Tang. H H; Zhao. J J; Xiang. X X; Ding. L L; Ma. L L; Yuan. F F; Fei. J J; Wang. W W; Wang. N N; Guan. Y Y; Tang. C C; Mulholland. M M; Zhang. W W
Key Findings
- Rapamycin raises blood levels of active (acylated) ghrelin and worsens glucose tolerance and insulin sensitivity in normal, obese, and diabetic mice.
- Blocking the ghrelin receptor with D‑Lys3‑GHRP‑6 or removing the ghrelin receptor gene stops rapamycin‑induced glucose problems.
- The protective effect of ghrelin‑receptor blockade is linked to preventing JNK activation and preserving GLUT4 levels and movement in muscle.
Practical Outcomes
- If you use rapamycin for longevity, be aware it may raise ghrelin and impair blood‑sugar control. Adding a ghrelin‑receptor antagonist (e.g., D‑Lys3‑GHRP‑6) could blunt this side effect, but using ghrelin‑agonist peptides like GHRP‑6 might worsen it. Monitor glucose and consider ghrelin‑blocking strategies when combining rapamycin with other peptides.
Summary
The study shows that the hormone ghrelin is partly responsible for the blood‑sugar problems caused by rapamycin in mice. When the ghrelin receptor was blocked, rapamycin no longer messed up glucose control. This means that the way rapamycin hurts insulin sensitivity goes through ghrelin and its effects on muscle glucose transport.
Abstract
Rapamycin impairs glucose tolerance and insulin sensitivity. Our previous study demonstrated that rapamycin significantly increases the production of gastric ghrelin, which is critical in the regulation of glucose metabolism. Here, we investigated whether ghrelin contributes to derangements of glucose metabolism induced by rapamycin. The effects of rapamycin on glucose metabolism were examined in mice receiving ghrelin receptor antagonist or with Ghsr1a gene knockout. Changes in GLUT4, c-Jun N-terminal kinase (JNK) and phosphorylated ribosomal protein S6 (pS6) were investigated by immunofluorescent staining or western blotting. Related hormones were detected by radioimmunoassay kits. Rapamycin impaired glucose metabolism and insulin sensitivity not only in normal C57BL/6J mice but also in both obese mice induced by a high fat diet and db/db mice. This was accompanied by elevation of plasma acylated ghrelin. Rapamycin significantly increased the levels of plasma acylated ghrelin in normal C57BL/6J mice, high-fat-diet-induced obese mice and db/db mice. Elevation in plasma acylated ghrelin and derangements of glucose metabolism upon administration of rapamycin were significantly correlated. The deterioration in glucose homeostasis induced by rapamycin was blocked by D: -Lys3-GHRP-6, a ghrelin receptor antagonist, or by deletion of the Ghsr1a gene. Ghrelin receptor antagonism and Ghsr1a knockout blocked the upregulation of JNK activity and downregulation of GLUT4 levels and translocation in the gastrocnemius muscle induced by rapamycin. The current study demonstrates that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the content and translocation of GLUT4 in muscles.
Study Information
pubmed
2012
2012-03-03T00:00:00.000Z
10.1007/s00125-012-2509-1
38
50