Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Cell Physiol Biochem. 2016;40(5):1175-1185. doi: 10.1159/000453171. Epub 2016 Dec 14.


Background/aims: The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2) receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD)/streptozotocin (STZ)-induced mice.

Methods: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of β-cell function. Pancreases and skeletal muscles were also obtained for histological analyses.

Results: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601-treated mice, which could partly be attributed to improved islet β-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice.

Conclusion: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.

MeSH terms

  • Adiposity / drug effects
  • Animals
  • Cannabinoid Receptor Agonists / administration & dosage
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Diet, High-Fat
  • Glucose / pharmacology
  • Insulin / metabolism*
  • Insulin Resistance
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Lipolysis / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice, Inbred ICR
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Streptozocin


  • Cannabinoid Receptor Agonists
  • Insulin
  • Receptor, Cannabinoid, CB2
  • Streptozocin
  • Glucose