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

• Published in: Cellular physiology and biochemistry Vol. 40; no. 5; pp. 1175 - 1185
• Main Authors: Zhang, Xiuyuan, Gao, Shan, Niu, Jinfeng, Li, Pan, Deng, Juan, Xu, Shixin, Wang, Zhihong, Wang, Weiwei, Kong, Deling, Li, Chen
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Cell Physiol Biochem Press GmbH & Co KG 01.01.2016
• Subjects: Adiposity - drug effects; Animals; Cannabinoid 2 receptor; Cannabinoid Receptor Agonists - administration & dosage; Cannabinoid Receptor Agonists - pharmacology; Cell Proliferation - drug effects; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diet, High-Fat; Glucose - pharmacology; Inflammation; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Lipolysis - drug effects; Lipolytic; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Mice, Inbred ICR; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Original Paper; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; Streptozocin; Cannabinoid 2 receptor; Inflammation; Diabetes; Insulin secretion; Lipolytic
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000453171

Background/Aims: The endocannabinoid signalling (ECS) system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB 2 ) 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 CB 2 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 CB 2 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 CB 2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.