Antidiabetic actions of GPR55 agonist Abn-CBD and sitagliptin in obese-diabetic high fat fed mice.

Abstract

GPR55 has been recognized as a novel anti-diabetic target exerting positive effects on beta cell function and mass. This study evaluated the metabolic actions and therapeutic efficacy of GPR55 agonist abnormal cannabidiol (Abn-CBD) administered alone and in combination with sitagliptin in diet-induced obese-diabetic mice. Chronic effects of 21-day oral administration of Abn-CBD (0.1 µmol/kg BW) monotherapy and in combination with sitagliptin (50 mg/kg BW) were assessed in obese-diabetic HFF mice (n = 8). Assessments of plasma glucose, circulating insulin, DPP-IV activity, CRP, amylase, lipids, body weight and food intake were undertaken. Glucose tolerance, insulin sensitivity, DEXA scanning and islet morphology analysis were performed at 21-days. Sitagliptin, Abn-CBD alone and in combination with sitagliptin attenuated plasma glucose by 37-53 % (p < 0.01 - p < 0.001) and enhanced circulating insulin concentrations by 23-31 % (p < 0.001). Abn-CBD alone and with sitagliptin reduced bodyweight by 9-10 % (p < 0.05). After 21-days, Abn-CBD in combination with sitagliptin (44 %; p < 0.01) improved glucose tolerance, whilst enhancing insulin sensitivity by 79 % (p < 0.01). Abn-CBD increased islet area (86 %; p < 0.05), beta cell mass (p < 0.05) and beta cell proliferation (164 %; p < 0.001), whilst in combination with sitagliptin islet area was decreased (50 %; p < 0.01). Abn-CBD alone, in combination with sitagliptin or sitagliptin alone decreased triglycerides by 34-65 % (p < 0.001) and total cholesterol concentrations by 15-25 % (p < 0.001). In addition, Abn-CBD in combination with sitagliptin reduced fat mass by 19 % (p < 0.05) and reduced CRP concentrations (39 %; p < 0.05). These findings advocate Abn-CBD monotherapy and in combination with sitagliptin as a novel and effective approach for bodyweight control and the treatment of glucose intolerance and dyslipidaemia in type-2-diabetes.

• Authors: Andrew G McCloskey, Michael G Miskelly, Ryan A Lafferty, Peter R Flatt, Aine M McKillop
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 208 Pg. 115398 (02 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 36581052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Inc.

Chemical References

• Hypoglycemic Agents
• Sitagliptin Phosphate
• 4-(3-3,4-p-menthadien-(1,8)-yl)olivetol
• Receptors, Cannabinoid
• Blood Glucose
• Insulin
• GPR55 protein, mouse

Topics

• Mice
• Animals
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Sitagliptin Phosphate (pharmacology, therapeutic use)
• Receptors, Cannabinoid (metabolism)
• Insulin Resistance
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Insulin (metabolism)
• Obesity (drug therapy)