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

Andrew G McCloskey, Michael G Miskelly, Ryan A Lafferty, Peter R Flatt, Aine M McKillop

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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 (0.1µmol/kg BW) monotherapy and in combination with sitagliptin (50mg/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.

Original languageEnglish
Article number115398
Pages (from-to)115398
JournalBiochemical Pharmacology
Volume208
Early online date26 Dec 2022
DOIs
Publication statusPublished online - 26 Dec 2022

Bibliographical note

Copyright © 2022. Published by Elsevier Inc.

Funding Information:
These studies were supported by Diabetes UK and the Department of Education and Learning, Northern Ireland.

Publisher Copyright:
© 2022

Keywords

  • Abnormal Cannabidiol
  • Beta Cell
  • DPP-IV Inhibition
  • Diabetes
  • GPR55
  • Incretins

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