Abstract | AIMS/HYPOTHESIS:
Abnormal cannabidiol ( Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice. METHODS: RESULTS:
Abn-CBD and AS-1269574 decreased plasma glucose (20-26%, p < 0.05) and increased circulating insulin (47-48%, p < 0.05) by 10-28 days, compared with saline-treated diabetic controls. Food intake and polydipsia were reduced by both agonists (21-23%, p < 0.05 and 33-35%, p < 0.01, respectively). After 28 days of treatment, plasma glucagon concentrations were reduced (p < 0.01) and glucose tolerance was enhanced by 19-44% by Abn-CBD (p < 0.05 or p < 0.001) and AS-1269574 (p < 0.05 to p < 0.001). Plasma insulin responses were improved (p < 0.01) and insulin resistance was decreased (p < 0.05 or p < 0.01) in both Abn-CBD- and AS-1269574-treated groups. Triacylglycerols were decreased by 19% with Abn-CBD (p < 0.05) and 32% with AS-1269574 (p < 0.01) while total cholesterol was reduced by 17% (p < 0.01) and 15% (p < 0.05), respectively. Both agonists enhanced beta cell proliferation (p < 0.001) although islet area was unchanged. Acute studies in Gipr- and Glp1r-knockout mice revealed an important role for the glucagon-like peptide 1 (GLP-1) receptor in the actions of both agonists, with the glucose-lowering effects of Abn-CBD also partly mediated through the glucose-dependent insulinotropic peptide ( GIP) receptor. CONCLUSIONS/INTERPRETATION:
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Authors | Aine M McKillop, Brian M Moran, Yasser H A Abdel-Wahab, Noella M Gormley, Peter R Flatt |
Journal | Diabetologia
(Diabetologia)
Vol. 59
Issue 12
Pg. 2674-2685
(12 2016)
ISSN: 1432-0428 [Electronic] Germany |
PMID | 27677765
(Publication Type: Journal Article)
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Chemical References |
- 2-(2-(4-bromophenyl)-6-methylpyrimidin-4-yl)aminoethanol
- 4-(3-3,4-p-menthadien-(1,8)-yl)olivetol
- Ethanolamines
- GPR119 protein, human
- GPR55 protein, human
- Incretins
- Peptide Fragments
- Pyrimidines
- Receptors, Cannabinoid
- Receptors, G-Protein-Coupled
- Resorcinols
- exendin (9-39)
- Streptozocin
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Topics |
- Animals
- Diabetes Mellitus, Experimental
(drug therapy, genetics, metabolism)
- Eating
(drug effects, genetics)
- Ethanolamines
(therapeutic use)
- Incretins
(metabolism)
- Insulin Resistance
(genetics)
- Insulin-Secreting Cells
(drug effects, metabolism)
- Male
- Mice
- Mice, Knockout
- Peptide Fragments
(therapeutic use)
- Pyrimidines
(therapeutic use)
- Receptors, Cannabinoid
- Receptors, G-Protein-Coupled
(agonists, genetics, metabolism)
- Resorcinols
(therapeutic use)
- Streptozocin
(pharmacology)
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