Once-daily oral administration of gpr55 agonist ml-184 has direct and indirect benefits on [beta]-cell and gastrointestinal health in obese-diabetic mice

Reece Corbett; Adeoluwa Owolabi; Peter Flatt; Aine McKillop

doi:10.1530/endoabs.104.OC6

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Endocrine Abstracts (2024) 104 OC6 | DOI: 10.1530/endoabs.104.OC6

SFEIES24 Oral Communications Oral Communications (10 abstracts)

Once-daily oral administration of gpr55 agonist ml-184 has direct and indirect benefits on β-cell and gastrointestinal health in obese-diabetic mice

Reece Corbett , Adeoluwa Owolabi , Peter Flatt & Aine McKillop

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Ulster University, Coleraine, United Kingdom

Background: G-Protein-Coupled Receptor GPR55, a member of the endocannabinoid system, has gained significant interest as a treatment for diabetes. This study aimed to investigate GPR55 as a drug target using a novel GPR55-agonist, ML-184 (high selectivity EC50=0.26µM), and the downstream induction of signalling pathways.

Methods: High-fat-fed (HFF) C57BL/6 mice were treated with a daily oral dose of ML-184 (0.1μmol/kg) alone or in combination with Sitagliptin (50 mg/kg) for 21-days. After long-term treatment of obese-diabetic mice, food intake, metabolic effects (insulin sensitivity, glucose tolerance, insulinotropic response), islet morphology, tissue gene (qPCR) and protein (immunohistochemistry) expression, biochemical analytes and intracellular signalling were investigated.

Results: ML-184 alone and in combination with Sitagliptin, improved glucose tolerance (26-30%, P < 0.001) and enhanced insulin sensitivity (29-37%, P < 0.05-0.01) and insulinotropic response (63-110%, P < 0.001) in HFF mice. Islet Ki-67 staining found that ML-184 increased β-cell proliferation in HFF mice (7%, P < 0.001), and upregulated pancreatic gene expression of GPR55 (78%, P < 0.01), ERK1 (56%, P < 0.01) and ERK2 (43%, P < 0.05). ML-184 increased β-cell area (45%, P < 0.01) and β-cell mass (45%, P < 0.05), and decreased α-cell area (59%, P < 0.001) and mass (43%, P < 0.01). There was a marked increase in circulating GIP following monotherapy (47%, P < 0.05) and dual agonism (ML-184/sitagliptin) (203%, P < 0.001). qPCR showed that dual agonism also significantly upregulated GIP gene expression in jejunum (90%, P < 0.05). Food intake was reduced by 26-36% (P < 0.001) by ML-184 and dual agonism (ML-184/Sitagliptin). HFF jejunal gene expression of GPR55 and JNK1 were upregulated by 336% and 472% (P < 0.001), respectively, while dual agonism decreased their expression by 58% (P < 0.05) and 72% (P < 0.01).

Conclusions: ML-184 is a viable option for T2DM drug development, as GPR55 agonism has beneficial effects on β-cells partially mediated by GIP from gastrointestinal K-cells, as well as gastrointestinal benefits mediated by direct GPR55 activation in the intestine evoking potent antimotility effects leading to reduced food intake.