Metabolic effects of orally administered small-molecule agonists of GPR55 and GPR119 in multiple low-dose streptozotocin-induced diabetic and incretin-receptor-knockout mice

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 Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0.1 μmol/kg) or saline vehicle (0.9% wt/vol. NaCl) over 28 days. Body weight, food intake, fluid intake, plasma glucose, insulin, glucose tolerance, insulin release, lipid profile and pancreatic morphology were examined. Mechanism of action of agonists was assessed in acute studies using incretin-receptor-knockout mice. 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 glucosedependent insulinotropic peptide (GIP) receptor. Conclusions/interpretation These data highlight the potential for fatty acid G-protein-coupled receptor-based therapies as novel insulinotropic and glucose-lowering agents acting partly through the activation of incretin receptors.

GPR55: a new promising target for metabolism?

“…In agreement, glucose-responsive BRIN-BD11 cells stimulated with a range of GPR55 agonists at different concentrations display greater insulin release, whereas inhibition of insulin secretion is detected after exposure of the cells to a GPR55 antagonist (McKillop et al 2013). In line with this, daily oral administration of Abn-CBD, a potent selective agonist for GPR55 (McKillop et al 2013), lowered blood glucose and plasma glucagon and increased plasma insulin and pancreatic insulin content in streptozotocin-induced diabetic mice (McKillop et al 2016). After long-term administration of Abn-CBD, glucose tolerance and insulin sensitivity were markedly improved, and total cholesterol and triacylglycerol were decreased (McKillop et al 2016).…”

“…After long-term administration of Abn-CBD, glucose tolerance and insulin sensitivity were markedly improved, and total cholesterol and triacylglycerol were decreased (McKillop et al 2016). In this report, the GPR55 agonist decreased food consumption, though no effect on overall body weight was detected (McKillop et al 2016).…”

“…In line with this, daily oral administration of Abn-CBD, a potent selective agonist for GPR55 (McKillop et al 2013), lowered blood glucose and plasma glucagon and increased plasma insulin and pancreatic insulin content in streptozotocin-induced diabetic mice (McKillop et al 2016). After long-term administration of Abn-CBD, glucose tolerance and insulin sensitivity were markedly improved, and total cholesterol and triacylglycerol were decreased (McKillop et al 2016). In this report, the GPR55 agonist decreased food consumption, though no effect on overall body weight was detected (McKillop et al 2016).…”

LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling

“…In the present study we measured insulin release from isolated mouse and human islets under dynamic conditions, where the continuous flow of perifusing buffers minimizes autocrine and paracrine effects of secreted products that may occur in static incubation protocols . In terms of ligand selectivity, it has been shown that some CB1 antagonists, such as AM251 and rimonabant, can also act as agonists for GPR55, which is expressed by islet β‐cells and whose activation increases insulin secretion from both human and mouse islets, and this may have led to differences in interpretation of earlier studies.…”

“…CB1 and GPR55 have in common an abundant expression in the central nervous system and metabolic tissues and a proposed role in energy balance, that may be secondary to their regulation of insulin secretion . We, and others, have shown that CB1 and GPR55 activation in isolated rodent and human islets is associated with insulinotropic properties, although a shared consensus in the scientific community has still not been reached with respect to the role of CB1 receptors in islets …”