👤 Aine M McKillop

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. 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. 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. 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. Show less

Guanine nucleotide regulatory proteins (G-proteins) are central to normal hepatocyte function and are implicated in hepatic disease initiation and progression. Regulators of G-protein signaling (RGS) are critical to defining G-protein-dependent signal fidelity, yet the role of RGS proteins in the liver is poorly defined. The aims of this study were to determine RGS17 expression in normal and transformed hepatic tissue and cells, and address the function of RGS17 in hepatic tumorgenicity. RGS17 expression was determined in human and rat HCC tissue and cell lines. Molecular approaches were used to alter RGS17 expression in HCC cells, effects on cell function measured, and RGS17 association with specific Gα-subunits determined. Using these approaches RGS17 mRNA, but not protein, was detectable in human and rat HCC tissue and cells. Conversely, RGS17 mRNA was not detected in normal tissue, isolated hepatocytes, or non-tumorigenic hepatic cells. Subsequent studies using transfected cells demonstrated that RGS17 proteins were not post-translationally modified in HCC cells, and RGS17 expression is governed by protein degradation and not via miRNAs. Notwithstanding inherently low RGS17 protein levels, altering RGS17 expression profoundly affected HCC cell mitogenesis and migration. Analysis of RGS17-G-protein interaction demonstrated RGS17 associates with both Giα- and Gqα-subunits in HCC cells of human and rat origin. In conclusion, these data demonstrate that, despite difficulties in measuring endogenous RGS protein expression, RGS17 is differentially expressed in HCC and plays a central role in regulating transformed hepatocyte tumorgenicity. Show less