Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508

Aims: To assess the role of GPR120 in glucose metabolism and incretin regulation from enteroendocrine L- and K-cells with determination of the cellular localisation of GPR120 in intestinal tissue and clonal Glucagon-Like Peptide-1 (GLP-1)/Gastric Inhibitory Polypeptide (GIP) cell lines. Main methods: Anti-hyperglycaemic, insulinotropic and incretin secreting properties of the GPR120 agonist, GW-9508 were explored in combination with oral and intraperitoneal glucose tolerance tests (GTT) in lean, diabetic and incretin receptor knockout mice. Cellular localisation of GPR120 was assessed by double immunofluorescence. Key findings: Compared to intraperitoneal injection, oral administration of GW-9508 (0.1 μmol/kg body weight) together with glucose reduced the glycaemic excursion by 22–31 % (p &lt; 0.05-p &lt; 0.01) and enhanced glucose-induced insulin release by 30 % (p &lt; 0.01) in normal mice. In high fat fed diabetic mice, orally administered GW-9508 lowered plasma glucose by 17–27 % (p &lt; 0.05-p &lt; 0.01) and augmented insulin release by 22–39 % (p &lt; 0.05-p &lt; 0.001). GW-9508 had no effect on the responses of GLP-1 receptor knockout mice and GIP receptor knockout mice. Consistent with this, oral GW-9508 increased circulating total GLP-1 release by 39–44 % (p &lt; 0.01) and total GIP by 37–47 % (p &lt; 0.01-p &lt; 0.001) after 15 and 30 min in lean NIH Swiss mice. Immunocytochemistry demonstrated GPR120 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Significance: GPR120 is expressed on intestinal L- and K-cells and stimulates GLP-1/GIP secretory pathways involved in mediating enhanced insulin secretion and improved glucose tolerance, following oral GW-9508. These novel data strongly support the development of potent and selective GPR120 agonists as an effective therapeutic approach for diabetes.</p

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

Recently, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) have received much attention regarding possible roles in aetiology and treatment of type 2 diabetes. However, peptides co-secreted from the same enteroendocrine cells are less well studied. The present investigation was designed to characterise the in vitro and in vivo effects of xenin, a peptide co-secreted with GIP from intestinal K-cells. We examined the enzymatic stability, insulin-releasing activity and associated cAMP production capability of xenin in vitro. In addition, the effects of xenin on satiety, glucose homoeostasis and insulin secretion were examined in vivo