Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C10 and PC10
GPR119 activation integrates the secretion of gastrointestinal peptides and islet hormones
K. K. Brown1, D. K. Croom1, A. J. Carpenter1, J. A. McNulty1, A. A. Young1, D. J. Nunez1, P. L. Feldman1
1. Enteroendocrine Research Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, United States.
GPR119 is mainly expressed in pancreatic islets and in the gastrointestinal (GI) tract. By immunohistochemistry, GPR119 co-localizes with GIP and GLP-1 in K-cells and L-cells, respectively. In islets, GPR119 appears to co-localize with pancreatic polypeptide in rodents, and in both β-cells and α-cells in rodents and humans. We have previously demonstrated that GPR119 agonists potentiate glucose stimulated insulin secretion in vivo and in vitro, suggesting a role in coordinating secretion of enteroendocrine and islet hormones in response to ingested nutrients. To evaluate the effect of activation of GPR119 on gut peptides, male crl: SD (CD) rats were cannulated (under isoflurane (2% in oxygen) anaesthesia) via the portal vein, recovered for 7 days and tethered in custom cages to facilitate unperturbed sampling. Rats received a single oral dose of a GPR119 agonist (GSK706,n=8) or placebo (Pbo,n=7) one hour prior to the start of the dark cycle and were followed for 24 hours. Measured analytes included plasma glucose (G), insulin, active(a) and total(t) GLP-1, tGIP, tPYY, PP and glucagon. Prior to the onset of feeding, there were no changes in analytes in the Pbo group. In the agonist treated rats, mean glucose decreased (~0.8mM by 30 minutes post-dose) while (a) and (t)GLP-1, glucagon, tPYY and tGIP were significantly (p<.005 for all, Dunnett's) increased 3, 3, 2.8, 2 and 1.5 fold over baseline respectively with no change in PP. The elevation in glucagon was transient returning to baseline 4 hours post dose. With the onset of feeding, G increased modestly in both groups (~ 1.1mM) and there were no treatment-related changes in plasma insulin. Compared to the other analytes, tGIP increased most robustly in both groups with the onset of feeding (2.3 and 3.8 fold, Pbo and agonist, respectively). During feeding, the changes in all other peptides measured with Pbo were < 1.5 fold and all returned toward baseline values at the end of the dark cycle. In contrast, treatment with the agonist was associated with sustained significant increases compared to Pbo in (a) and (t) GLP-1, tGIP for 24 hours post dose. tPYY remained elevated compared to Pbo only during feeding. Perfusions in situ of isolated gut segments with GSK706 in anesthetized (ketamine/xylazine) male crl: SD (CD)rats enabled assessment of the relative contribution of each segment to portal appearance of total GLP-1, GIP, and PYY in the absence of nutrients. Within 5-10 minutes after the start of the perfusion there were rapid and robust increases in tPYY and tGLP-1 during perfusion of the duodenum, lesser change with colonic perfusion, and little with perfusion of jejunum or ileum. There was little change in GIP. The rapid effects of GPR119 agonism to prime K- and L-cell secretion in concert with islet hormone secretion suggests a role for GPR119 signalling in nutrient sensing and disposal.
Where applicable, experiments conform with Society ethical requirements