BACKGROUND AND PURPOSEThe G protein-coupled receptor 119 (GPR119) mediates insulin secretion from pancreatic b cells and glucagon-like peptide 1 (GLP-1) release from intestinal L cells. While GPR119-mediated insulin secretion is glucose dependent, it is not clear whether or not GPR119-mediated GLP-1 secretion similarly requires glucose. This study was designed to address the glucosedependence of GPR119-mediated GLP-1 secretion, and to explore the cellular mechanisms of hormone secretion in L cells versus those in b cells. EXPERIMENTAL APPROACHGLP-1 secretion in response to GPR119 agonists and ion channel modulators, with and without glucose, was analysed in the intestinal L cell line GLUTag, in primary intestinal cell cultures and in vivo. Insulin secretion from Min6 cells, a pancreatic b cell line, was analysed for comparison. KEY RESULTSIn GLUTag cells, GPR119 agonists stimulated GLP-1 secretion both in the presence and in the absence of glucose. In primary mouse colon cultures, GPR119 agonists stimulated GLP-1 secretion under glucose-free conditions. Moreover, a GPR119 agonist increased plasma GLP-1 in mice without a glucose load. However, in Min6 cells, GPR119-mediated insulin secretion was glucose-dependent. Among the pharmacological agents tested in this study, nitrendipine, an L-type voltage-dependent calcium channel blocker, dose-dependently reduced GLP-1 secretion from GLUTag cells, but had no effect in Min6 cells in the absence of glucose. CONCLUSIONS AND IMPLICATIONSUnlike that in pancreatic b cells, GPR119-mediated GLP-1 secretion from intestinal L cells was glucose-independent in vitro and in vivo, probably because of a higher basal calcium tone in the L cells.
In this study, 60 patients with proven growth hormone deficiency (GHD) of hypothalamic origin were randomized into three equal groups, and received growth hormone‐releasing hormone(1–29)‐NH, (GHRH(1–29)‐NH,), 30 or 60 μg/kg/day, or growth hormone (GH), 0.1 IU/kg/day, for 6 months. There were no significant differences in growth between the two groups given GHRH(1–29)‐NH, but growth in the GH group was significantly better than in the other two groups (p< 0.01). Mean height velocities at 6 months were 9.2, 9.3 and 14.6 cm/year for the three groups, respectively. Plasma GHRH concentrations increased steadily over the 6‐month treatment period, with higher levels in the group on the higher dose. During GHRH(1–29)‐NH2 treatment, serum concentrations of insulin‐like growth factor I rose initially, but then fell to values similar to those before treatment. No GH antibodies were detected, but all 20 patients on high‐dose GHRH(1–29)‐NH, and 19 of 20 patients on low‐dose GHRH(1–29)‐NH2 developed GHRH antibodies. These had almost disappeared by 9 months after stopping treatment. There was no correlation between antibody titres and increase in height. No serious side‐effects were seen, but three patients receiving GHRH(1–29)‐NH, reported mild irritation at the injection site. These results from the continuous infusion of GHRH(1–29)‐NH2 over 6 months suggest that this treatment, or the related use of a depot preparation, is unlikely to be as effective as GH for the promotion of growth in GHD.
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