Glucagon-like peptide 1 (GLP-1), an intestinal hormone released in response to a meal, is involved in glucose homeostasis via inhibition of gastric emptying and intestinal motility, increasing insulin secretion, and, possibly, via insulin-independent effects on glucose turnover. This latter effect appears to be mediated by receptors situated in the portohepatic area. In a previous study we have shown, in dogs, that infusion of intraportal glucose and GLP-1, at values and pattern simulating those seen during a meal, produces lower peripheral glucose than infusion of intraportal glucose alone. The lower glycemia occurred without a corresponding increase in peripheral insulin and was accompanied by a counterregulatory response, as indicated by increases in glucagon and cortisol. The aim of the current study was to identify the mechanism by which intraportal GLP-1 produces lower peripheral glycemia, namely to determine whether it is due to increased peripheral glucose uptake, decreased hepatic glucose output. or both. Experiments were performed in 24-hour fasted conscious dogs (n = 2), in which either intraportal glucose and GLP-1, or intraportal glucose and saline, were infused, in paired experiments performed at 1-week intervals. Tracer techniques and arteriovenous differences across the liver were used to determine whole body glucose turnover and net hepatic glucose balance. Intraportal glucose and GLP-1 infusion produced, similarly to our published results, lower glycemia than infusion of portal glucose alone: during the last 2 hours of the experiment the average glycemia was 101 ± 1 mg/dL with intraportal GLP-1 vs 109 ± 1 mg/dL without GLP-1. The lower peripheral glucose occurred in the absence of a corresponding increase in insulin secretion (AUC 26417 pmol/L*min with GLP-1 vs 28,064 pmol/L*min without GLP-1) as previously described. Tracer counts showed lower values during intraportal glucose and GLP-1, confirming the increased glucose disposal in the presence of GLP-1 indicated by the lower peripheral glucose. The liver appeared not to be involved in the increased glucose disappearance: hepatic vein plasma glucose concentration was not different between intraportal glucose and GLP-1 and intraportal glucose alone experiments. We conclude that the increased glucose turnover seen with intraportal GLP-1 is due to an increase in peripheral glucose disappearance, probably via an indirect, neural mechanism initiated in the portohepatic area.
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