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148 PORTAL GLUCAGON-LIKE PROTEIN 1 PRODUCES AN INSULIN-INDEPENDENT REDUCTION IN GLYCEMIA BY INCREASING PERIPHERAL GLUCOSE DISPOSAL, WITHOUT CHANGING HEPATIC GLUCOSE BALANCE.
  1. V. Ionut,
  2. D. Stefanovski,
  3. M. Lottati,
  4. E. Kirkman,
  5. R. N. Bergman
  1. Keck School of Medicine of USC, Los Angeles, CA

Abstract

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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