Role of intestinal hormone glucagon-like peptide-1 (GLP-1) in glycemic regulation

Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone released in response to nutrient ingestion. Though it is traditionally thought that GLP-1 exerts its effects on glucose homeostasis by binding to pancreatic receptors, it is possible that GLP-1 also acts via an indirect mechanism, perhaps initiated by activation of GLP-1 sensors in the porto-hepatic area. The overall goal of the current dissertation research was to examine the role of GLP-1 in glucose homeostasis. In particular, we wanted to investigate the existence of a putative portal GLP-1 sensor and to examine its impact on glucoregulation. Administration of a mixed meal in conscious dogs resulted in a strong insulin response, with increases in portal glucose and GLP-1, but only small, non-significant increases in peripheral glucose and GLP-1, suggesting that portal presence of these two signaling molecules is important for the insulinotropic effect. To determine whether the small increases in peripheral glucose and GLP-1 seen during the meal can account for the insulin response, we simulated these levels by exogenous systemic infusion. We found that peripheral glucose and GLP-1 infusion did not reproduce the meal test's insulin response. To investigate whether portal glucose and GLP-1 can account for the meal's insulinotropic effect, we simulated via intraportal infusion the portal levels of glucose and GLP-1 seen during the meal. Infusion of intraportal glucose plus GLP-1 resulted in lower peripheral glycemia (compared to glucose infusion alone), accompanied by a strong counterregulatory response, manifested by increases in glucagon and cortisol. Interestingly, this hypoglycemia occurred in the absence of a corresponding insulin rise, suggesting an insulin-independent increase in glucose turnover produced by intraportal infusion of glucose and GLP-1. Infusion of intraportal GLP-1 alone or with systemic glucose did not produce the insulin-independent hypoglycemia seen with intraportal glucose and GLP-1, indicating that simultaneous activation of portal receptors by portal glucose and GLP-1 is required for the effect. Our data suggests the existence of a portal GLP-1 sensor, activated in the presence of portal glucose, and producing an insulin-independent increase in glucose turnover, perhaps via porto-hepatic initiated neural mechanisms. More research is necessary to further characterize this sensing mechanism.