CNS GLP-1 regulation of peripheral glucose homeostasis.

Abstract

Glucagon-like peptide 1 (GLP-1) is a gut hormone that broadly promotes glucose homeostasis through the regulation of islet hormone secretion, as well as hepatic and gastric function. GLP-1 is also synthesized in the brain, where it regulates food intake. However, our work suggests that the CNS GLP-1 system also provides an important input to regulate glucose tolerance as well. Central administration of a GLP-1 antagonist to male rats caused relative hyperglycemia during a glucose tolerance test suggesting that activation of CNS GLP-1 receptors contributes to normal post-prandial glucose homeostasis. To determine if CNS GLP-1 influences insulin secretion, we performed an intravenous glucose tolerance test. We found that insulin levels were increased in a glucose dependent manner after central administration of GLP-1. Furthermore, during a physiological hyperinsulinemic euglycemic clamp, direct infusion of GLP-1 into the arcuate nucleus of the hypothalamus reduced glucose production, an effect that was not evident when the same dose was given into the third cerebral ventricle indicating it is specific to GLP-1R activation in the arcuate. Interestingly, both direct arcuate and third ventricle infusion of GLP-1 reduced glucose rate of disappearance. To test the role of CNS KATP channels, glibenclamide, a KATP channel blocker, was co-infused with GLP-1 into the arcuate nucleus during the glycemic clamp. Glibenclamide had no affect on the GLP-1 induced reduction in glucose production but did prevent GLP-1 induced decreases in glucose uptake. These data suggest a novel role for CNS GLP-1 signaling to improve glucose homeostasis by regulating insulin secretion, glucose production and utilization and also suggests that regulation of the latter depends on CNS KATP channels. Lastly, GLP-1 injected directly into the arcuate nucleus did not alter food intake. These data illustrate the importance of GLP-1r in the arcuate nucleus in regulating glucose homeostasis but not food intake. We hypothesize that after a meal the coordinated effects of the CNS GLP-1 system are to stimulate the pancreas to secrete insulin and inhibit glucose production as well as satiation. Thus, the CNS makes key contributions to the overall effects of GLP-1 to limit post-prandial glucose fluctuations. Research Supported by NIH/NIDDK 1 K01 DK075365-01.