Darleen Sandoval

University of Cincinnati, USA

Abstract

[O07] GLP-1 Regulation of Glucose Homeostasis: Central vs. Peripheral Actions

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 important input to regulate glucose homeostasis via actions on the pancreas, the liver, and skeletal muscle. Importantly, we have found that 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 the relative roles of the pancreas, liver and skeletal muscle we performed intravenous glucose tolerance tests and hyperinsulinemic euglycemic clamps, respectively. We have found that ICV administered GLP-1 increases insulin response to an intravenous glucose load in a glucose dependent manner.  We have also found that direct infusion of GLP-1 into the arcuate nucleus of the hypothalamus during a physiological hyperinsulinemic euglycemic clamp reduced glucose production. This effect 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 i3vt infusion of GLP-1 reduced glucose rate of disappearance. Glibenclamide, a KATP channel blocker, co-infused with GLP-1 into the arcuate nucleus during the glycemic clamp blocked GLP-1 induced reduction in glucose production but not decreases in glucose uptake. We also find GLP-1r mRNA in ~68% of POMC neurons while half of the GLP-1r expressing neurons did not express POMC and none expressed NPY. Supporting the heterogeneity of CNS GLP-1 function, while GLP-1 administration in the ARC regulated glucose homeostasis, it did not reduce food intake, and conversely, GLP-1 administration into the PVN did not regulate glucose homeostasis but did inhibit food intake. Lastly, like the beta-cell, we find that the CNS effects of GLP-1 on food intake are glucose-dependent. 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

Biography

Dr. Darleen Sandoval is currently a Research Assistant Professor in the Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine at the University of Cincinnati. Her graduate and postdoctoral studies focused on neuroendocrine mechanisms that regulate peripheral glucose levels. Her current work focuses on a direct central nervous system regulation of peripheral metabolism that may even be involved in the dysregulation that accompanies diabetes. Dr. Sandoval received her B.S. in Exercise Technology in 1993, her M.S. in Exercise Science from Central Washington University in 1995 and her Ph.D. in Exercise Science at Arizona State University in 1999. She then did a Postdoctoral Fellowship at Vanderbilt University in the Division of Endocrinology and Diabetes.