Central Nervous System GLP-1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats

• Published in: Endocrinology (Philadelphia) Vol. 158; no. 7; pp. 2124 - 2133
• Main Authors: Jessen, Lene, Smith, Eric P., Ulrich-Lai, Yvonne, Herman, James P., Seeley, Randy J., Sandoval, Darleen, D’Alessio, David
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.07.2017; Oxford University Press
• Subjects: Animals; Blood glucose; Brain; Brain - metabolism; Central nervous system; Control; Control systems; Corticosterone; Eating - physiology; Editor's Choice; Endocrinology; Energy Metabolism - drug effects; Epinephrine; Fasting; Fasting - metabolism; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - metabolism; Glucagon-Like Peptide-1 Receptor - physiology; Glucose; Glucose - metabolism; Glucose tolerance; Hindbrain; Homeostasis; Homeostasis - drug effects; Hyperglycemia; Hyperglycemia - metabolism; Infusions, Intraventricular; Insulin; Insulin secretion; Intestine; Intolerance; Intravenous administration; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Laboratory testing; Male; Mesencephalon; Nervous system; Peptides; Rats; Rats, Long-Evans; Receptors; Regulations; Rodents; Satiety; Stress response; Sympathetic nervous system
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2016-1826

The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 receptors (GLP-1rs) expressed in brain regions involved in metabolic regulation. GLP-1 in the central nervous system (CNS) induces satiety, visceral illness, and stress responses. However, recent evidence suggests CNS GLP-1 is also involved in glucose regulation. To test the hypothesis that central GLP-1 regulates islet hormone secretion, conscious rats were given intracerebroventricular (ICV) GLP-1, GLP-1r antagonist exendin-[9-39] (Ex-9), or saline during fasting or hyperglycemia from intravenous glucose. Administration of CNS GLP-1 increased fasting glucose, glucagon, corticosterone, and epinephrine and blunted insulin secretion in response to hyperglycemia. Paradoxically, GLP-1r blockade with ICV Ex-9 also reduced glucose-stimulated insulin secretion, and administration of ICV Ex-9 to freely feeding rats caused mild glucose intolerance. Thus, direct administration of CNS GLP-1 affected islet hormone secretion counter to what is seen with peripherally administered GLP-1, an effect likely due to stimulation of sympathetic nervous system activity. In contrast, blockade of brain GLP-1r supports a role for CNS GLP-1 on glucose-stimulated insulin secretion and glucose control after a meal. These findings suggest a model in which activation of CNS GLP-1r by endogenous peptide promotes glucose tolerance, an effect that can be overridden by stress responses stimulated by exogenous GLP-1.Blockade of GLP-1 receptors in the midbrain of rats supports a role for central nervous system GLP-1 in the regulation of islet hormone secretion and prandial glucose tolerance.