Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake

DA Sandoval, D Bagnol, SC Woods, DA D'Alessio… - Diabetes, 2008 - Am Diabetes Assoc
DA Sandoval, D Bagnol, SC Woods, DA D'Alessio, RJ Seeley
Diabetes, 2008Am Diabetes Assoc
OBJECTIVE—Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through
regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-
1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the
central GLP-1 system regulates glucose tolerance as well. RESEARCH DESIGN AND
METHODS—We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to
assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and …
OBJECTIVE—Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well.
RESEARCH DESIGN AND METHODS—We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons.
RESULTS—We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide tyrosine.
CONCLUSIONS—These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production.
Am Diabetes Assoc