Hypothalamic glucagon signaling inhibits hepatic glucose production
| Autor: | Maureen J. Charron, Madhu Chari, Nikita R Christian, Jessica T.Y. Yue, Beatrice M. Filippi, Clair S. Yang, Carol K.L. Lam, Tony K.T. Lam, Patricia I. Mighiu, Mona A. Abraham |
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| Rok vydání: | 2013 |
| Předmět: |
Male
endocrine system medicine.medical_specialty medicine.medical_treatment Hypothalamus Diet High-Fat Glucagon Glucagon-Like Peptide-1 Receptor Article General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley Mice Internal medicine Diabetes mellitus Receptors Glucagon medicine Animals Receptor Chemistry Kinase Insulin digestive oral and skin physiology Gluconeogenesis General Medicine medicine.disease Cyclic AMP-Dependent Protein Kinases Rats Glucose Endocrinology Liver Knockout mouse Glucagon receptor hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Nature Medicine. 19:766-772 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.3115 |
| Popis: | Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity. |
| Databáze: | OpenAIRE |
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