title: Acute glucagon induces postprandial peripheral insulin resistance.
abstract: Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions.
authors.affiliation: Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.
authors.forename: Rita S
authors.initials: RS
authors.lastname: Patarrão
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: W Wayne
authors.initials: WW
authors.lastname: Lautt
authors.affiliation: Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal; APDP-ERC Portuguese Diabetes AssociationEducationand Research Center, Rua do Salitre, Lisboa, Portugal.
authors.forename: M Paula
authors.initials: MP
authors.lastname: Macedo
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003994:Bucladesine / Q000378:metabolism / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005978:Glutathione / Q000378:metabolism*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011169:Portal Vein; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003994:Bucladesine; D005934:Glucagon; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005978:Glutathione