title: Differential effects of oxyntomodulin and GLP-1 on glucose metabolism.
abstract: Glucagon-like peptide-1 (GLP-1) and oxyntomodulin (OXM) are peptide hormones secreted postprandially from the gut that stimulate insulin secretion in a glucose-dependent manner. OXM activates both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). It has been suggested that OXM acutely modulates glucose metabolism solely through GLP1R agonism. Because OXM activates the GLP1R with lower affinity than GLP-1, we generated a peptide analog (Q→E, OXMQ3E) that does not exhibit glucagon receptor agonist activity but retains the same affinity as OXM for GLP1R. We compared the effects of OXM and OXMQ3E in a glucose tolerance test and, to better characterize the effect on glucose metabolism, we performed controlled infusions of OXM or OXMQ3E during a hyperglycemic clamp performed in wild-type, Glp1r(-/-), and Gcgr(-/-) mice. Our findings show that OXM, but not OXMQ3E, activates the GCGR in vivo. Second, OXM and OXMQ3E improve glucose tolerance following an acute glucose challenge and during a hyperglycemic clamp in mice. Finally, OXM infusion during a glucose clamp reduces the glucose infusion rate (GIR) despite a simultaneous increase in insulin levels in Glp1r(-/-) mice, whereas OXM and OXMQ3E increase GIR to a similar extent in Gcgr(-/-) mice. In conclusion, activation of the GCGR seems to partially attenuate the acute beneficial effects on glucose and contributes to the insulinotropic action of oxyntomodulin.
authors.affiliation: In Vivo Pharmacology, Merck Sharp & Dohme Corporation, Rahway, NJ 07065, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Du
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Kosinski
authors.forename: Julie
authors.initials: J
authors.lastname: Lao
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053772:Oxyntomodulin / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005947:Glucose