2011
DOI: 10.1124/jpet.111.179986
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Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Abstract: Pharmacologic contributions of directly agonizing glucagonlike peptide 1 (GLP-1) receptor or antagonizing glucagon receptor (GCGR) on energy state and glucose homeostasis were assessed in diet-induced obese (DIO) mice. Metabolic rate and respiratory quotient (RQ), hyperglycemic clamp, stable isotopebased dynamic metabolic profiling (SiDMAP) studies of 13 Clabeled glucose during glucose tolerance test (GTT) and gene expression were assessed in cohorts of DIO mice after a single administration of GLP-1 analog [G… Show more

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Cited by 29 publications
(28 citation statements)
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“…The increase in GLUT4 expression suggests that CNS–GLP-1 signaling contributes to increased insulin-stimulated glucose uptake in BAT. This is supported by recent data showing that a long-lasting GLP-1 agonist similarly increases insulin responsiveness in this tissue (42). Cold exposure increases plasma triglyceride uptake (43), as well as lipogenesis in iBAT (44,45).…”
Section: Discussionsupporting
confidence: 83%
“…The increase in GLUT4 expression suggests that CNS–GLP-1 signaling contributes to increased insulin-stimulated glucose uptake in BAT. This is supported by recent data showing that a long-lasting GLP-1 agonist similarly increases insulin responsiveness in this tissue (42). Cold exposure increases plasma triglyceride uptake (43), as well as lipogenesis in iBAT (44,45).…”
Section: Discussionsupporting
confidence: 83%
“…The apparent EC 50 value for the cardiac glycolytic response is 0.03 nM, nearly 5 times lower than the EC 50 value of 0.14 nM for the hepatic metabolic response, leaving open the possibility that the cardiac insulin-like effect is mediated by a non-GPCR. A recent report is consistent with that hypothesis [86]. In pre-glucose clamped dietinduced obese mice, administration of anti-glucagon GPCR antibodies markedly elevated plasma glucagon concentrations, decreased plasma glucose and insulin levels, and reduced hepatic glucose output.…”
Section: Heartsupporting
confidence: 52%
“…Aglucagonemic mice, whose alpha cells had been transgenically ablated, display pronounced (70%) suppression of basal hepatic PEPCK expression and moderately decreased glucose output, also with normal insulin levels [154]. In the dietinduced obese mouse study mentioned above, administration of anti-glucagon GPCR antibodies markedly decreased hepatic PEPCK expression without altering the expression of pyruvate kinase [86], as predicted for these enzymes in Table 2. Thus, a substantial body of evidence, both ex vivo and in vivo, is consistent with the hypothesis that endogenous glucagon regulates the hepatic expression of PEPCK and glucose output by activating a high-affinity GPCR and a signal that does not involve activating the PKA-dependent TORC2/CREB pathway [155].…”
Section: Transcriptional Regulation Of Phosphoenolpyruvate Carboxykinasementioning
confidence: 85%
“…[57][58][59]61 Mice with impaired glucagon signaling have modestly decreased β-cell mass and/or pancreas insulin content 7,62,70 and plasma insulin levels tend to be lower compared with wild-type mice. 67,69,72,73,78 These mutant mice manifest increased wholebody insulin sensitivity, 73,79 decreased β-cell mass, and impaired glucose-stimulated insulin secretion. 79 These findings are consistent with a lesser requirement for insulin in the absence of the insulin-counter-regulatory actions of glucagon.…”
mentioning
confidence: 99%