Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor

Gu, Wei; Winters, Katherine A.; Motani, Alykhan; Komorowski, Renée; Zhang, Ying; Liu, Qingxiang; Wu, Xingkun; Rulifson, Ingrid C.; Sivits, Glenn; Graham, Melissa; Yan, Hai; Wang, Paul; Moore, Steve; Meng, Shi-Yuan; Lindberg, Richard A.; Véniant, Murielle M.

doi:10.1152/ajpendo.00102.2010

Cited by 53 publications

(43 citation statements)

References 29 publications

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“…We collected enough blood to measure glucose levels but not enough to be able to measure insulin levels at time points earlier than 120 min. We have measured insulin levels during ipGTT in previous studies and have shown that, as expected, insulin levels were increased at 15 min (Gu et al, 2010). Endogenous active GLP-1 levels were increased in GCGR Ab-treated mice (Fig.…”

Section: Glp-1-(23) and Gcgr Ab Similarly Improved Ipgttsupporting

confidence: 67%

“…We have demonstrated that the antidiabetic effects of GCGR antagonism depended on GLP-1R agonism and were not just associated with enhanced GLP-1 levels (Gu et al, 2010). Using two independent experimental approaches, GLP-1R antagonism and genetic loss of GLP-1R function, we demonstrated that complete efficacy of a GCGR antagonist requires a functional GLP-1 receptor.…”

Section: Introductionmentioning

confidence: 92%

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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

Lloyd²,

Chinookswong³

et al. 2011

J Pharmacol Exp Ther

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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 [GLP-1-(23)] or anti-GCGR antibody (Ab). GLP-1-(23) and GCGR Ab similarly improved GTT. GLP-1-(23) decreased food intake and body weight trended lower. GCGR Ab modestly decreased food intake without significant effect on body weight. GLP-1-(23) and GCGR Ab decreased RQ with GLP-1, causing a greater effect. In a hyperglycemic clamp, GLP-1-(23) reduced hepatic glucose production (HGP), increased glucose infusion rate (GIR), increased glucose uptake in brown adipose tissue, and increased whole-body glucose turnover, glycolysis, and rate of glycogen synthesis. GCGR Ab slightly decreased HGP, increased GIR, and increased glucose uptake in the heart. SiDMAP showed that GLP-1-(23) and GCGR Ab increased 13 C lactate labeling from glucose, indicating that liver, muscle, and other organs were involved in the rapid disposal of glucose from plasma. GCGR Ab and GLP-1-(23) caused different changes in mRNA expression levels of glucose-and lipid metabolism-associated genes. The effect of GLP-1-(23) on energy state and glucose homeostasis was greater than GCGR Ab. Although GCGR antagonism is associated with increased circulating levels of GLP-1, most GLP-1-(23)-associated pharmacologic effects are more pronounced than GCGR Ab.

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Section: Glp-1-(23) and Gcgr Ab Similarly Improved Ipgttsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 92%

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Lloyd²,

Chinookswong³

et al. 2011

J Pharmacol Exp Ther

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“…However, the acute nature of the increase in circulating glucagon also suggests that partial blockade of the glucagon receptor is most likely driven by a direct systemic feedback loop but might also be impacted by decreased overall glucagon clearance. Studies in mice have provided conflicting results regarding the role of GLP-1 in the improved glucose metabolism observed in glucagon receptor knockouts (26,27). Our results suggest that GLP-1 is unlikely to contribute to the efficacy of LY2409021 because active hormone levels are unchanged.…”

Section: Discussionmentioning

confidence: 67%

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Kazda¹,

et al. 2015

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OBJECTIVEType 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSThe efficacy (HbA 1c and glucose) and safety (serum aminotransferase) of oncedaily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTSLY2409021 produced reductions in HbA 1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA 1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA 1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] £10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONSIn patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA 1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

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“…In line with this, we observed increased phosphorylation of p38 MAPK and reduced activities of ACC and GPAT, direct downstream targets of SREBP-1c (39), in livers of Pemt Ϫ/Ϫ mice fed the HFHC diet. In addition, it has been demonstrated that genetic elimination or antagonism of the glucagon receptor lowers fasting glucose, improves the GTT and pancreatic ␤-cell function in mice (22,40), humans (41), and other rodent models (42). Consistently, antagonism of the glucagon receptor in Pemt Ϫ/Ϫ mice fed the HFHC diet improved insulin sensitivity and enhanced hepatic TG, which occurred in conjunction with inactivating AMPK and increasing hepatic malonyl-CoA levels.…”

Section: Dissociation Of Fatty Liver From Choline-induced Hepatic Insmentioning

confidence: 92%

Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action

Zhang

et al. 2013

Journal of Biological Chemistry

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Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor

Cited by 53 publications

References 29 publications

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Pharmacological Targeting of Glucagon and Glucagon-Like Peptide 1 Receptors Has Different Effects on Energy State and Glucose Homeostasis in Diet-Induced Obese Mice

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action

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