Abstract
Pharmacologic contributions of directly agonizing glucagon-like 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 isotope-based dynamic metabolic profiling (SiDMAP) studies of 13C-labeled 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 13C 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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179986.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- GLP-1
- glucagon-like peptide 1
- GLP-1R
- GLP-1 receptor
- GCGR
- glucagon receptor
- SiDMAP
- stable isotope-based dynamic metabolic profiling
- HGP
- hepatic glucose production
- DIO
- diet-induced obese
- Ab
- antibody
- GTT
- glucose tolerance test
- ipGTT
- intraperitoneal GTT
- RQ
- respiratory quotient
- PBS
- phosphate-buffered saline
- 2-[14C]DG
- 2-deoxy-d-[1-14C] glucose
- TCA
- tricarboxylic acid
- WAT
- white adipose tissue
- BAT
- brown adipose tissue
- G6PDH
- glucose-6-phosphate dehydrogenase
- Pepck
- phosphoenolpyruvate carboxykinase
- Pklr
- pyruvate kinase
- PEG
- polyethylene glycol.
- Received January 26, 2011.
- Accepted March 28, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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