Abstract
Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic β-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.
Footnotes
A part of the manuscript has been published as an abstract at the 69th Scientific Sessions of the American Diabetes Association. Chen L, McNulty J, Anderson D, Liu Y, Nystrom C, Collins J, Handlon T, Klein R, Grimes A, Murray D, et al. (2009) Cholestyramine reverses hyperglycemia and enhances GLP-1 release in Zucker Diabetic Fatty rats. Diabetes 58 (Suppl. 1): A713.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.166892.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- FXR
- farnesoid X receptor
- BAS
- bile acid sequestrant
- ZDF
- Zucker diabetic fatty
- OGTT
- oral glucose tolerance test
- GLP-1
- glucagon-like peptide 1
- PYY
- peptide YY
- LXR
- liver X receptor
- SHP
- small heterodimer partner
- T2DM
- type 2 diabetes mellitus
- HbA1c
- blood glucose and hemoglobin A1c
- IVITT
- intravenous insulin tolerance test
- PEPCK
- phosphoenolpyruvate carboxykinase
- G6Pase
- glucose-6-phosphate dehydrogenase
- TGR5 and GPBAR1
- G protein-coupled bile acid receptor 1
- NR1H4
- nuclear receptor subfamily 1, group H, member 4
- GW4064
- an FXR agonist.
- Received February 3, 2010.
- Accepted April 20, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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