RT Journal Article
SR Electronic
T1 Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 164
OP 170
DO 10.1124/jpet.110.166892
VO 334
IS 1
A1 Lihong Chen
A1 Judi McNulty
A1 Don Anderson
A1 Yaping Liu
A1 Christopher Nystrom
A1 Sarah Bullard
A1 Jon Collins
A1 Anthony L. Handlon
A1 Ryan Klein
A1 Angela Grimes
A1 David Murray
A1 Roger Brown
A1 David Krull
A1 Bill Benson
A1 Elena Kleymenova
A1 Katja Remlinger
A1 Andrew Young
A1 Xiaozhou Yao
YR 2010
UL http://jpet.aspetjournals.org/content/334/1/164.abstract
AB 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics