Cholestyramine Reverses Hyperglycemia and Enhances Glucose-Stimulated Glucagon-Like Peptide 1 Release in Zucker Diabetic Fatty Rats

被引：64

作者：

Chen, Lihong ^{[1
]}

McNulty, Judi ^{[1
]}

Anderson, Don ^{[1
]}

Liu, Yaping ^{[1
]}

Nystrom, Christopher ^{[1
]}

Bullard, Sarah ^{[1
]}

Collins, Jon ^{[2
]}

Handlon, Anthony L. ^{[2
]}

Klein, Ryan ^{[3
]}

Grimes, Angela ^{[4
]}

Murray, David ^{[4
]}

Brown, Roger ^{[5
]}

Krull, David ^{[5
]}

Benson, Bill ^{[4
]}

Kleymenova, Elena ^{[4
]}

Remlinger, Katja ^{[6
]}

Young, Andrew ^{[1
]}

Yao, Xiaozhou ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Metab Drug Discovery, Dept Biol, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline Inc, Metab Drug Discovery, Dept Med Chem, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline Inc, Metab Drug Discovery, Dept DMPK, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline Inc, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline Inc, Safety Assessment, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Discovery Analyt & Drug Dev Sci, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2010年 / 334卷 / 01期

关键词：

FARNESOID-X-RECEPTOR; BILE-ACID SEQUESTRANTS; SMALL HETERODIMER PARTNER; ORPHAN NUCLEAR RECEPTOR; INSULIN-RESISTANCE; CARBOHYDRATE-METABOLISM; MELLITUS; FXR; OBESITY; LIVER;

D O I：

10.1124/jpet.110.166892

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.

引用

页码：164 / 170

页数：7

共 40 条

[1] DEOXYCHOLATE IS AN IMPORTANT RELEASER OF PEPTIDE-YY AND ENTEROGLUCAGON FROM THE HUMAN COLON [J].

ADRIAN, TE ;

BALLANTYNE, GH ;

LONGO, WE ;

BILCHIK, AJ ;

GRAHAM, S ;

BASSON, MD ;

TIERNEY, RP ;

MODLIN, IM .

GUT, 1993, 34 (09) :1219-1224

[2] Peptide YY(1-36) and peptide YY(3-36): Part I. Distribution, release and actions [J].

Ballantyne, GH .

OBESITY SURGERY, 2006, 16 (05) :651-658

[3]

Bays Harold E, 2007, Am J Ther, V14, P567, DOI 10.1097/MJT.0b013e31815a69fc

[4] Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulation [J].

Brinton, Eliot A. .

DIABETES OBESITY & METABOLISM, 2008, 10 (11) :1004-1011

[5] Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis [J].

Cao, GQ ;

Liang, Y ;

Broderick, CL ;

Oldham, BA ;

Beyer, TP ;

Schmidt, RJ ;

Zhang, YY ;

Stayrook, KR ;

Suen, C ;

Otto, KA ;

Miller, AR ;

Dai, JN ;

Foxworthy, P ;

Gao, H ;

Ryan, TP ;

Jiang, XC ;

Burris, TP ;

Eacho, PI ;

Etgen, GJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (02) :1131-1136

[6] The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice [J].

Cariou, B ;

van Harmelen, K ;

Duran-Sandoval, D ;

van Dijk, TH ;

Grefhorst, A ;

Abdelkarim, M ;

Caron, S ;

Torpier, G ;

Fruchart, JC ;

Gonzalez, FJ ;

Kuipers, F ;

Staels, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (16) :11039-11049

[7]

Dar M, 2009, CURR OPIN INVEST DR, V10, P1078

[8] Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum [J].

Dumoulin, V ;

Moro, F ;

Barcelo, A ;

Dakka, T ;

Cuber, JC .

ENDOCRINOLOGY, 1998, 139 (09) :3780-3786

[9] The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition [J].

Duran-Sandoval, D ;

Cariou, B ;

Percevault, F ;

Hennuyer, N ;

Grefhorst, A ;

van Dijk, TH ;

Gonzalez, FJ ;

Fruchart, JC ;

Kuipers, F ;

Staels, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (33) :29971-29979

[10] Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 Receptor Agonists [J].

Evans, Karen A. ;

Budzik, Brian W. ;

Ross, Sean A. ;

Wisnoski, David D. ;

Jin, Jian ;

Rivero, Ralph A. ;

Vimal, Mythily ;

Szewczyk, George R. ;

Jayawickreme, Channa ;

Moncol, David L. ;

Rimele, Thomas J. ;

Armour, Susan L. ;

Weaver, Susan P. ;

Griffin, Robert J. ;

Tadepalli, Sarva M. ;

Jeune, Michael R. ;

Shearer, Todd W. ;

Chen, Zibin B. ;

Chen, Lihong ;

Anderson, Donald L. ;

Becherer, J. David ;

De Los Frailes, Maite ;

Javier Colilla, Francisco .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (24) :7962-7965

← 1 2 3 4 →