A review of bile acid sequestrants: potential mechanism(s) for glucose-lowering effects in type 2 diabetes mellitus.
ABSTRACT Clinical evidence has demonstrated that bile acid sequestrants reduce glucose levels in patients with type 2 diabetes mellitus (T2DM). This effect has been confirmed in multiple double-blind, placebo-controlled clinical studies with the bile acid sequestrant colesevelam hydrochloride (HCl). Colesevelam HCl was approved by the US Food and Drug Administration in January 2008 as an adjunctive therapy for patients with T2DM to improve glycemic control. However, the mechanism of action for the glucose-lowering effect of bile acid sequestrants is unclear. Bile acid sequestrants are nonsystemic pharmacological agents that bind bile acids in the gastrointestinal tract, thereby diverting bile acids from the enterohepatic circulation. This, in turn, upregulates bile acid synthesis (via cholesterol 7-alpha-hydroxylase), which utilizes cholesterol, resulting in reduced low-density lipoprotein cholesterol levels. Recent research has revealed that bile acids are tightly controlled signaling molecules that have metabolic effects beyond their primary role in bile to aid in the digestion of lipids and fat. Bile acids signal via various membrane and nuclear receptors. Therefore, bile acid sequestrants may exert glycemic effects by altering the interaction of these bile acid pathways. This article reviews the role for bile acids in glucose regulation and discusses the potential mechanism(s) of action for the glycemic effects of bile acid sequestrants.
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ABSTRACT: Farnesoid X receptor (FXR) is highly expressed in liver and intestine where it controls bile acid (BA), lipid and glucose homeostasis. Here we show that FXR is expressed and functional, as assessed by target gene expression analysis, in human islets and beta-cell lines. FXR is predominantly cytosolic-localized in the islets of lean mice, but nuclear in obese mice. Compared to FXR+/+ mice, FXR-/- mice display a normal architecture and beta-cell mass but the expression of certain islet-specific genes is altered. Moreover, glucose-stimulated insulin secretion (GSIS) is impaired in the islets of FXR-/- mice. Finally, FXR activation protects human islets from lipotoxicity and ameliorates their secretory index.FEBS letters 07/2010; 584(13):2845-51. DOI:10.1016/j.febslet.2010.04.068 · 3.34 Impact Factor
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ABSTRACT: Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs.01/2015; 2015:584546. DOI:10.1155/2015/584546
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ABSTRACT: Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.Current Diabetes Reports 02/2010; 10(1):70-7. DOI:10.1007/s11892-009-0087-5 · 3.38 Impact Factor