A review of bile acid sequestrants: Potential mechanism(s) for glucose-lowering effects in type 2 diabetes mellitus

Universite Lille Nord de France, Inserm U545, UDSL, Lille, France.
Postgraduate Medicine (Impact Factor: 1.7). 06/2009; 121(3 Suppl 1):25-30. DOI: 10.3810/pgm.2009.05.suppl53.290
Source: PubMed


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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    • "Moreover, FXR mRNA levels are increased in livers of diabetic db/db mice [9]. Treatment of type 2 diabetic dyslipidaemic patients, with intestinal-acting bile acid sequestrants, such as cholestyramine or colesevelam, resulted in lower plasma glucose and HbA1C concentrations [10]. Several authors suggested that BA decrease hepatic glucose production by the liver and therefore improve hyperglycemia by regulating enzymes of gluconeogenesis [11] [12] [13]. "
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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.
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    • "CYP7A1—cytochrome P450 enzyme cholesterol 7 α-hydroxylase; FGF-15/19—fibroblast growth factor 15/19; FGFR4—fibroblast growth factor receptor 4; FXR—farnesoid X receptor; GLP-1—glucagon-like peptide-1; GR—glucocorticoid receptor; HNF-4—hepatocyte nuclear factor-4; JNK—c-jun N-terminal kinase; LRH-1—liver receptor homologue-1; PEPCK—phosphoenolpyruvate carboxykinase; SHP—small heterodimer partner; SREBP-1c—sterol regulatory element-binding protein-1c; TGs—triglycerides; VLDL—very low density lipoprotein. (Adapted from Staels [49] and Thomas et al. [50].) "
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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.
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