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: 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. · 2.50 Impact Factor
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ABSTRACT: Macromolecular binders consist of polymers, dendrimers, and oligomers with binding properties for endogenous or exogenous substrates. This field, at the frontier of host/guest chemistry and pharmacology, has met a renewed interest in the past decade due to the clinical success of several sequestrants, like sevelamer hydrochloride (Renagel®) or sugammadex (Bridion®). In many instances, multivalent binding by the macromolecular drugs can modify the properties of the substrate, and may prevent it from reaching its site of action and/or trigger a biological response. From small (e.g., ions) to larger substrates (e.g., bacteria and cells), this review presents the state-of-the-art of macromolecular binders and provides detailed illustrative examples of recent developments bearing much promise for future pharmaceutical applications.Journal of Controlled Release 05/2011; 155(2):200-10. · 5.73 Impact Factor