Bile Acids and Metabolic Regulation
Mechanisms and clinical responses to bile acid sequestration
- 1Institut Pasteur de Lille, INSERM U545, Université Lille Nord de France, Lille, France;
- 2Section of Endocrinology, Diabetes and Metabolism, Tulane University Health Science Center, New Orleans, Louisiana.
- Corresponding author: Bart Staels, .
Bile acids have long been known to facilitate digestion and absorption of lipids in the small intestine as well as regulate cholesterol homeostasis (1,2). Over the last decade, however, it has become clear that bile acids are not simply digestive detergents and the primary route governing cholesterol catabolism. Bile acids are now recognized as hormones involved in the regulation of various metabolic processes (3). Through activation of various signaling pathways, bile acids regulate not only their own synthesis and enterohepatic circulation, but also triglyceride, cholesterol, glucose, and energy homeostasis (2).
Manipulation of bile acid enterohepatic circulation by bile acid sequestration with nonsystemically absorbed resins can modulate the processes regulated by bile acids. Whereas bile acid sequestrants (BASs) have been used for over 40 years in the treatment of dyslipidemia (1), more recent data have emerged that have expanded their role in the treatment of dysglycemia in type 2 diabetes (4–9). The initial data suggesting such an effect were derived from post hoc analysis of a clinical trial for dyslipidemia that determined that BASs lowered glucose, particularly when compared with other lipid-lowering drugs (4). This concept was subsequently proven in several studies showing that BASs, such as colesevelam, lower glucose (5–8).
This review examines recent data exploring possible mechanisms involved in regulation of glucose metabolism by bile acids and the potential impact of disruption of their enterohepatic circulation on diabetes. We will also summarize the available clinical trial data that supported the regulatory approval of colesevelam for the treatment of hyperglycemia in type 2 diabetes.
TRADITIONAL ROLE OF BILE ACIDS: DIGESTION, EXCRETION, AND AUTOREGULATION
Bile acids are potent “digestive surfactants” that promote absorption of lipids (including fat-soluble vitamins), acting as emulsifiers (1,2).
Bile acids represent the primary pathway for cholesterol catabolism and account for ∼50% of the daily turnover …