In HEPATOLOGY, Brufau et al.1 recently reported their examination of the effect of colesevelam, a potent bile acid sequestrant, on glycemic control and bile acid kinetics in patients with type 2 diabetes. Colesevelam improved glycemic parameters and caused the expected increase in cholic acid synthesis. However, the authors “found no correlation between markers of insulin resistance/glucose metabolism and bile acid metabolism,” and they concluded that a firm link between bile acid and glucose metabolism in type 2 diabetes mellitus remained elusive.
The purpose of this note is to propose a mechanism by which colesevelam improves glycemic control in patients with type 2 diabetes. The mechanism is increased release of glucagon-like peptide 1 (GLP-1) from the L cells of the ileum. This GLP-1 release is induced by fatty acids that reach the ileum because of defective micellar solubilization in the jejunum.
In a healthy person, fatty acids are generated by pancreatic lipases acting at the triglyceride/water interface. Fatty acids are solubilized in mixed micelles with conjugated bile acids. Normally, fatty acid absorption is remarkably efficient and complete by the proximal jejunum. When a bile acid sequestrant is administered, it binds bile acids, removes them from solution, and decreases the fatty acid concentration in the aqueous phase.2 Fatty acids that are not solubilized in micelles can be absorbed by the diffusion of individual molecules through the aqueous boundary layer, but this is a slow process. Fatty acids will remain in an emulsified form; experimentally, absorption from an emulsion is slower than absorption from a micellar solution.3 As a result, fatty acids will pass into the ileum, where they will enter L cells and stimulate GLP-1 release. In rats, biliary diversion changes the site of fatty acid absorption from predominantly the jejunum to both the jejunum and the ileum.4
This proposed mechanism can also explain why intestinal transposition or anti-obesity operations that cause fatty acids to reach the ileum improve type 2 diabetes.