Elucidating the glucose‐lowering effect of the bile acid sequestrant sevelamer

Abstract

AbstractAim: Bile acid sequestrants are cholesterol‐lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose‐lowering effect is unknown but has been proposed to be mediated by increased glucagon‐like peptide‐1 (GLP‐1) secretion. Here, we investigated the glucose‐lowering effects of sevelamer including any contribution from GLP‐1 in people with type 2 diabetes.Materials and Methods: In a randomized, double‐blind, placebo‐controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17‐day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash‐out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4‐h liquid meal tests and application of concomitant infusion of exendin(9‐39)NH2 or saline.Results: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta‐cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9‐39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9‐39)NH2 abolished the sevelamer‐induced improvement in beta‐cell glucose sensitivity.Conclusions: The bile acid sequestrant sevelamer improved insulin sensitivity and beta‐cell sensitivity to glucose, but using the GLP‐1 receptor antagonist exendin(9‐39)NH2 we were not able to detect a GLP‐1‐mediated glucose‐lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer‐induced improvement of beta‐cell sensitivity to glucose was shown to be GLP‐1‐dependent.