Atypical Mechanism of Glucose Modulation by Colesevelam in Patients with Type 2 Diabetes

Abstract

Colesevelam’s glucose-lowering mechanism of action is not completely understood. Clinical trials of colesevelam suggest that its mechanism, and often adverse effects, differ from those of other oral antidiabetes drugs. Colesevelam does not affect insulin sensitivity (unlike thiazolidinediones), insulin secretion (unlike sulfonylureas and meglitinides), or early insulin response or glucagon (unlike dipeptidyl peptidase-4 inhibitors). Colesevelam may have some effect on glucose absorption, but likely via a different mechanism than α-glucosidase inhibitors. Colesevelam and metformin have similarities regarding hepatic glucose production, but divergent effects on gluconeogenesis versus glycogenolysis, suggesting differing mechanisms of drug action for improving glycemic control. Colesevelam is thought to be a portal glucagon-like peptide-1 (GLP-1) secretagogue with primarily hepatic effects. Bile acid binding by colesevelam leads to TGR5 activation, increased secretion of GLP-1 or other incretins, and inhibition of hepatic glycogenolysis. Colesevelam’s mechanism of action appears to be atypical of other antidiabetes medications, making it a potentially suitable component of many combination regimens in the treatment of type 2 diabetes.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…Bile acid sequestrants have long been used for treating gallstone disease. The second-generation bile acid sequestrants are currently in clinical trials for metabolic diseases (Davidson et al, 1999;Aldridge and Ito, 2001;Bays et al, 2008;Brufau et al, 2010;Shang et al, 2010;Nwose and Jones, 2013). Gastric bypass surgeries are effective in reducing weight and improving insulin resistance and are increasingly popular for treatment of T2DM (Patti et al, 2009;Simonen et al, 2012;Gerhard et al, 2013).…”

“…Colesevelam may reduce hepatic glucose production and improve hyperglycemia and hyperinsulinemia in dietinduced obese mice (Potthoff et al, 2013). This effect may be mediated through activation of TGR5 and GLP-1 release (Nwose and Jones, 2013). A recent study shows that colesevelam increases GLP-1 levels and improves b-cell function, but has no effect on insulin sensitivity (Beysen et al, 2012).…”

1H NMR-based Plasma Metabolic Profiling of Dairy Cows with Type I and Type II Ketosis

“…Skeletal muscle cells oxidize glucose via glycolysis and produce energy. Lactic acid from anaerobic glycolysis may be converted into glucose by hepatic gluconeogenesis [30]. However, lactate significantly increased in K2 compared with K1; therefore, more glycolysis occurred in K2 to meet the energy demands of type II ketosis.…”

Bile Acid Uptake Transporters as Targets for Therapy

“…Similarly, colesevelam improved glucose homeostasis. This effect seems mostly mediated by TGR5 activation [63,64], and partially through the inhibition of FXR signaling [65]. Bile acid-induced GLP1 release occurs upon the activation of TGR5 at the basolateral (blood) side of L-cells [66,67].…”