Mechanisms of Glucose Lowering Effect of Colesevelam HCl
Condition: Diabetes
MeSH terms: Diabetes Mellitus; Insulin Resistance
Study type: Interventional

Summary: 
      The mechanism by which colesevelam HCl lowers glucose is not known. Knowledge of the
      potential mechanism of action is important for defining the role of the drug among oral
      antidiabetic agents available for use in subjects with diabetes. The objective of this study
      is to provide insight into the mechanisms of action of colesevelam HCl in T2DM. The
      mechanisms of interest include hepatic insulin sensitivity, rate of appearance of exogenous
      glucose and changes in incretin hormone concentrations.
    

Detailed description: 
      Colesevelam HCl (marketed in the U.S. as WelChol®) is a non-absorbed polymer that binds bile
      acids in the intestine, impeding their reabsorption, and is indicated to lower low-density
      lipoprotein cholesterol (LDL-C) in subjects with hypercholesterolemia. As the bile acid pool
      becomes depleted, the hepatic enzyme cholesterol 7-(alpha)-hydroxylase is upregulated,
      increasing the conversion of cholesterol to bile acids. This causes an increased demand for
      cholesterol in the liver, resulting in the dual effect of increasing transcription and
      activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG CoA)
      reductase, and increasing the number of hepatic low-density lipoprotein (LDL) receptors.
      These compensatory effects increase the clearance of LDL-C from the blood, decreasing serum
      LDL C levels (1; 2).

      Recently, it has been shown that colesevelam HCl also improves glycemic control in subjects
      with T2DM who are not controlled adequately on metformin, sulfonylurea or a combination of
      the two drugs (3). The mechanism of action for glucose lowering is not known. Improved
      glycemic control with colesevelam HCl treatment could be due to any of several mechanisms.
      Colesevelam HCl could reduce hepatic insulin resistance and lead to a decrease in hepatic
      glucose production (HGP). The observation by Schwartz et al (4) of significantly reduced
      fasting plasma glucose concentrations in colesevelam-treated T2DM patients suggests such a
      reduction in HGP, as fasting hyperglycemia is a direct function of HGP. Colesevelam HCl could
      also decrease post-prandial glucose absorption. Changes in glucose absorption with other bile
      acid sequestrants (BAS) (5) and bile acids (6) have been reported.

      With regard to molecular mediators of the colesevelam effect on glucose metabolism, there is
      considerable evidence emerging about the role of bile acids and nuclear transcription
      factors, such as the farnesyl X receptor (FXR), in the regulation of glucose and lipid
      metabolism (7) (8) (9-15). Changes in cellular lipids or nuclear hormone receptors might
      directly alter HGP although mechanisms leading to changes in hepatic lipid and glucose
      metabolism by colesevelam HCl have not previously been investigated.

      Significant changes in cholesterol and bile acid synthesis rates are expected with
      colesevelam treatment. BAS treatment can alter the transhepatic flux and compositional
      profile of the circulating bile acid pool (16), and thus its hydrophobicity, and this may
      effect the activation of nuclear receptors, including FXR (17; 18). Determination of the
      effect of colesevelam treatment on bile acid synthesis may provide evidence for its metabolic
      effects. The effects on hepatic fatty acid synthesis (de novo lipogenesis or DNL) have not
      been investigated and may provide further evidence for a metabolic effect of colesevelam.

      Specific hypotheses about its mode of action will be tested, focusing on hepatic glucose
      metabolism and intestinal glucose absorption.
    

Intervention name(s): Colesevelam HCL; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Colesevelam HCL 625 mg: 3 tablets twice per day; Placebo tablets: 3 tablets twice per day
Other intervention name(s): WelChol
Intervention MeSH terms: Colesevelam Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: type two diabetes; gluconeogenesis; glucose; lipid synthesis; hepatic insulin sensitivity; colesevelam HCl