The effect of a bile acid sequestrant on bile acid- and glucose metabolism in patients with impaired glucose tolerance.

Objective:
To investigate the effects of colesevelam (bile acid sequestrant) on bile acid composition, insulin resistance, glucose metabolism and composition of faecal flora in patients with an impaired glucose tolerance or newly diagnosed type 2 diabetes.

Study design:
Double blind randomized controlled single center trial.

Study Population:
Male obese subjects with an impaired glucose tolerance or newly diagnosed type 2 diabetes mellitus (fasting glucose > 6,0 mmol/l).

Treatment:
Patients will be randomised to either colesevelam treatment or placebo treatment for a period of 12 weeks.

Outcome measures:
The primary endpoints are changes in bile acid composition. Secondary endpoints are changes in hepatic and peripheral insulin resistance (assessed by hyperinsulinemic euglycemic clamp at baseline and after 12 weeks), metabolic parameters (lipid profile, glycemic control) as well as changes in faecal microbiota, glucose and lipid content (assessed by analysing faeces samples). Finally, muscle and adipose tissue samples will be obtained to assess D2 mRNA and activity and phosphorylation status of the insulin signalling cascade.

Powercalculation:
It is estimated that a total of 24 patients (12 patients per treatment arm) are needed to achieve statistical significant outcomes.

Colesevelam is a bile sequestrant that not only improves lipid parameters, but also improves glycemic control. The workingsmechanismen of colesevelam is yet unknown. We hypothezize that treatment of obese insulin resistant subjects with colesevelam increases hepatic insulin sensitivity. In this study we want to investigate effect of colesevelam on bile acid composition, insulin resistance and glucose metabolism in patients with an impaired glucose tolerance or newly diagnosed type 2 diabetes.

Bile acid metabolism will be measured before and after 12 weeks, using stable isotopes. Additionally insulin sensitivity is determined before and after 12 weeks by a two-step hyperinsulinemic euglycemic clamp using stable isotopes. Changes in liopid parameters/metabolic control and faecal flora composition will be determined before as well as after 4, 8 and 12 weeks after start of the trial.

Patients will be randomised to either colesevelam treatment or placebo treatment for a period of 12 weeks.