This project will compare the amount of bile acids and their kinetics in overweight and obese people with normal glucose metabolism, impaired glucose tolerance and frank type 2 diabetes. We hypothesize that bile acids will behave differently in these groups. We will also explore the effects of Colesevelam HCl, a medicine that lowers LDL cholesterol by binding bile acids, on bile acids in those groups. We hypothesize the drug may have different actions on bile acids in subjects with different degrees of abnormal glucose metabolism.

Bile acids, which are synthesized from cholesterol in the liver, play a key role in digestion as they solubilize dietary lipids and aid their absorption in the digestive tract. While for many years bile acids have been characterized by this digestive role, recent research indicates that bile acids play other important roles. Because bile acids have been shown to act in signaling pathways that affect metabolism, there has been renewed interest in investigations of their effects. This study explores potential differences in bile acid kinetics based on insulin resistance or type 2 diabetes at baseline.

Colesevelam HCl is a bile acid sequestrant, which in addition to its primary role in lowering serum LDL-C levels, has secondarily been implicated in lowering blood glucose levels. This study explores the relationship between insulin resistance and type 2 diabetes and changes in bile acid pool sizes and kinetics with colesevelam treatment. Isotopically labeled bile acids will be administered to subjects before and after treatment with colesevelam and comparisons will be made in bile acid pool size, fractional turnover rate, and synthesis rate in the three study groups.

Inclusion Criteria:

• Have given written informed consent
• BMI 25-35 kg/m^2, inclusive
• Normal liver and thyroid function
• No history of liver, biliary, or intestinal disease

Diabetic Subjects

• Diagnosed Type 2 Diabetes Mellitus
• HbA1C = 6.7-10%

Normal Subjects

• 2 hr OGTT glucose < 140 mg/dL
• fasting glucose < 100 mg/dL
• TG < 150 mg/dL
• HDL cholesterol >= 40 mg/dL

Impaired Glucose Tolerance Subjects

• 2 hr OGTT glucose >= 140 and < 200 mg/dL

Exclusion Criteria:

• T1DM or history of diabetic ketoacidosis
• treatment with blood pressure lowering therapy that has not been stable for three months before screening
• colesevelam HCl, cholestyramine, or colestipol treatment for hyperlipidemia within the last three months
• treatment with thiazolidinedione (TZD) at any time
• treatment with insulin within past 6 months
• treatment with antibiotics within last 3 months
• extreme sportsmen
• treatment with medication affecting liver or intestinal function within the last 3 months
• allergic or toxic rxn to colesevelam HCl
• history of dysphagia, swallowing disorders, or intestinal motility disorder
• Serum Triglycerides > 500 mg/dL at visit 1
• Serum LDL-C < 60 mg/dL at visit 1
• any condition or therapy investigator believes not in subjects best interest
• use of any investigational drug within 30 days before screening
• chronic treatment with oral corticosteroids at any time or acute treatment within last three months
• hyperthyroidism or treatment with thyroid hormone/levothyroxine

overweight and obese people with normal glucose metabolism, impaired glucose tolerance and frank type 2 diabetes