Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
Condition: Glucose Metabolism Disorders; Diabetes
MeSH terms: Metabolic Diseases; Glucose Intolerance; Glucose Metabolism Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      Subjects with impaired glucose tolerance will be randomized to receive pioglitazone or
      metformin for 10 weeks. Measurements of insulin sensitivity, body composition, glucose
      tolerance, and muscle lipid accumulation will be performed. Adipose tissue and muscle
      biopsies are performed. The goal of the study is to determine whether the lipotoxiciy of
      impaired glucose tolerance is ameliorated by pioglitazone.
    

Detailed description: 
      The progression to type 2 diabetes represents an evolution, which results from a vicious
      cycle where both glucotoxicity and lipotoxicity act to reduce insulin secretion and insulin
      action. Lipotoxicity is a new concept, which refers to overaccumulation of lipids in
      non-adipose tissue reflecting increased free fatty acid delivery. Increased fat content of
      skeletal muscle and islet cell is associated with insulin resistance and impaired pancreatic
      -cell function respectively in animal models. Whether lipotoxicity is the link between
      obesity and diabetes, in humans, and whether reducing intracellular fat content will improve
      insulin secretion and sensitivity in humans is not known. In this study, we will focus on
      obese subjects with impaired glucose tolerance (IGT) who have not yet developed glucose
      toxicity. We will examine insulin secretion, insulin action, hepatic glucose production, and
      muscle lipid metabolism in response to two insulin sensitizers with two different modes of
      action. We propose that thiazolidinediones will improve cell function by reversing
      lipotoxicity as reflective in reduced muscle lipid accumulation.

      Hypothesis 1. In subjects with impaired glucose tolerance, who are insulin resistant and also
      have an insulin secretory defect, thiazolidinediones, but not biguanides, improve cell
      function.

      Hypothesis 2. In subjects with impaired glucose tolerance, thiazolidinediones, but not
      biguanides, decrease the accumulation of fat in non-adipose tissues including muscle,
      pancreas, liver and myocardium.

      Specific Aim 1. Fifty subjects with impaired glucose tolerance will be recruited and
      randomized to pioglitazone or metformin treatment

      Specific Aim 2. cell function will be evaluated by measuring changes in acute insulin
      response to glucose and non-glucose secretagogues in subjects with IGT and it will be
      compared in response to treatment with pioglitazone versus metformin.

      Specific Aim 3. The muscle fat content will be evaluated as the surrogate measure for
      lipotoxicity and overaccumulation of fat in non-adipose tissue. From the muscle biopsy
      specimens, we will measure the amount of intramyocellular triglyceride before and after
      treatment with pioglitazone versus metformin.

      Specific Aim 4. Adipose tissue cytokine expression is associated with changes in muscle lipid
      accumulation.
    

Intervention name(s): Metformin; Pioglitazone; Metformin; Pioglitazone; CT scans; Oral glucose tolerance test
Intervention type(s): Drug; Drug; Drug; Drug; Radiation; Procedure
Intervention description(s): To measure changes in adipose tissue volumes; To detect a change in glucose tolerance
Intervention MeSH terms: Metformin; Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science