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.
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
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
- Impaired glucose tolerance
- Body mass index (BMI) of 28-38
- Heart disease
- Renal disease
- Liver disease