Ghrelin Regulation and Structure: Effect of Thiazolidinedione Therapy on Ghrelin

• Secondary outcomes for this aim include the degree of insulin suppressibility as measured by a hyperinsulinemic-euglycemic clamp. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Secondary outcome for this aim include the degree of insulin suppressibility as measured by an area-under-the-curve measurements during the 12½ hours of meal testing for ghrelin, glucose,insulin and gut-peptides. [ Time Frame: 3 months ] [ Designated as safety issue: No ]

The purpose of this study is to learn more about how insulin resistance (inability to process glucose correctly resulting in mildly elevated glucose levels) affects the hormone ghrelin.

Insulin resistance suppresses fasting ghrelin levels and impairs postprandial ghrelin suppression. Improved insulin sensitivity with a thiazolidinedione will raise ghrelin levels, enhance meal-related suppression, but not change the ratio of total to active ghrelin or result in an alteration of ghrelin structure.

• Obesity
• Insulin Resistance

• Drug: placebo
  treatment with placebo for 3 months
  Other Name: placebo
• Drug: pioglitazone
  treatment with 30mg daily for two weeks then 45mg every day with pioglitazone for three months
  Other Name: thiazolidinedione therapy

• Placebo Comparator: Placebo
  Treatment with placebo for 3 months before spectroscopy, hyperinsulinemic-euglycemic clamp, control diet, blood sampling.
  Intervention: Drug: placebo
• Active Comparator: 2
  Treatment with pioglitazone for 3 months before hyperinsulinemic-euglycemic clamp, control diet with blood sampling and spectroscopy.
  Intervention: Drug: pioglitazone

Inclusion Criteria:

• Age 18 to 80, weight stable for at least 3 months

• At lifetime maximal body weight and impaired glucose tolerance (ICT) by the World Health ORganization criteria:

  • fasting plasma glucose level of 100- 125mg/dL or
  • plasma glucose level between 140 to 149mg/dL following a 75gram oral glucose load

Exclusion Criteria:

• Actively losing weight
• Smokers
• Alcohol consumption > 2 drinks/day
• Prescription drug use
• Recreational drug use
• Type 2 Diabetes
• Conditions that contraindicate treatment with pioglitazone such as CHF, impaired liver or kidney function or known sensitivity to pioglitazone