Effects of Pioglitazone on Igh-density Lipoprotein (HDL) Function in Persons With Diabetes

• changes in HDL density and particle size distribution [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Lipoproteins will be isolated and analyzed using the gradient ultracentrifugation-HPLC technique to isolate VLDL, IDL, LDL, and three HDL subfractions that correspond roughly to HDL2b, HDL2a+3a, and HDL3b+3c. Each fraction will be anlyzed for protein and lipid composition
• Cholesterol efflux capacity of HDL [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  The ability of serum HDL to remove cholesterol from cultured cells will be assessed as an in vitro method to evaluate a functional changes in HDL mediated by changes due to pioglitazone treatment

Metabolic defects contributing to the development of type 2 diabetes (T2D) are relative insulin insufficiency and insulin resistance, that are associated with a cluster of abnormalities that increase the risk for cardiovascular disease including dyslipidemia, inflammation, hemodynamic changes and endothelial dysfunction. The dyslipidemia associated with T2D is characterized by elevated triglycerides and decreased igh-density lipoprotein-cholesterol (HDL). The ability of the insulin sensitizing agent pioglitazone (ACTOS®) , to improve hyperglycemia in subjects with T2D is now well established. Pioglitazone functions as a PPAR-γ agonists and this class of drugs have demonstrated several other potential benefits, in addition to their effects on glucose homeostasis. PPAR-γ agonists can improve diabetic dyslipidemia, in which PIO increases HDL cholesterol and lowers triglycerides. Evidence demonstrating that TZDs reduce carotid arterial intima-media thickness provide evidence of an anti-atherogenic effect of PPAR-γ activators and might imply benefits beyond glycemic control for patients treated with this class of drugs. A potential beneficial effect on reverse cholesterol transport may be mediated by the increased HDL levels. This proposal aims to examine the effect of PPAR-γ activation by PIO on various aspects of reverse cholesterol transport by testing the hypothesis that PIO treatment affects key steps in the reverse cholesterol transport pathway either directly, through induction of protein expression, or indirectly, by altering HDL structure and composition leading to increase cholesterol flux through this pathway.

The investigators hypothesize that increased levels of HDL resulting from PIO therapy will affect particle size, density distribution and the lipid and lipoprotein composition of HDL and that such changes may alter the activity of several key steps involved in reverse cholesterol transport, namely the ability to promote cellular cholesterol efflux, cholesterol esterification by LCAT and transport of esterified cholesterol from HDL to the apoB containing lipoproteins.

• Active Comparator: Pioglitazone Group
  This is a baseline versus treatment study comparing subjects on pioglitazone to a matched group of subjects treated with either metformin or sulfonylurea with the intent of controlling blood sugar to a comparable level
  Intervention: Drug: pioglitazone
• No Intervention: Comparator Group
  This group of subjects will be maintained on standard treatment with either metformin or sulfonylurea with the intent of controlling blood sugar to a comparable level as group treated with pioglitazone.

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Inclusion Criteria:

• Type 2 diabetes, men and women, WHO criteria, aged 35-70 years
• HbA1c 7.5-10.0%
• BMI 26-39 Kg/m2
• Either receiving dietary therapy only or monotherapy with either sulfonylurea or metformin
• Already on statin therapy

Exclusion Criteria:

• Cardiovascular disease
• Renal disease
• Other systemic disease
• Abnormal liver function tests (ALT or AST>1.5 X ULN)
• Uncontrolled hypertension (BP >160/110)
• Triglyceride levels >400 mg/dl
• Lipid modifying drugs; fibrates, ezetemibe, niacin, bile sequestrants, but not statins (see below),
• Estrogen treatment or thyroid disease
• Psychiatric condition or substance abuse