Pioglitazone and Serum Asymmetric Dimethylarginine (ADMA) in Patients With Diabetes

Pioglitazone and Serum Asymmetric Dimethylarginine (ADMA) in Patients With Diabetes

SPECIFIC AIMS

1. To determine whether pioglitazone will reduce levels of asymmetric dimethylarginine(ADMA) in patients with diabetes.
2. To determine whether nitric oxide(NOx) products are increased with pioglitazone treatment.
3. To determine whether pioglitazone reduces oxidative stress (F2-isoprostanes).

The primary purpose of this study is to determine whether treatment with pioglitazone can reduce serum levels of asymmetric dimethylarginine (ADMA) in patients with adult diabetes. Recent research has found that elevated serum ADMA is associated with increased cardiovascular events and mortality, particularly in people with diabetes (Boger 2005, Zoccali 2006, Ueda 2007). ADMA, by mediating nitric oxide (NO) availability, may trigger pro-atherogenic effects. High plasma concentration of this substance has been associated with intima-media thickening, left ventricular hypertrophy and all-cause and cardiovascular mortality in patients with end-stage renal disease, and associated with increased cardiovascular events in patients with diabetes (Kryzazanowska 2007). The result of higher levels of ADMA and reduced output of NO increases vasoconstriction, increases inflammation, and interferes with endothelial function. Preliminary studies indicate that pioglitazone may reduce ADMA levels, and thus lower cardiovascular risk.Thus, this protocol will test whether pioglitazone can reduce ADMA levels in adult patients with diabetes.

Inclusion Criteria:

• Adults age 40--75 years-of-age, non-pregnant
• Informed consent
• History of type 2 Diabetes Mellitus
• Stable weight for the last 3 months (no change greater than +5% of body weight)
• ADMA > 0.50 µM/L (mean of non-diabetic reference group) (Devangelio 2007)
• On stable medical therapy for at least 3 months
• A working telephone

Exclusion Criteria:

• Any history of known coronary heart disease, including a history of congestive heart failure, myocardial infarction, coronary re-vascularization, or stroke
• Pregnancy
• Chronic kidney disease, serum creatinine >2.0mg/dl, chronic liver disease, or uncontrolled hypertension (>160/100).
• Current participation in a formal weight loss program or planning to start such a program during the next 3 months
• Collagen vascular disease, infection, or other inflammatory condition
• Electrocardiogram (EKG) evidence of ischemia or infarction
• Macular edema (swelling of the back of the eye), recent excessive weight gain (over 5% of weight in 30 days), elevated liver function tests > 2.5 X the upper limit, or history of osteoporosis