Does Pioglitazone Increase the Production of Prostacyclin (PGI2) and/or 15-EPI-Lipoxin A4 in Humans With Diabetes Mellitus Type 2?

Type-2 diabetes mellitus is a public health concern. According to the World health
organization (WHO), diabetes mellitus affects more than 180 million people worldwide. Type 2
diabetes mellitus accounts for 80-95% of diabetes cases in developed countries and a higher
proportion in developing countries (IDF 2006). Patients with type 2 diabetes mellitus are at
high risk of developing cardiovascular complications. Diabetic patients are two to
four-times more likely to develope cardiovascular disease. The mortality of diabetic
patients with cardiovascular disease is much higher than in non-diabetic matched patients
with cardiovascular disease. Recently, it has become apparent that not all anti-diabetic
drugs have the same effect on the progression of atherosclerosis and on cardiovascular
outcomes. There is a great need to understand the potential protective mechanisms of the
various anti-diabetic drugs in order to decrease their risk for cardiovascular morbidity and
mortality. In addition to increasing insulin sensitivity, Pioglitazone (PIO) has
anti-inflammatory properties. Several studies have suggested that PIO decreases serum
markers of inflammation including C-reactive protein (CRP). However, the underlying
mechanisms of these anti-inflammatory (and probably anti-atherosclerotic) effects of PIO are
unknown. We have shown in the rat that 3-day pretreatment with PIO increases myocardial
cyclooxygenase-2 (COX2) activity and levels of both 6-keto-PGF1a, the stable metabolite of
prostacyclin (PGI2) and 15-epi-lipoxin A4, a lipid mediator with a strong anti-inflammatory
properties. Prostacyclin inhibits platelet aggregation and causes vasodilatation. Increased
levels of 6-keto-PGF1a and 15-epi-lipoxin A4 may thus be the explanation for the
anti-inflammatory and anti-atherosclerosis effects of PIO. Several clinical studies have
shown that COX2 inhibition is associated with increased cardiovascular events. Thus,
augmenting COX2 activity and the production of prostacyclin and 15-epi-lipoxin A4 may have
potential favorable effects. The purpose of the study is to test whether PIO therapy is
associated with an increase in serum and/or urine levels of 6-keto-PGF1a and 15-epi-lipoxin
A4 in patients with diabetes mellitus type 2.