Glucose-mediated impairment of homocysteine (Hcy) metabolism and decrease in renal clearance contribute to hyperhomocysteinemia (HHcy) in diabetes. The Hcy induces oxidative stress, inversely relates to the expression of peroxisome proliferators activated receptor (PPAR), and contributes to diabetic complications. Extracellular matrix (ECM) functionally links the endothelium to the myocyte and is important for cardiac synchronization. However, in diabetes and hyperhomocysteinemia, a "disconnection" is caused by activated matrix metalloproteinase with subsequent accumulation of oxidized matrix (fibrosis) between the endothelium and myocyte (E-M). This contributes to "endothelial-myocyte uncoupling," attenuation of cardiac synchrony, leading to diastolic heart failure (DHF), and cardiac dys-synchronizatrion. The decreased levels of thioredoxin and peroxiredoxin and cardiac tissue inhibitor of metalloproteinase are in response to antagonizing PPARgamma.