Lipin functions in mammalian phospholipid biosynthesis through its phosphatidate phosphohydrolase 1 (PAP,) activity. Here, we studied cardiac PAP, activity and lipin expression ex vivo in 8-month-old Zucker diabetic fatty (ZDF) rats and humans with type 2 diabetes mellitus undergoing open heart surgery for coronary bypass grafting. Compared to non-diabetic littermates (ZDF-fa/(+)), left ventricular PAP, activity was 29% lower in diabetic ZDF-fa/fa rats. Left ventricular PAP, activities were 2.1-fold (ZDF-fa/fa) and 3.6-fold (ZDF-fa/(+)) higher than the respective atrial activities, indicating marked differences in cardiac distribution of PAP(1), PAP(1) activity was highly related with cardiac lipin-1 and lipin-3 mRNA expression in ZDF rats (r = 0.99 and 0.96). Consistent with the findings in experimental animals, human atrial tissue displayed PAP, activity that was 33% lower in those having diabetes than in non-diabetic controls. Accordingly, atrial lipin-1 and lipin-3 mRNA expression in diabetic patients was 50% and 59% lower as in non-diabetic patients, respectively. Insulin therapy increased both PAP, activity and lipin mRNA expression in diabetic patients. We conclude that suppression of cardiac PAP(1) activity/lipin expression may contribute to metabolic dysfunction of the diabetic heart. (c) 2009 Elsevier Inc. All rights reserved.