sitagliptin-phosphate and 8-hydroxyguanine

Type 2 diabetes is associated with an increased risk of cardiac complications. Inhibitors of dipeptidylpeptidase 4 (DPP-4) are novel drugs for the treatment of patients with type 2 diabetes. The effect of DPP-4 inhibitors on myocardial metabolism has not been studied in detail. In wild-type C57Bl6-mice, 3weeks of treatment with sitagliptin had no effect on body weight and glucose tolerance nor on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoAcarboxylase (ACC), phosphofructokinase-2 (PFK2) or tuberin-2 (TSC2) in the left ventricular myocardium. However, in 10week old db/db-/- mice, a model of diabetes and obesity, sitagliptin potently reduced plasma glucose rise in peritoneal glucose tolerance tests and reduced weight increase. The myocardium of untreated db/db-/- mice exhibited a marked increase of the phosphorylation of AMPK, ACC, TSC2, expression of p53 and fatty acid translocase (FAT/CD36) membrane expression. These changes were reduced by DPP-4 inhibition. Sitagliptin showed no effect on cardiomyocyte size but prevented myocardial fibrosis in the 10week old db/db-/- mice and reduced expression of TGF-β1, markers of oxidative stress and the accumulation of advanced glycation end products in cardiomyocytes. Working heart analyses did not show an effect of sitagliptin on parameters of systolic cardiac function. In animals with diabetes and obesity, sitagliptin improved glucose tolerance, reduced weight gain, myocardial fibrosis and oxidative stress. Furthermore the study provides evidence that treatment with sitagliptin decreases elevated myocardial fatty acid uptake and oxidation in the diabetic heart. These observations show beneficial myocardial metabolic effect of DPP-4 inhibition in this mouse model of diabetes and obesity.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Body Weight; CD36 Antigens; Cell Membrane; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Glucose Tolerance Test; Glucose Transporter Type 4; Glycation End Products, Advanced; Guanine; Heart; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Phosphorylation; Protein Transport; Pyrazines; Sitagliptin Phosphate; Triazoles; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Protein p53; Tumor Suppressor Proteins