The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes

The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 +/- 1.59 vs 5.12 +/- 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 +/- 11.3 vs 14.3 +/- 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).

The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes

The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 +/- 1.59 vs 5.12 +/- 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 +/- 11.3 vs 14.3 +/- 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).

Sitagliptina, un inhibidor de la enzima DPP-IV, aumenta el colesterol plasmático total, altera el perfil de colesterol lipoproteico y disminuye el transporte reverso de colesterol en ratones / Sitagliptine, an DPP-IV enzyme inhibitor, raises total cholesterol and decreases reversal cholesterol transport in mice

Antecedentes: Las hormonas insulina y glucagón regulan la expresión de proteínas claves en el metabolismo lipídico. En pacientes diabéticos, la enfermedad cardiovascular ateroesclerótica es la principal causa de muerte, siendo la dislipidemia un importante factor de riesgo patogénico. La sitagliptina, un inhibidor de la enzima dipeptidilpeptidasa tipo IV (DPP-IV) que controla el metabolismo de las incretinas, es una nueva droga hipogli-cemiante utilizada para el tratamiento de la diabetes tipo 2, aunque sus implicancias en el metabolismo lipídico no han sido establecidas claramente. Objetivo: Estudiar el efecto de la sitagliptina sobre algunos parámetros relacionados con el metabolismo del colesterol en el ratón. Material y Métodos: Se utilizaron ratones C57BL6/J silvestres, siendo un grupo alimentado con dieta estándar y el otro con dieta estándar suplementada con sitagliptina (0,6 por ciento P/Pde dieta) por 8 semanas. La actividad plasmática de DPP-IV y el colesterol plasmático total y lipoproteico fueron medidos por métodos enzima-ticos. La expresión hepática de SR-BI y LDLR se cuantificó por western blot. El transporte reverso de colesterol (TRC) fue evaluado inyectando intraperitonealmente macrófagos cargados con colesterol-14C y midiendo posteriormente los niveles de 14C en plasma y deposiciones en los ratones controles o tratados con sitagliptina. Resultados: La sitagliptina inhibió en un 38 por ciento la actividad de DPP-IV medida en plasma de los ratones. El colesterol plasmático aumentó significativamente (+60 por ciento) con una elevación preferente del colesterol HDL en los ratones tratados con sitagliptina versus los animales controles. Con respecto al TRC, la sitagliptina indujo una mayor recuperación (+20 por ciento) en el plasma y una menor excresión (-30 por ciento) en las deposiciones del 14C-colesterol inyectado versus el grupo control. Finalmente, la sitagliptina disminuyó la expresión hepática de los receptores lipoproteicos ...

Background: Insulin and glucagon regulate the expression of key lipoprotein metabolism enzymes. Dyslipidemia is a significant risk factor for cardiovascular disease, the main cause of death in diabetic patients. Sitagliptine, an inhibitor of type IV dipep-tidil-peptidase (DPP-IV), controlling the metabolism of incretins, is a new hypoglycemic agent used for treatment of type II diabetes. Its effects on lipid metabolism are not clearly defined. Aim: to study the effects of sitagliptine upon parameters of cholesterol metabolism in mice. Methods: C5BL6/J mice were assigned to receive either a standard diet or one with sitagliptine supplementation (0.6 percent P/P) for 8 weeks. DPP-IV plasma, total and lipoprotein cholesterol were measured using enzyme methods. Reverse cholesterol transport was evaluated through the peritoneal injection of cholesterol loaded macrophages followed by measurement of plasma and fecall4C labeled cholesterol. Results: compared to controls, sitagliptine treated mice exhibited a 38 percent decrease in plasma DPP-IV Total plasma cholesterol increased by 60 percent with a marked increase in HDL cholesterol. Also, an increased HDL cholesterol recovered from plasma along with a 30 percent decrease in fecal cholesterol was observed Finally, sitagliptine administration was associated to a decreased LDL and SR-BI hepatic receptors. Conclusion: Sitagliptine administration is associated to increased levels of plasma cholesterol, mainly the HDL fraction, and decreased reverse cholesterol transport and fecal excretion. This effects seem to be mediated by a decreased expression of SR-BI in the liver. The expected increase in atherosclerosis associated to the atherogenic changes induced by sitagliptine should be the subject for further studies in mice.