Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial.

We investigated whether metformin can improve endothelial function and decrease inflammatory activity, and thereby decrease the risk of atherothrombotic disease. A randomized, placebo-controlled trial with a follow-up period of 4.3 years set in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden Hospitals, the Netherlands). A total of 390 patients with type 2 diabetes treated with insulin were included. Either metformin 850 mg or placebo (one to three times daily) was added to insulin therapy. Urinary albumin excretion and plasma levels of von Willebrand factor (vWf), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured at baseline and after 4, 17, 30, 43 and 52 months. Metformin significantly reduced levels of vWF, sVCAM-1, t-PA, PAI-1, CRP and sICAM-1, which, except for CRP, remained significant after adjustment for baseline differences in age, sex, smoking and severity of previous cardiovascular (CV) disease. No effects on urinary albumin excretion or sE-selectin were observed. The improvements in vWf and sVCAM-1 statistically explained about 34% of the reduction in the risk of CV morbidity and mortality associated with metformin treatment in this study. Metformin is associated with improvement in some (vWF and sVCAM-1) but not all markers of endothelial function, which may explain why it is associated with a decreased risk of CV disease in type 2 diabetes.

de Jager J ，Kooy A ，Schalkwijk C ，van der Kolk J ，Lehert P ，Bets D ，Wulffelé MG ，Donker AJ ，Stehouwer CD ... -  《-》

Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial.

De Jager J ，Kooy A ，Lehert P ，Bets D ，Wulffelé MG ，Teerlink T ，Scheffer PG ，Schalkwijk CG ，Donker AJ ，Stehouwer CD ... -  《JOURNAL OF INTERNAL MEDICINE》

The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial.

Activation of the peroxisome proliferator-activator receptor gamma (PPARgamma) improves insulin resistance and glycemic control in patients with diabetes. As PPARgamma is expressed in the endothelial cell, we have investigated the effect of troglitazone, a PPARgamma activator, on the endothelial function in people with type 2 diabetes in a 12-week, prospective, randomized, double-blinded clinical trial. We studied 87 type 2 diabetic patients who were divided into 3 groups. Group A consisted of 27 patients with recently diagnosed diabetes and no clinical manifestations of macrovascular disease; group B, 29 patients with long-term diabetes and no clinically evident macrovascular disease; and group C, 31 diabetic patients with documented macrovascular disease (cardiovascular, cerebrovascular, or peripheral vascular disease). High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD, endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) in the brachial artery. Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach, endothelium-dependent) and 1% sodium nitroprusside (NaNP, endothelium-independent). The plasma concentrations of von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The FMD improved in the troglitazone-treated patients in group A (7.72 +/- 3.4 v 5.27 +/- 2.0, P <.05 [exit visit v baseline, percent of increase in brachial artery diameter, mean +/- SD]). The fasting insulin level also improved in this group (15.6 +/- 10 v 19.7 +/- 10, P <.05) and was strongly correlated to changes in FMD (r = -.73, P <.01). No changes were found in the FMD or the fasting insulin levels in the troglitazone-treated patients in groups B or C. The NID was not changed by troglitazone treatment in any of the 3 groups. Also, no differences were found in the microcirculation reactivity measurements or in the biochemical markers of endothelial dysfunction in all 3 groups. A small, but significant, improvement of the FMD was found in placebo-treated patients in group B, probably related to the low FMD levels at baseline in the patients (5.40 +/- 3.0 v 4.36 +/- 2.4, P <.05). We concluded that troglitazone treatment for 12 weeks improved endothelial function in the macrocirculation of patients with recently diagnosed type 2 diabetes and no clinical evidence of macrovascular disease. This improvement was strongly associated with the improvement of fasting plasma insulin concentrations.

Caballero AE ，Saouaf R ，Lim SC ，Hamdy O ，Abou-Elenin K ，O'Connor C ，Logerfo FW ，Horton ES ，Veves A ... -  《METABOLISM-CLINICAL AND EXPERIMENTAL》

Meal-induced platelet activation in Type 2 diabetes mellitus: effects of treatment with repaglinide and glibenclamide.

Yngen M ，Ostenson CG ，Hjemdahl P ，Wallén NH ... -  《DIABETIC MEDICINE》

Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin.

Diamanti-Kandarakis E ，Paterakis T ，Alexandraki K ，Piperi C ，Aessopos A ，Katsikis I ，Katsilambros N ，Kreatsas G ，Panidis D ... -  《HUMAN REPRODUCTION》