Effects of pravastatin on serum osteoprotegerin levels in patients with hypercholesterolemia and type 2 diabetes.

Osteoprotegerin is a secretory glycoprotein. Recent experimental findings have suggested that osteoprotegerin may protect against vascular calcification and/or atherosclerosis. In humans, osteoprotegerin levels are positively correlated with the presence and severity of coronary artery disease and the progression of atherosclerosis. However, it is unclear how osteoprotegerin levels are regulated. Statins are known to have beneficial pleiotropic effects against atherosclerosis beyond their lipid-lowering effects. In this study, we examined whether treatment with pravastatin can alter osteoprotegerin levels in patients with hypercholesterolemia and type 2 diabetes. Osteoprotegerin levels were significantly increased from 6.64 +/- 2.18 pmol/L at baseline to 7.08 +/- 2.29 pmol/L (P = .024) after 3-month treatment with pravastatin. These increases in osteoprotegerin levels remained after 6 months of treatment (7.05 +/- 2.22 pmol/L, P = .026). These findings suggest that pravastatin may exert its pleiotropic effects in part through alteration of osteoprotegerin levels.

Intrarenal hemodynamic changes after captopril test in patients with type 2 diabetes: a duplex Doppler sonography study.

OBJECTIVE: ACE inhibitors are known to be effective in preventing the progression of diabetic nephropathy. Activation of the renin-angiotensin system (RAS) is reported to contribute to intrarenal hemodynamic abnormality in diabetic patients. We examined whether RAS blockade by captopril induces intrarenal hemodynamic changes in normotensive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The patients ranged in age from 40 to 65 years (20 men and 20 women). A total of 15 age- and sex-matched healthy individuals served as control subjects. Resistive index (RI) of interlobar arteries was examined by duplex Doppler sonography before and after the oral captopril (25 mg) test. RESULTS: At baseline, no significant differences in RI values or plasma renin activity (PRA) were seen between the patients and healthy subjects. In healthy subjects, the RI values after the captopril test were significantly higher than baseline values (P < 0.01). However, in patients with type 2 diabetes, both with normoalbuminuria and microalbuminuria, RI values after the test were significantly lower than baseline values (P < 0.001). There were significant negative correlations between DeltaRI value and HbA1c (r = -0.458, P < 0.005) and between DeltaRI value and baseline PRA in diabetic patients (r = -0.339, P < 0.05). Multiple regression analysis showed that HbA1c and baseline PRA significantly and independently affected the magnitude of decrease in RI values after captopril administration in diabetic patients (R2 = 0.391, P < 0.0001). CONCLUSIONS: These results indicate that the intrarenal RAS may be activated in diabetic patients, that such activation may be affected by poor glycemic control, and that blockade of RAS activation by ACE inhibitor reduces intrarenal vascular resistance in diabetic patients. The results emphasize the beneficial effects of ACE inhibition in improving intrarenal hemodynamics in diabetic patients.

ecNOS gene polymorphism is associated with endothelium-dependent vasodilation in Type 2 diabetes.

The association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and vascular endothelial function has not been clarified. We investigated the impact of ecNOS gene polymorphism on endothelial function in 95 patients with Type 2 diabetes (ecNOS genotype: 4b/b, n = 62; 4b/a, n = 30; 4a/a, n = 3). Flow-mediated (endothelium dependent, FMD) and nitroglycerin-induced (endothelium independent, NTG) vasodilations of the right brachial artery were studied using a phase-locked echotracking system. There were no significant differences in clinical characteristics among the ecNOS genotypes. The FMD was significantly lower in the patients with ecNOS4a allele than in those without ecNOS4a allele (P < 0.05). Multiple regression analysis showed that ecNOS4a allele and mean blood pressure were significant independent determinants for reduced FMD in all patients (R(2) = 0.122, P = 0.0025). The ecNOS4a allele was an independent determinant for reduced FMD in smokers but not in nonsmokers. These results suggest that ecNOS4a allele is a genetic risk factor for endothelial dysfunction in diabetic patients, especially in smokers.

Advanced atherosclerosis in predialysis patients with chronic renal failure.

BACKGROUND: Atherosclerosis is advanced in hemodialysis patients as shown by increased intima-media thickness of carotid arteries (CA-IMT), although it is not established whether the advanced atherosclerosis results from hemodialysis treatment or from chronic renal failure. The purpose of this study was to evaluate the effects of hemodialysis and renal failure on CA-IMT in patients with chronic renal failure. METHODS: CA-IMT was measured by high-resolution B-mode ultrasonography in 110 patients with chronic renal failure before starting dialysis (CRF group), and compared with CA-IMT of 345 hemodialysis patients (HD group) and 302 healthy control subjects. They were all nondiabetic and the three groups were comparable in age and gender. RESULTS: As compared with the healthy control subjects, the CRF and HD groups had greater CA-IMTs, whereas CA-IMTs of the CRF and HD groups were not statistically different. There was no significant correlation between duration of hemodialysis and CA-IMT in the HD group. Multiple regression analysis in the total subjects indicated that presence of renal failure, but not being treated with hemodialysis, was a significant factor associated with increased CA-IMT independent of age, gender, blood pressure, smoking, high-density lipoprotein (HDL) and non-HDL cholesterol levels. CONCLUSIONS: These results demonstrate that thickening of arterial wall is present in patients with chronic renal failure before starting hemodialysis treatment, and support the concept that advanced atherosclerosis in hemodialysis patients is due not to hemodialysis treatment, but to renal failure and/or metabolic abnormalities secondary to renal failure.

Smoking and proteinuria impair vasodilatory response of intrarenal arteries to nitroglycerine in patients with type 2 diabetes mellitus.

BACKGROUND: Few studies have addressed the effect of vasodilatory stimuli on the intrarenal arterial system in type 2 diabetes mellitus (DM), and factors affecting its responsiveness. METHODS: One hundred twenty-four patients with type 2 DM without renal failure were enrolled, and 25 subjects served as controls. Using duplex Doppler sonography, resistive indices (RI) of interlobar arteries were measured before and after sublingual nitroglycerine (NTG) (0.3 mg) spray over a 10-min period. RESULTS: Per cent changes in RI (%DeltaRI) in the DM group were significantly less than in controls (P<0.05), as was the area over the %DeltaRI-time curve (AOC-%DeltaRI, total responsiveness to nitroglycerine) (P<0.05). In the DM group, significant negative correlations were found between AOC-%DeltaRI and age (r=-0.492, P<0.0001). AOC-%DeltaRI in DM patients with proteinuria was significantly lower than without it (P<0.003). AOC-%DeltaRI in smokers was also significantly lower than in nonsmokers (P<0.05). By multiple regression analysis of the DM group, AOC-%DeltaRI was found to be significantly and independently affected by age (beta=-0.394), smoking (beta=-0.211), and the presence of proteinuria (beta=-0.270; R(2)=0.354, P<0.0001). CONCLUSIONS: Diabetic patients have a lower level of responsiveness to NTG. Advanced age, smoking, and proteinuria significantly affect response to NTG in DM patients, suggesting that advanced intrarenal arteriosclerosis may be contributory. Smoking is suggested to be a risk factor for progression of diabetic nephropathy, likely contributing to poor responsiveness of the intrarenal arterial system to vasodilatory stimuli.