Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats.

To assess the beneficial effects of the angiotensin II type 1 receptor blocker telmisartan on a non-obese animal model of reduced function and mass of islet beta-cells prior to the development of diabetes, Spontaneously Diabetic Torii (SDT) rats were treated with telmisartan at 8 weeks of age. At 24 weeks of age, the treatment with telmisartan dose-dependently ameliorated hyperglycemia and hypoinsulinemia, and high-dose (5 mg/kg/day) treated SDT rats did not developed diabetes. Real-time RT-PCR analysis revealed that treatment with high-dose telmisartan reduced mRNA expression of local renin-angiotensin system (RAS) components, components of NAD(P)H oxidase, transforming growth factor-beta1 and vascular endothelial growth factor in the pancreas of male SDT rats. Immunohistochemical and Western blot analyses revealed that treatment with telmisartan also reduced expression of p47(phox). These results suggest that treatment with telmisartan reduces oxidative stress by local RAS activation and protects against islet beta-cell damage and dysfunction. These findings provide at least a partial explanation for the reduced incidence of new-onset diabetes that has been observed in several clinical trials involving angiotensin II type 1 receptor blockers and ACE inhibitors.

Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance.

Oxidative stress is recognized widely as being associated with various disorders including diabetes, hypertension, and atherosclerosis. It is well established that hydrogen has a reducing action. We therefore investigated the effects of hydrogen-rich water intake on lipid and glucose metabolism in patients with either type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). We performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with T2DM controlled by diet and exercise therapy and 6 patients with IGT. The patients consumed either 900 mL/d of hydrogen-rich pure water or 900 mL of placebo pure water for 8 weeks, with a 12-week washout period. Several biomarkers of oxidative stress, insulin resistance, and glucose metabolism, assessed by an oral glucose tolerance test, were evaluated at baseline and at 8 weeks. Intake of hydrogen-rich water was associated with significant decreases in the levels of modified low-density lipoprotein (LDL) cholesterol (ie, modifications that increase the net negative charge of LDL), small dense LDL, and urinary 8-isoprostanes by 15.5% (P < .01), 5.7% (P < .05), and 6.6% (P < .05), respectively. Hydrogen-rich water intake was also associated with a trend of decreased serum concentrations of oxidized LDL and free fatty acids, and increased plasma levels of adiponectin and extracellular-superoxide dismutase. In 4 of 6 patients with IGT, intake of hydrogen-rich water normalized the oral glucose tolerance test. In conclusion, these results suggest that supplementation with hydrogen-rich water may have a beneficial role in prevention of T2DM and insulin resistance.

Bone stiffness in men with type 2 diabetes mellitus.

Osteoporosis in elderly men as well as women is increasingly recognized, and patients with type 2 diabetes mellitus have higher risk of fracture than nondiabetic subjects. The aim of the present study was to investigate the relationship between bone stiffness and serum testosterone concentration as well as other variables in men with type 2 diabetes mellitus. The relationships between bone stiffness and serum bioavailable testosterone concentrations as well as other variables including age, duration of diabetes, glycemic control (hemoglobin A(1c)), or body mass index were evaluated in 294 men with type 2 diabetes mellitus. An inverse correlation was found between stiffness index and age. A positive correlation was found between stiffness index and serum bioavailable testosterone concentration (r = 0.231, P = .0005). Stiffness index was significantly less in current smokers (81.6 +/- 17.7) than in past smokers (86.6 +/- 17.8, P = .0396) or nonsmokers (87.7 +/- 15.2, P = .0426). Multiple regression analysis demonstrated that serum bioavailable testosterone concentration (beta = .271, P = .0006) and smoking status (beta = -0.147, P = .0408) were independent determinants of stiffness index. In conclusion, bone stiffness was associated with serum bioavailable testosterone concentration but not associated with hemoglobin A(1c) or duration of diabetes in men with type 2 diabetes mellitus.

Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes.

Previous studies showed that low serum bilirubin concentrations are associated with increased risk of cardiovascular disease. To explore this further, we evaluated the relationships between serum bilirubin concentrations and the degree of urinary albumin excretion and other markers of subclinical atherosclerosis in 633 consecutive patients with type 2 diabetes. Multiple regression analysis showed that the serum bilirubin concentration was an independent determinant of and had a significant inverse correlation to the log urinary albumin excretion. Serum bilirubin concentrations were significantly lower in patients with than in those without cardiovascular disease. A significant inverse correlation was found between the serum bilirubin concentration and pulse wave velocity, while a significant positive correlation was found to the ankle-brachial index in a subgroup of 386 patients. Our study shows that the serum bilirubin level is associated with microalbuminuria and subclinical atherosclerosis in patients with type 2 diabetes.

Bone mass and bone resorption in postmenopausal women with type 2 diabetes mellitus.

The aim of the present study was to examine the relationships between bone mass or bone resorption evaluated by urinary cross-linked N-telopeptides of type I collagen (NTx) concentration and known and potential contributors to bone mass or bone resorption such as sex hormones, age, duration of diabetes, glycemic control (hemoglobin A(1c) [HbA(1c)]), body mass index (BMI), severity of diabetic complications, smoking status, and current treatment of diabetes in postmenopausal women with type 2 diabetes mellitus (n = 196). In addition, the relationship of bone mass to pulse wave velocity, which is an earlier indicator of cardiovascular disease, was investigated in a subgroup of patients (n = 120). Bone mass was evaluated by the quantitative ultrasound method. A higher stiffness index indicates higher bone mass. Inverse correlations were found between the stiffness index and age (r = -0.374, P < .0001) and between the stiffness index and log (urinary albumin excretion) (r = -0.170, P = .0398), and a positive correlation was found between the stiffness index and serum dehydroepiandrosterone sulfate (DHEA-S) concentration (r = 0.201, P = .0136). No significant correlations were found between the stiffness index and duration of diabetes, HbA(1c), BMI, or serum estradiol concentration. No significant correlations were found between urinary NTx concentration and age, duration of diabetes, HbA(1c), BMI, serum estradiol concentration, or serum DHEA-S concentration. The stiffness index correlated inversely with urinary NTx concentration (r = -0.262, P = .0002). No significant correlation was found between the stiffness index and pulse wave velocity (r = -0.165, P = .0714). Multiple regression analysis demonstrated that serum DHEA-S concentration was an independent determinant of the stiffness index (beta = .207, P = .0428). In conclusion, serum DHEA-S concentration correlated positively with bone mass, whereas glycemic control, BMI, or duration of diabetes did not correlate with bone mass or urinary NTx concentration in postmenopausal women with type 2 diabetes mellitus.

Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus.

Hyperuricemia has been reported to be associated with increased risk of renal insufficiency as well as cardiovascular events. The aim of this study was to evaluate the relationships between serum uric acid concentration and degree of urinary albumin excretion as well as markers of subclinical atherosclerosis in men with type 2 diabetes mellitus. Serum uric acid concentrations were measured in 343 men with type 2 diabetes mellitus. We then evaluated relationships of serum uric acid concentrations to degree of urinary albumin excretion as well as to major cardiovascular risk factors, including age, blood pressure, serum lipid concentration, and glycemic control (hemoglobin A1c). The relationships between serum uric acid concentration and pulse wave velocity or ankle-brachial index (n=236) and between serum uric acid concentration and carotid intima-media thickness or plaque score (n=125) were investigated additionally in a subgroup of patients. Serum uric acid concentration correlated positively with logarithm of urinary albumin excretion (r=0.302, P<.0001). Positive correlation was found between serum uric acid concentration and intima-media thickness (r=0.233, P=.0087), whereas inverse correlation was found between serum uric acid concentration and ankle-brachial index (r=-0.150, P=.0207). Multiple regression analysis demonstrated that serum uric acid concentration (beta=.281, P<.0001), duration of diabetes (beta=.253, P<.0001), hemoglobin A1c (beta=.166, P=.0034), serum triglyceride concentration (beta=.125, P=.0472), and systolic blood pressure (beta=.275, P=.0013) were independent determinants of logarithm of urinary albumin excretion. In conclusion, serum uric acid concentration is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus.

Association between serum testosterone concentration and collagen degradation fragments in men with type 2 diabetes mellitus.

The aim of the present study was to evaluate relationships between serum endogenous androgens and urinary concentration of cross-linked N-telopeptides of type I collagen (NTx), a bone resorption marker, in men with type 2 diabetes mellitus because low androgen concentrations are associated with both osteoporosis and cardiovascular disease. Relationships between serum free testosterone and urinary NTx concentrations were investigated in 246 consecutive men with type 2 diabetes mellitus. In addition, relationships between urinary NTx concentration and other variables including age, duration of diabetes, blood pressure, serum lipid concentration, hemoglobin A(1c), and body mass index were evaluated. Urinary NTx concentrations were 27.8 (26.4-29.3) nmol of bone collagen equivalent per millimole of creatinine, correlating inversely with serum free testosterone (r = -0.263, P < .0001). Multiple regression analysis identified serum free testosterone (beta = -.292, P < .0001), hemoglobin A(1c) (beta = .144, P = .0404), and smoking status (beta = .143, P = .0402) as independent determinants of urinary NTx. In conclusion, serum free testosterone concentration correlated inversely with urinary NTx concentration, which may partly account for an observed link between osteoporosis and cardiovascular disease in men with type 2 diabetes mellitus.

Differential regulation of intracellular redox state by extracellular matrix proteins in glomerular mesangial cells: potential role in diabetic nephropathy.

Advanced diabetic nephropathy is characterized by abnormal synthesis of extracellular matrix (ECM) proteins, such as collagen I (COL I). The present experiments were designed to test the hypothesis that the presence of abnormal ECM proteins may be responsible for increased generation of reactive oxygen species (ROS) that are thought to have an important role in the pathogenesis of diabetic nephropathy. SV40 MES 13 murine mesangial cells were plated on COL I or collagen IV (COL IV) for 3 h at 5.5 or 25 mM D-glucose concentration. Increased intracellular ROS generation and reduced intracellular nitric oxide (NO) production was measured in cells attached to COL I compared with cells attached to COL IV. Treatment with N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of NO synthase, reduced this difference in ROS generation between cells attached to either COL I or IV. The results using antibodies against integrins also indicated that an alpha(2) integrin-mediated pathway was involved in the different response in ROS generation caused by ECM proteins. These results suggest that contact between altered ECM proteins that are present in advanced diabetic nephropathy and mesangial cells has the potential to increase intracellular oxidative stress, leading to progressive glomerular damage.