Muhei Tanaka

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.

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.

Visit-to-visit variability in systolic blood pressure is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes

OBJECTIVE Recent studies make remarks on the effect of variability in systolic blood pressure (SBP) on the development of cardiovascular disease. The aim of this study was to investigate the relationship between the variability in SBP and the degree of diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. METHODS We measured SBP in 422 consecutive patients with type 2 diabetes at every visit during a year, and we calculated the coefficient of variation (CV) of SBP. Then, we evaluated relationships of variability of SBP to degree of urinary albumin excretion (UAE), which is a useful marker for cardiovascular disease as well as diabetic nephropathy, ankle-brachial index (ABI) and pulse wave velocity (PWV). RESULTS CV of SBP positively correlated with logUAE (r=0.210, P<0.0001) or PWV (r=0.409, P<0.0001), whereas CV of SBP inversely correlated with ABI (r=-0.098, P=0.0463). Multiple regression analysis demonstrated that CV of SBP independently correlated with logUAE (β=0.149, P=0.0072), PWV (β=0.337, P<0.0001) or ABI (β=-0.162, P=0.0101). CONCLUSIONS Not only average SBP but also variability in SBP is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes.

Low serum bilirubin concentration is associated with coronary artery calcification (CAC).

BACKGROUND Bilirubin is a potent antioxidant and previous studies have reported the relationship between low serum bilirubin concentration and atherosclerosis. The purpose of this study was to assess the correlation between serum bilirubin concentration and coronary artery calcification (CAC). METHODS This study consisted of 637 participants and we evaluated the relationship between CAC score determined by multislice computed tomography and serum bilirubin concentration. RESULTS An inverse correlation was found between serum bilirubin concentration and log(CAC+1) (r=-0.361, P<0.0001). Multiple regression analysis also demonstrated that age (beta=0.261, P=0.0125), systolic blood pressure (beta=0.153, P=0.0237), uric acid (beta=0.126, P=0.0441), estimated glomerular filtration rate (beta=-0.139, P=0.0416) and serum bilirubin concentration (beta=-0.281, P<0.0001) were independent determinants of log(CAC+1). An increment of 1 micromol/L in serum bilirubin concentration was associated with 14% decrease in the odds for CAC score > or =400 after adjustment for several risk factors. Both age and SBP were also positively associated with CAC score > or =400, but the odds ratio for CAC score > or =400 was greater for every 1 micromol/L increment in serum bilirubin concentration than for every 1-year increment in age and 1-mmHg increment in SBP. CONCLUSIONS Low serum bilirubin concentration is associated with coronary artery calcification. Serum bilirubin concentration can be measured easily in the clinical laboratory and applied in medical practice, and low serum bilirubin concentration would be useful as a provisional new risk factor of CAC.

Metabolically Healthy Obesity and Risk of Incident CKD

BACKGROUND AND OBJECTIVES Metabolically healthy obesity (MHO) is a unique obesity phenotype that apparently protects people from the metabolic complications of obesity. The association between MHO phenotype and incident CKD is unclear. Thus, this study investigated the association between MHO phenotype and incident CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 3136 Japanese participants were enrolled in an 8-year follow-up cohort study in 2001. Metabolically healthy status was assessed by common clinical markers: BP, triglycerides, HDL cholesterol, and fasting plasma glucose concentrations. Body mass index ≥25.0 kg/m(2) was defined as obesity. CKD was defined by proteinuria or eGFR of <60 ml/min per 1.73 m(2). To calculate the odds ratio for incident CKD, logistic regression analyses were performed. RESULTS The crude incidence proportions of CKD were 2.6% (56 of 2122 participants) in participants with the metabolically healthy nonobesity phenotype, 2.6% (8 of 302) in those with the MHO phenotype, 6.7% (30 of 445) in those with the metabolically abnormal nonobesity phenotype, and 10.9% (29 of 267) in those with the metabolically abnormal obesity phenotype. Compared with metabolically healthy nonobesity phenotype, the odds ratios for incident CKD were 0.83 (95% confidence interval [95% CI], 0.36 to 1.72; P=0.64) for MHO, 1.44 (95% CI, 0.80 to 2.57; P=0.22) for metabolically abnormal nonobesity, and 2.80 (95% CI, 1.45 to 5.35; P=0.02) for metabolically abnormal obesity phenotype after adjustment for confounders, including age, sex, smoking statues, alcohol use, creatinine, uric acid, systolic BP, HDL cholesterol, and impaired fasting glucose or diabetes. CONCLUSION MHO phenotype was not associated with higher risk of incident CKD.

The coefficient variation of home blood pressure is a novel factor associated with macroalbuminuria in type 2 diabetes mellitus.

The purpose of this study was to investigate the association between day-by-day variability in home blood pressure (HBP) on 14 consecutive days and macroalbuminuria in patients with type 2 diabetes. We compared the coefficient of variation (CV) of HBP in 858 Japanese patients with and without macroalbuminuria. Next, we analyzed the relationship between the logarithm of urinary albumin excretion (UAE) and the CV of HBP using linear regression analysis. Then, we evaluated the association between the CV of HBP and macroalbuminuria, defined as UAE ⩾300 mg g−1 creatinine, using logistic regression analysis. The CVs of morning and evening systolic blood pressure (SBP) were significantly greater in patients with macroalbuminuria than in those without (8.08±3.35 vs. 7.19±2.25%, P<0.05 and 9.01±3.58 vs. 7.98±2.57%, P<0.05, respectively). Multivariate linear regression analyses indicated that the CVs of morning SBP (P<0.05) and diastolic blood pressure (DBP; P<0.05), and those of evening SBP (P<0.05) were the independent explanatory variables for the logarithm of UAE. Multivariate logistic regression analyses also demonstrated that the odds ratio for the CVs of morning SBP, morning DBP and evening SBP for macroalbuminuria were 1.35 (P<0.05), 1.29 (P<0.05) and 1.44 (P<0.05), respectively. We conclude that the CV of HBP is correlated with macroalbuminuria, independent of the known risk factors, in Japanese patients with type 2 diabetes.

Visit-to-Visit Blood Pressure Variability Is a Novel Risk Factor for the Development and Progression of Diabetic Nephropathy in Patients With Type 2 Diabetes

OBJECTIVE Recent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 ± 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. RESULTS Multiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (β = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008–1.302). CONCLUSIONS Visit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.

Senescence Marker Protein-30/Gluconolactonase Deletion Worsens Glucose Tolerance through Impairment of Acute Insulin Secretion

Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wild-type (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mm glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mm in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging.

Home blood pressure variability on one occasion is a novel factor associated with arterial stiffness in patients with type 2 diabetes

Recent studies have suggested that not only mean blood pressure but also variability in blood pressure might be related to cardiovascular disease. The aim of this study was to investigate the association between home blood pressure variability on one occasion and markers of arterial stiffness in patients with type 2 diabetes. We investigated the relationship between the s.d. of clinic- or home-measured systolic blood pressure on one occasion and pulse wave velocity (PWV) in 332 patients with type 2 diabetes, and we evaluated whether the SD of clinic- or home-measured systolic blood pressure on one occasion was an independent determinant of PWV by multivariate linear regression analysis, after adjustment for known risk factors for arterial stiffness, including sex, age, duration of diabetes, body mass index, hemoglobin A1c, serum total cholesterol, triglycerides, smoking status, drinking alcohol, presence of antihypertensive medication, average systolic blood pressure and heart rate. Age, average morning home-measured systolic blood pressure, heart rate and PWV (r=0.259, P<0.0001) were positively correlated with the s.d. of morning home blood pressure on one occasion. Multiple regression analysis demonstrated that age, average morning home-measured systolic blood pressure (P=0.0019), heart rate and the s.d. of morning home-measured systolic blood pressure on one occasion (P=0.0159) were independently associated with PWV. In conclusion, home blood pressure variability on one occasion was correlated with PWV, independent of other known risk factors, in Japanese patients with type 2 diabetes.

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.