N-terminal pro-brain natriuretic peptide could be a marker of subclinical atherosclerosis in patients with type 2 diabetes.

N-terminal pro-brain natriuretic peptide (NT-proBNP), which is a useful biomarker of chronic heart failure, has been shown to be a strong predictor of cardiovascular mortality. The aim of this study was to evaluate the relationships between NT-proBNP and markers of subclinical atherosclerosis in patients with type 2 diabetes. Relationships of NT-proBNP to pulse wave velocity (PWV) or ankle-brachial index (ABI) as well as to various parameters, including body mass index, blood pressure, serum lipid concentration, serum uric acid concentration, and glycemic control (hemoglobin A1c), age, hemoglobin, serum creatinine concentration, severity of diabetic nephropathy or retinopathy, current treatment of diabetes, cardiothoracic ratio on chest radiograph, presence of left ventricular hypertrophy and/or ST-T changes evaluated by electrocardiograph, smoking status and presence of cardiovascular disease were investigated in 323 consecutive patients with type 2 diabetes. Log (NT-proBNP) correlated positively with PWV (r = 0.283, p < 0.0001) and correlated negatively with ABI (r = -0.144, p = 0.0094). Multiple regression analysis demonstrated that age (ß = 0.200, p = 0.0033), systolic blood pressure (ß = 0.246, p < 0.0001), total cholesterol (ß = -0.135, p = 0.0326), uric acid (ß = 0.133, p = 0.0462), creatinine (ß = -0.184, p = 0.0122), smoking status (ß = -0.129, p = 0.0499) and log (NT-proBNP) (ß = 0.177, p = 0.0149) were independently correlated with PWV and that systolic blood pressure (ß = -0.145, p = 0.0310), log triglyceride (ß = -0.151, p = 0.0397) and log (NT-proBNP) (ß = -0.207, p = 0.0094) were independently correlated with ABI. In conclusion, NT-proBNP could be a marker of subclinical atherosclerosis in patients with type 2 diabetes.

Serum pepsinogen I/II ratio is correlated with albuminuria in patients with type 2 diabetes.

Helicobacter pylori infection, which is a common cause of atrophic gastritis, has been reported to represent a causal factor increasing the vascular damage and consequent albuminuria. On the other hand, decreased serum pepsinogen (PG) I/II ratio can be used to assess gastric mucosal atrophy. To the best of our knowledge, there are no studies investigating the correlation between PG I/II ratio and diabetic nephropathy. Therefore, we investigated a relationship between PG I/II ratio and degree of urinary albumin excretion (UAE) in patients with type 2 diabetes. We evaluated relationships between PG I/II ratio and degree of UAE or estimated glomerular filtration rate as well as various factors, including age, body mass index, blood pressure, hemoglobin A1c, serum lipid concentrations, uric acid or C-reactive protein in 333 consecutive patients with type 2 diabetes. PG I/II ratio correlated positively with logarithm of UAE in all patients (r = 0.174, P = 0.0016) and in patients without Helicobacter pylori infection (r = 0.352, P < 0.0001). Multiple regression analysis identified that PG I/II ratio correlated independently with logarithm of UAE in all patients (ß = 0.264, P = 0.0005) and in patients without Helicobacter pylori infection (ß = 0.295, P = 0.0022). These data suggest that serum PG I/II ratio is correlated with diabetic nephropathy.

Low daily salt intake is correlated with albuminuria in patients with type 2 diabetes.

Both high and low salt intakes have been reported to be associated with an increased risk of cardiovascular events. The aim of this study was to investigate the relationship between daily salt intake and albuminuria, a marker of diabetic nephropathy and cardiovascular disease, in patients with type 2 diabetes. We classified 270 patients with type 2 diabetes, who were not receiving antihypertensive medication into four groups according to their daily salt intake (<8, 8-10, 10-12 and >12 g per day). We investigated the relationship between daily salt intake and the logarithm of urinary albumin excretion (UAE). A multivariate linear regression analysis was used to evaluate whether daily salt intake independently correlated with the logarithm of UAE. In addition, we assessed the contribution of the variables, including age, sex, duration of diabetes, body mass index, systolic blood pressure, hemoglobin A(1C), low-density lipoprotein cholesterol, triglycerides, serum creatinine, alcohol intake, smoking status and square of (daily salt intake-10) on albuminuria, defined as a UAE>30 mg g(-1) of creatinine, using a multiple logistic regression analysis. The logarithm of the UAE was lowest in the third quartile of daily salt intake. The multivariate linear regression analysis demonstrated that the logarithm of the UAE was significantly correlated with the quadratic term of daily salt intake centered at 10 g per day (ß=0.170, P=0.008). The multivariate logistic regression analysis demonstrated that the odds ratio (95% confidence interval) of albuminuria was 3.996 (1.295-12.327; P=0.016) in patients whose daily salt intake was less than 8 g per day compared with patients whose daily salt intake was 10-12 g per day. In conclusion, low daily salt intake was correlated with albuminuria in patients with type 2 diabetes, who were not receiving antihypertensive medication.

Second measurement of morning systolic blood pressure is more closely associated with albuminuria.

BACKGROUND/AIMS: It is important to control blood pressure as well as to control blood glucose for the prevention of diabetic nephropathy. However, to our knowledge, there are no reports investigating which blood pressure, including morning, evening and clinic, is more closely associated with albuminuria and whether one measurement is sufficient or not in patients with Type 2 diabetes. METHODS: We measured morning, evening and clinic blood pressure and compared the area under the curve (AUC) of blood pressure for urinary albumin excretion equal to or more than 30 mg/g creatinine using receiver-operating characteristic curve analyses and odds ratio for albuminuria defined as urinary albumin excretion equal to or more than 30 mg/g creatinine in 858 patients with Type 2 diabetes. RESULTS: Odds ratio (95% confidence interval (CI)) of morning, evening and clinic systolic blood pressure for albuminuria was 1.034 (1.024 - 1.044), 1.033 (1.023 - 1.043) and 1.013 (1.055 - 1.021), respectively (p < 0.001 in all), and AUC of morning, evening and clinic systolic blood pressure was 0.644 (0.628 - 0.700) (p < 0.001 vs. clinic), 0.660 (0.623 - 0.696) (p < 0.001 vs. clinic) and 0.597 (0.559 - 0.636), respectively. AUC of the second morning systolic blood pressure was greater than the first (p = 0.033). CONCLUSION: The second measurement of morning systolic blood pressure is more closely associated with albuminuria than the first measurement of the morning in addition to clinic systolic blood pressure.

Toe-brachial index is associated more strongly with albuminuria or glomerular filtration rate than ankle-brachial index in patients with type 2 diabetes.

The aim of this study was to investigate whether toe-brachial index (TBI) is more strongly associated with albuminuria or estimated glomerular filtration rate (eGFR) than ankle-brachial index (ABI), and thus is a more suitable tool for evaluating the association between peripheral artery disease (PAD) and diabetic nephropathy than ABI in patients with type 2 diabetes. We evaluated the relationships between ABI or TBI and the degree of urinary albumin excretion or eGFR, as well as the major cardiovascular risk factors, in 390 patients with type 2 diabetes. Furthermore, we compared the area under the receiver-operator characteristic curve (AUC) of TBI or ABI for albuminuria or chronic kidney disease (CKD). Low-density lipoprotein cholesterol was negatively associated with ABI. Age and duration of diabetes were negatively associated with TBI, and diastolic blood pressure and high-density lipoprotein cholesterol were positively associated with TBI. Log (urinary albumin excretion) was associated more strongly with TBI (r=-0.265, P<0.0001) than with ABI (r=-0.132, P=0.0111), and eGFR was positively associated with TBI (r=0.195, P=0.0002) but not with ABI (r=0.023, P=0.6571). The AUCs of TBI for albuminuria (P=0.0002) and CKD (P=0.0322) were significantly greater than those of ABI. In conclusion, TBI is associated more strongly with albuminuria and eGFR than ABI in patients with type 2 diabetes. Our study suggests that TBI may be a more suitable tool for evaluating the association between PAD and diabetic nephropathy than ABI in patients with type 2 diabetes.

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 (ß=0.149, P=0.0072), PWV (ß=0.337, P<0.0001) or ABI (ß=-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.

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.

Risk factors for development of diabetes mellitus, hypertension and dyslipidemia.

We investigated the risk factors for the development of diabetes mellitus, hypertension and dyslipidemia simultaneously in a community-based observational cohort study (n=4304). When hypertension or dyslipidemia was present at baseline, hazard ratio (95% CI) of developing diabetes mellitus at year 5 is 3.014 (2.131-4.264) or 2.112 (1.520-2.936), respectively.

Uncontrolled home blood pressure in the morning is associated with nephropathy in Japanese type 2 diabetes.

The purposes of this study were to investigate the state of blood pressure control level and to investigate the relationship between blood pressure control level and nephropathy in Japanese type 2 diabetes. We measured clinic and home blood pressure in 923 type 2 diabetic patients. According to the criteria for hypertension in the Japanese Society of Hypertension Guidelines 2009, patients were classified into four groups by clinic systolic blood pressure (130 mmHg) and morning systolic blood pressure (125 mmHg), as follows: controlled hypertension (CH), white-coat hypertension (WCH), masked hypertension (MH), and sustained hypertension (SH). Of all patients, 13.9, 12.6, 13.3, and 60.2% were identified as having CH, WCH, MH, and SH, respectively. The average number of drugs prescribed was 1.8. We assessed the association between blood pressure control level and nephropathy in diabetic patients. The degree of urinary albumin excretion and the prevalence of nephropathy in diabetic patients were higher in MH and SH groups than those in the CH group. The majority of patients had poor blood pressure control, regardless of ongoing conventional antihypertensive therapy, and diabetic patients with MH and SH were associated with nephropathy. It is suggested that more aggressive antihypertensive treatment is recommended to prevent nephropathy in diabetic patients.

Hemoglobin concentration in men with type 2 diabetes mellitus.

Anemia is a common but often overlooked complication of diabetes. We investigated the relationship between hemoglobin concentration and various factors as well as markers of subclinical atherosclerosis in men with type 2 diabetes mellitus. Hemoglobin concentration was measured in 319 men with type 2 diabetes mellitus. We evaluated the relationship between hemoglobin concentration and various factors including age, body mass index, and glycemic control, as well as between hemoglobin concentration and pulse wave velocity or ankle-brachial index (n = 209) and between hemoglobin concentration and carotid intima-media thickness or plaque score (n = 125). Mean hemoglobin concentration was 14.2 +/- 0.80 g/dL. Body mass index (r = 0.340, P < .0001) and estimated glomerular filtration rate (r = 0.219, P = .0011) were positively associated with hemoglobin concentration, whereas age (r = -0.388, P < .0001), glycated albumin (r = -0.148, P = .0121), serum creatinine concentration (r = -0.206, P = .0019), and log (urinary albumin excretion) (r = -0.188, P = .0010) were negatively associated with hemoglobin concentration. Multiple regression analysis identified age (beta = -0.222, P = .0019), body mass index (beta = 0.145, P = .0432), systolic blood pressure (beta = 0.214, P = .0015), total cholesterol concentration (beta = 0.170, P = .0077), and serum creatinine concentration (beta = -0.181, P = .0045) as independent determinants of hemoglobin concentration. No significant association was observed between hemoglobin concentration and serum erythropoietin concentration (r = -0.079, P = .2980). Negative correlations were found between hemoglobin concentration and pulse wave velocity (r = -0.289, P < .0001) and between hemoglobin concentration and plaque score (r = -0.275, P = .0024). In conclusion, hemoglobin concentration was associated with various factors; and decreased hemoglobin concentration was associated with subclinical markers of atherosclerosis in men with type 2 diabetes mellitus.

Eosinophil count is positively correlated with albumin excretion rate in men with type 2 diabetes.

BACKGROUND AND OBJECTIVES: Patients with allergic disorders such as allergic rhinitis or asthma have been reported to be at increased risk for atherosclerosis. In this study, we evaluated the relationships between peripheral eosinophil count and degree of albumin excretion rate, which is a useful marker of cardiovascular mortality as well as diabetic nephropathy in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated relationships of peripheral eosinophil count to degree of albumin excretion rate as well as to major cardiovascular risk factors, including age, BP, serum lipid concentration, and glycemic control (glycosylated hemoglobin); body mass index; current treatment for diabetes; smoking status; and presence of cardiovascular disease in 783 patients (416 men and 367 women) with type 2 diabetes. RESULTS: Log(eosinophil count) was positively associated with systolic BP (r = 0.124, P = 0.0108), serum triglyceride concentration (r = 0.108, P = 0.0284), and log(albumin excretion rate) (r = 0.301, P < 0.0001) in men; however, no association was found between log(eosinophil count) and log(albumin excretion rate) (r = 0.085, P = 0.1050) in women. Multivariate linear regression analysis demonstrated that log(eosinophil count) (beta = 0.260, P < 0.0001), duration of diabetes (beta = 0.203, P = 0.0003), glycosylated hemoglobin (beta = 0.117, P = 0.0238), systolic BP (beta = 0.205, P = 0.0001), and serum triglyceride concentration (beta = 0.162, P = 0.0038) were independent determinants of log(albumin excretion rate) in men. CONCLUSIONS: Allergic disorders may be associated with microalbuminuria in men with type 2 diabetes.

Plasma serotonin is a predictor for deterioration of urinary albumin excretion in men with type 2 diabetes mellitus.

We performed an observational study to investigate if plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of serotonin (5-hydroxytryptamine), concentration could be a predictor for deterioration of urinary albumin excretion. The relationship between baseline plasma 5-HIAA concentration and changes in urinary albumin excretion for 24 months was investigated in 162 male patients with type 2 diabetes mellitus. Patients were divided into tertiles according to plasma 5-HIAA concentration. Greater changes in urinary albumin excretion were seen in patients with high plasma 5-HIAA concentration (112.8 +/- 36.2 mg/g creatinine) than in patients with low plasma 5-HIAA concentration (7.6 +/- 8.0 mg/g creatinine, P = .0011) or in patients with intermediate plasma 5-HIAA concentration (25.6 +/- 15.0 mg/g creatinine, P = .0070) after adjustment for baseline values of urinary albumin excretion. A positive correlation was observed between log (plasma 5-HIAA concentration) and changes in urinary albumin excretion (r = 0.314, P < .0001). Multiple regression analysis demonstrated that log (plasma 5-HIAA concentration) (beta = .284, P = .0013) was an independent determinant of changes in urinary albumin excretion. In conclusion, plasma 5-HIAA concentration was positively correlated with changes in urinary albumin excretion, which may indicate causality in diabetic nephropathy in male patients with type 2 diabetes mellitus and high plasma 5-HIAA concentration.

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.