Goji Hasegawa

Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease.

BackgroundHyperlipidemia, insulin resistance, and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Currently, there is no established treatment for this disease. Recently, several studies have shown that ezetimibe (EZ), a lipid-lowering drug, attenuates liver steatosis in an experimental NAFLD model. This study was designed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD.MethodsA total of 45 patients with newly diagnosed liver biopsy-proven NAFLD were treated with EZ (10xa0mg/day) for 24xa0months. NAFLD-related biochemical parameters, imaging by computerized tomography, and liver biopsy were studied before and after treatment.ResultsEzetimibe therapy significantly improved NAFLD-related metabolic parameters including visceral fat area, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-R), triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-Ch), oxidative-LDL, the net electronegative charge modified-LDL, profiles of lipoprotein particle size and fatty acids component, and estimated desaturase activity. EZ therapy also significantly lowered serum alanine aminotransferase and high-sensitivity C-reactive protein levels, whereas no significant changes were found in serum type IV collagen 7S, adiponectin, leptin, and resistin levels. Histological features of steatosis grade (Pxa0=xa00.0003), necroinflammatory grade (Pxa0=xa00.0456), ballooning score (Pxa0=xa00.0253), and NAFLD activity score (NAS) (Pxa0=xa00.0007) were significantly improved from baseline. However, the fibrosis stage was not significantly (Pxa0=xa00.6547) changed.ConclusionThe results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic, biochemical, and histological abnormalities of NAFLD. Therefore, EZ may be a promising agent for treatment of NAFLD.

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 ⩾300u2009mgu2009g−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.

Low serum bilirubin concentration in haemodialysis patients with Type 2 diabetes

Diabet. Med. 28, 96–99 (2011)

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.

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.

17β-Estradiol attenuates saturated fatty acid diet-induced liver injury in ovariectomized mice by up-regulating hepatic senescence marker protein-30.

Senescence marker protein-30 (SMP30) plays an important role in intracellular Ca(2+) homeostasis. The aim of the present study was to investigate the effects of estrogens on liver apoptotic damage and changes in SMP30 expression induced by a high saturated fatty acid diet (HSFD). Ovariectomized mice (OVX) and sham-operated mice (SHAM) were randomly divided into five groups: SHAM fed a normal diet (SHAM/ND), SHAM fed HSFD (SHAM/HSFD), OVX fed ND (OVX/ND), OVX fed HSFD (OVX/HSFD) and OVX fed HSFD with 17β-estradiol (E2) supplementation using an implanted slow-release pellet (OVX/HSFD+E2). After 8 weeks, markers of endoplasmic reticulum (ER) stress and apoptosis, and levels of tumor necrosis factor-α (TNFα and SMP30 expression were investigated. Compared with SHAM/ND, OVX/HSFD mice showed significantly increased spliced X-box protein-1 (s-XBP1), phosphorylated eukaryotic initiation factor-2α (p-eIF2α), glucose-regulated protein 78 (GPR78), C/EBP homologous protein (CHOP), cytosolic cytochrome c, caspase-3 activity, and TNFα, and significantly decreased SMP30. These differences in OVX/HSFD mice were restored to the levels of SHAM/ND mice by E2 supplementation. These results suggest that E2 supplementation attenuates HSFD-induced liver apoptotic death in ovariectomized mice by up-regulating SMP30.

Low insulin level is associated with aortic stiffness

Recent studies have demonstrated that hyperinsulinemia is a risk factor for cardiovascular disease. The aim of this study was to evaluate the relationship between serum insulin level and the cardio-ankle vascular index (CAVI), which was developed as a marker of arterial stiffness. We performed a cross-sectional study of 260 consecutive and nondiabetic subjects with clinical suspicion of coronary heart disease. We measured CAVI in all subjects. A standard 75-g oral glucose tolerance test was performed, and plasma glucose and serum insulin levels were measured in venous blood collected at 0, 30, 60 and 120u2009min after the test. Statistical analyses were conducted for four subgroups according to the insulin area under the concentration time curve (InsAUC). Mean CAVI and InsAUC were 8.7 and 109.5u2009μIUu2009ml–1u2009h–1, respectively. Unadjusted analysis demonstrated that the InsAUC quartiles were significantly associated with CAVI (P<0.0001), and the lowest InsAUC quartile (P=0.001) had a lower glucose AUC. Analysis of covariance demonstrated that the lowest InsAUC quartile had the highest CAVI, and, after adjusting for several coronary risk factors, the highest InsAUC quartile had a higher CAVI than the second and third InsAUC quartiles (P<0.0001). In conclusion, the lowest InsAUC quartile was related to CAVI, although the lowest InsAUC quartile maintained glucose homeostasis in this study population. Both hyperinsulinemia and low insulin level are independently associated with CAVI.

Serum accumulation of a creatinine oxidative metabolite (NZ-419: 5-hydroxy-1- methylhydatoin) as an intrinsic antioxidant in diabetic patients with or without chronic kidney disease.

AIMSnIn mammals, creatinine (Cr) is catabolized by a dual oxidative pathway via 5-hydroxy-1-methylhydantoin or 5-hydroxycreatinine. The former, an intrinsic antioxidant, termed NZ-419, has been reported to prevent the progression of chronic renal failure in animal models. However, its clinical intrinsic serum level has not yet been reported.nnnMETHODSnWe analyzed serum NZ-419 levels in diabetic and nondiabetic patients with or without Stage 3 - 5 chronic kidney disease (CKD).nnnRESULTSnThe levels of NZ-419 in diabetic patients with (88.1 ± 17.2 µg/dl, p < 0.001) or without (31.5 ± 2.4 µg/dl, p < 0.05) Stage 3 - 5 CKD were significantly higher than in nondiabetic normal controls (9.0 ± 5.6 µg/dl). The molar ratio data showed NZ-419/Cr was significantly higher in both diabetic patients with (p < 0.01) or without Stage 3 - 5 CKD (p < 0.001) compared to nondiabetic normal controls. No further increase occurred with increasing severity of renal failure. Furthermore, nondiabetic patients with or without Stage 3 - 5 CKD did not show significantly different molar ratio values than controls but had significantly higher values of NZ-419 levels (p < 0.001).nnnCONCLUSIONSnOverproduction and decreased clearance played a major role in the increased NZ-419 levels we observed in the patients with diabetes and Stage 3 - 5 CKD, respectively. The existence of chronic renal failure did not further enhance this overproduction.