研究者詳細 - 伊藤　裕

論文 - 伊藤　裕

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A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis

Yamaguchi, S., Maruyama, T., Wakino, S., Tokuyama, H., Hashiguchi, A., Tada, S., Homma, K., Monkawa, T., Thomas, J., Miyashita, K., Kurihara, I., Yoshida, T., Konishi, K., Hayashi, K., Hayashi, M. and Itoh, H.

BMC Nephrol 16 187 2015年11月

ISSN 1471-2369

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

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Comparison of the effects of low-dose rosuvastatin on plasma levels of cholesterol and oxidized low-density lipoprotein in 3 ultracentrifugally separated low-density lipoprotein subfractions

Homma, K., Homma, Y., Ozawa, H., Shiina, Y., Shibata, T., Yoshida, T., Hasegawa, K., Kanda, T., Tokuyama, H., Wakino, S., Hayashi, K., Itoh, H. and Hori, S.

J Clin Lipidol 9 （ 6 ） 751 - 757 2015年11月

ISSN 1933-2874

BACKGROUND: Plasma-oxidized (ox) low-density lipoprotein (LDL) is an atherogenic lipoprotein. The distribution of ox-LDL in plasma LDL subfractions and the effect of statins on this distribution have not been investigated in detail. OBJECTIVE: We examined the distribution of cholesterol and ox-LDL in 3 ultracentrifugally separated plasma LDL subfractions and investigated the effects of a statin, rosuvastatin, on the levels of these lipoproteins. MATERIALS AND METHODS: Thirty-one polygenic hypercholesterolemic subjects were included in this study. Levels of cholesterol and ox-LDL in 3 plasma LDL subfractions and plasma levels of remnant-like particle cholesterol, ox-LDL, and adiponectin were measured after 0, 3, 6, and 12 months of treatment with rosuvastatin. Sequential ultracentrifugation was performed to subfractionate plasma lipoproteins. RESULTS: The mean daily dose of rosuvastatin over the 12 months of treatment was 2.9 +/- 1.0 mg (mean +/- standard deviation). The cholesterol subfraction distribution was 43 +/- 10% as low-density LDL, 46 +/- 8% as medium-density LDL, and 13 +/- 5% as high-density LDL. Similarly, the distribution of ox-LDL was 31 +/- 10% as low-density LDL, 48 +/- 7% as medium-density LDL, and 22 +/- 8% as high-density LDL. After 12 months of treatment with rosuvastatin, the level of cholesterol was significantly reduced in all 3 subfractions (P < .0001), as was the level of ox-LDL (P < .0001). Furthermore, the plasma cholesterol level in high-density lipoprotein2 increased significantly. CONCLUSIONS: The distribution of ox-LDL in plasma LDL subfractions was more skewed toward the denser subfractions, compared with cholesterol. Rosuvastatin treatment significantly reduced plasma levels of cholesterol and ox-LDL in all LDL subfractions.

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Serum bilirubin concentration is associated with eGFR and urinary albumin excretion in patients with type 1 diabetes mellitus

Nishimura, T., Tanaka, M., Sekioka, R. and Itoh, H.

J Diabetes Complications 29 （ 8 ） 1223 - 7 2015年11月

ISSN 1056-8727

AIMS: Although relationships of serum bilirubin concentration with estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) in patients with type 2 diabetes have been reported, whether such relationships exist in patients with type 1 diabetes is unknown. METHODS: A total of 123 patients with type 1 diabetes were investigated in this cross-sectional study. The relationship between bilirubin (total and indirect) concentrations and log(UAE) as well as eGFR was examined by Pearson's correlation analyses. Multivariate regression analyses were used to assess the association of bilirubin (total and indirect) with eGFR as well as log(UAE). RESULTS: A positive correlation was found between serum bilirubin concentration and eGFR; total bilirubin (r=0.223, p=0.013), indirect bilirubin (r=0.244, p=0.007). A negative correlation was found between serum bilirubin concentration and log(UAE); total bilirubin (r=-0.258, p=0.005), indirect bilirubin (r=-0.271, p=0.003). Multivariate regression analyses showed that indirect bilirubin concentration was an independent determinant of eGFR and log(UAE). CONCLUSIONS: Bilirubin concentration is associated with both eGFR and log(UAE) in patients with type 1 diabetes. Bilirubin might have a protective role in the progression of type 1 diabetic nephropathy.

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Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria

Hayashi, K., Sasamura, H., Nakamura, M., Sakamaki, Y., Azegami, T., Oguchi, H., Tokuyama, H., Wakino, S., Hayashi, K. and Itoh, H.

Kidney Int 88 （ 4 ） 745 - 53 2015年10月

ISSN 0085-2538

Proteinuria is a central component of chronic kidney disease and an independent risk factor for cardiovascular disease. Kidney podocytes have an essential role as a filtration barrier against proteinuria. Kruppel-like Factor 4 (KLF4) is expressed in podocytes and decreased in glomerular diseases leading to methylation of the nephrin promoter, decreased nephrin expression and proteinuria. Treatment with an angiotensin receptor blocker (ARB) reduced methylation of the nephrin promoter in murine glomeruli of an adriamycin nephropathy model with recovery of KLF4 expression and a decrease in albuminuria. In podocyte-specific KLF4 knockout mice, the effect of ARB on albuminuria and the nephrin promoter methylation was attenuated. In cultured human podocytes, angiotensin II reduced KLF4 expression and caused methylation of the nephrin promoter with decreased nephrin expression. In patients, nephrin promoter methylation was increased in proteinuric kidney diseases with decreased KLF4 and nephrin expression. KLF4 expression in ARB-treated patients was higher in patients with than without ARB treatment. Thus, angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in proteinuric kidney diseases. This study provides a new concept that renin-angiotensin system blockade can exert therapeutic effects through epigenetic modulation of the kidney gene expression.

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Sirtuin and metabolic kidney disease

Wakino, S., Hasegawa, K. and Itoh, H.

Kidney Int 88 （ 4 ） 691 - 8 2015年10月

ISSN 0085-2538

Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.

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Effects of Liraglutide Monotherapy on Beta Cell Function and Pancreatic Enzymes Compared with Metformin in Japanese Overweight/Obese Patients with Type 2 Diabetes Mellitus: A Subpopulation Analysis of the KIND-LM Randomized Trial

Tanaka, K., Saisho, Y., Manesso, E., Tanaka, M., Meguro, S., Irie, J., Sugiura, H., Kawai, T., Jinzaki, M., Cobelli, C. and Itoh, H.

Clin Drug Investig 35 （ 10 ） 675 - 84 2015年10月

ISSN 1173-2563

BACKGROUND AND OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming one of the major therapeutic options for the treatment of type 2 diabetes mellitus (T2DM). This study was conducted as an exploratory analysis to clarify the effects of liraglutide, a GLP-1RA, on beta cell function, fat distribution and pancreas volume compared with metformin in Japanese overweight/obese patients with T2DM. METHODS: A subpopulation of the Keio study for Initial treatment of type 2 Diabetes with Liraglutide versus Metformin (KIND-LM) study participants (n = 20, 10 in oral metformin group and 10 in subcutaneous liraglutide group) who were enrolled at Keio University Hospital and underwent frequently sampled mixed meal tolerance test (MTT) and abdominal computed tomography (CT) at weeks 0 and 24 were included in this analysis. The patients were treated with either metformin or liraglutide throughout the 24-week study period. RESULTS: Changes in glycemic parameters such as glycated hemoglobulin (HbA1c), glycated albumin and 1,5-anhydroglucitol at week 24 were comparable between the groups. An oral minimal model based on MTT revealed that static-phase beta cell responsiveness (Phi s) and static-phase disposition index were significantly increased at week 24 in the liraglutide group but not in the metformin group. There was no significant change in fat distribution as well as body weight at week 24 in either group. Serum amylase and lipase levels modestly but significantly increased in the liraglutide group during the study; however, there was no incidence of pancreatitis and pancreas volume was not changed in the liraglutide group. CONCLUSION: Liraglutide monotherapy for 24 weeks improved beta cell responsiveness with no change in either body weight or fat distribution. Further investigation is needed to clarify the mechanism by which liraglutide increases serum pancreatic enzymes. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ); UMIN000004243.

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Improvement of Physical Decline Through Combined Effects of Muscle Enhancement and Mitochondrial Activation by a Gastric Hormone Ghrelin in Male 5/6Nx CKD Model Mice

Tamaki, M., Hagiwara, A., Miyashita, K., Wakino, S., Inoue, H., Fujii, K., Fujii, C., Sato, M., Mitsuishi, M., Muraki, A., Hayashi, K., Doi, T. and Itoh, H.

Endocrinology 156 （ 10 ） 3638 - 48 2015年10月

ISSN 0013-7227

Because a physical decline correlates with an increased risk of a wide range of disease and morbidity, an improvement of physical performance is expected to bring significant clinical benefits. The primary cause of physical decline in 5/6 nephrectomized (5/6Nx) chronic kidney disease model mice has been regarded as a decrease in muscle mass; however, our recent study showed that a decrease in muscle mitochondria plays a critical role. In the present study, we examined the effects of a gastric hormone ghrelin, which has been reported to promote muscle mitochondrial oxidation, on the physical decline in the chronic kidney disease model mice, focusing on the epigenetic modulations of a mitochondrial activator gene, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). Ghrelin treatment improved a decline in exercise endurance of 5/6Nx mice, associated with an increase in both of the muscle mass and mitochondrial amount. The expression level of PGC-1alpha was decreased in the skeletal muscle of 5/6Nx mice, which was associated with an increase in the methylation ratio of the cytosine residue at 260 base pairs upstream of the initiation point. Conversely, ghrelin treatment de-methylated the cytosine residue and increased the expression of PGC-1alpha. A representative muscle anabolic factor, IGF-1, did not affect the expression of PGC-1alpha and muscle mitochondrial amount, although it increased muscle mass. As a result, IGF-1 treatment in 5/6Nx mice did not increase the decreased exercise endurance as effectively as ghrelin treatment did. These findings indicate an advantage of ghrelin treatment for a recovery of physical decline.

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A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

Akaza H, Oya M, Iijima M, Hyodo I, Gemma A, Itoh H, Adachi M, Okayama Y, Sunaya T, Inuyama L

Japanese journal of clinical oncology 45 （ 10 ） 953 - 62 2015年10月

ISSN 0368-2811

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Impact of Switching From Darbepoetin Alfa to Epoetin Beta Pegol on Iron Utilization and Blood Pressure in Peritoneal Dialysis Patients.

Washida N, Inoue S, Kasai T, Shinozuka K, Hosoya K, Morimoto K, Wakino S, Hayashi K, Itoh H

Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 19 （ 5 ） 450 - 6 2015年10月

ISSN 1744-9979

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Relationships among different glycemic variability indices obtained by continuous glucose monitoring

Saisho, Y., Tanaka, C., Tanaka, K., Roberts, R., Abe, T., Tanaka, M., Meguro, S., Irie, J., Kawai, T. and Itoh, H.

Prim Care Diabetes 9 （ 4 ） 290 - 6 2015年08月

ISSN 1878-0210

The aim of this study was to assess the relationships among indices of glycemic variability obtained by continuous glucose monitoring (CGM). CGM was performed in 88 patients with diabetes (20 type 1 and 68 type 2 diabetes, age 59 +/- 15 years) admitted to our hospital (Keio University Hospital, Tokyo, Japan) between 2010 and 2012. Mean glucose, glucose standard deviation (SDglu) and other glycemic indices such as index of glycemic control (ICG), J-index, mean of daily differences (MODD), continuous overlapping net glycemic action 1 (CONGA1), mean amplitude of glycemic excursions (MAGE) and M value were calculated from CGM data, and the correlations among these indices were assessed. There were strong correlations between SDglu and the indices MAGE, CONGA1, MODD and M value (all r > 0.8, P < 0.05). On the other hand, mean glucose was strongly correlated with J index and M value (both r > 0.8, P < 0.05). SDglu and other glycemic variability indices were more strongly correlated with hypoglycemia than was mean glucose, and the combination of mean glucose and SDglu was useful for predicting hypoglycemia in patients with diabetes. In this study, we demonstrated the characteristics of various glycemic variability indices in relation to mean glucose and SDglu. This information will help physicians to understand the characteristics of various glycemic variability indices and to select an appropriate index for their purpose. Our results also underpin the importance of glycemic variability in relation to risk of hypoglycemia in patients with diabetes.

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Effects of Glucocorticoid Treatment on beta- and alpha-Cell Mass in Japanese Adults With and Without Diabetes

Sato, S., Saisho, Y., Inaishi, J., Kou, K., Murakami, R., Yamada, T. and Itoh, H.

Diabetes 64 （ 8 ） 2915 - 27 2015年08月

ISSN 0012-1797

The aim of this study was 1) to clarify beta-cell regenerative capacity in the face of glucocorticoid (GC)-induced insulin resistance and 2) to clarify the change in beta- and alpha-cell mass in GC-induced diabetes in humans. We obtained the pancreases from 100 Japanese autopsy case subjects. The case subjects were classified according to whether or not they had received GC therapy before death and the presence or absence of diabetes. Fractional beta-cell area (%BCA) and alpha-cell area (%ACA) were quantified, and the relationship with GC therapy was evaluated. As a result, in case subjects without diabetes, there was no significant difference in %BCA between case subjects with and without GC therapy (1.66 +/- 1.05% vs. 1.21 +/- 0.59%, P = 0.13). %ACA was also not significantly different between the two groups. In case subjects with type 2 diabetes, %BCA and %ACA were both significantly reduced compared with control subjects without diabetes; however, neither %BCA nor %ACA was significantly decreased in case subjects with GC-induced diabetes. There was a significant negative correlation between %BCA and HbA1c measured before death; however, this relationship was attenuated in case subjects with GC therapy. In conclusion, the current study suggests that beta- and alpha-cell mass remain largely unchanged in the face of GC-induced insulin resistance in Japanese individuals, implying limited capacity of beta-cell regeneration in adult humans. The absence of apparent beta-cell deficit in case subjects with GC-induced diabetes suggests that GC-induced diabetes is mainly caused by insulin resistance and/or beta-cell dysfunction, but not necessarily a deficit of beta-cell mass.

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Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Tagawa, H., Irie, J., Itoh, A., Kusumoto, Y., Kato, M., Kobayashi, N., Tanaka, K., Morinaga, R., Fujita, M., Nakajima, Y., Morimoto, K., Sugizaki, T., Kawano, Y., Yamada, S., Kawai, T., Watanabe, M. and Itoh, H.

Diabetes Res Clin Pract 109 （ 1 ） 85 - 94 2015年07月

ISSN 0168-8227

AIMS: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for >/=6 months. RESULTS: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.

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Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease

Hayashi, K. and Itoh, H.

Arch Immunol Ther Exp (Warsz) 63 （ 3 ） 193 - 6 2015年06月

ISSN 0004-069

Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of various diseases, including kidney diseases. In the present article, we review the current data regarding the role of epigenetic modulation in chronic kidney disease (CKD) and kidney fibrosis, including DNA methylation and histone modification. Especially we focused on the role of transcription factors in epigenetic modulation and the possibility of therapeutic target of CKD. We have recently reported that transcription factor Kruppel-like factor 4 (also known as gut-enriched Kruppel-like factor) is expressed in kidney podocytes (visceral epithelial cells) and modulates podocyte phenotype by gene-selective epigenetic control. Targeting transcription factors for epigenetic modification may be a good candidate for remission and regression of CKD. It is necessary for the therapy of CKD with an epigenetic-based approach to investigate organ-, tissue-, or gene-specific treatment methods for reduction of side effects.

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CT during Arteriography to Visualize the Right Adrenal Vein for Adrenal Venous Sampling

Oguro, S., Nakatsuka, S., Yashiro, H., Hashimoto, S., Miyashita, K., Kurihara, I., Itoh, H. and Jinzaki, M.

J Vasc Interv Radiol 26 （ 6 ） 910 - 4 2015年06月

ISSN 1051-0443

The present report describes 6 cases of adrenal venous sampling (AVS) in patients who underwent computed tomography (CT) during arteriography because cannulation of right adrenal veins was otherwise difficult. CT was performed during arteriography to obtain information on the location and direction of the right adrenal vein. Two right adrenal veins were visualized in 1 case. The right central adrenal vein was not visualized in 1 case owing to an injury from a previous unsuccessful AVS procedure, but the right renal capsular vein was well visualized. CT during arteriography could contribute to a high AVS success rate.

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C-peptide immunoreactivity index is associated with improvement of HbA1c: 2-Year follow-up of sitagliptin use in patients with type 2 diabetes

Nishimura, T., Meguro, S., Sekioka, R., Tanaka, K., Saisho, Y., Irie, J., Tanaka, M., Kawai, T. and Itoh, H.

Diabetes Res Clin Pract 108 （ 3 ） 441 - 7 2015年06月

ISSN 0168-8227

AIMS: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL]x100). METHODS: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n=285) were: continuation of sitagliptin for >/=700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (DeltaHbA1c </=-0.4% [</=-4 mmol/mol]) and non-responder (DeltaHbA1c >-0.4% [>-4 mmol/mol]) groups. RESULTS: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 +/- 0.8% [57 +/- 9 mmol/mol], 7.3 +/- 0.9% [57 +/- 9 mmol/mol], 7.4 +/- 0.9% [58 +/- 10 mmol/mol], 7.1 +/- 0.8% [55 +/- 9 mmol/mol], and 7.3 +/- 0.9% [57 +/- 10 mmol/mol], respectively, all P<0.001 vs. baseline [8.0 +/- 1.0%, 64 +/- 11 mmol/mol] and CPR index: 1.69 +/- 0.96, 1.71 +/- 1.10, 1.62 +/- 0.96, 1.64 +/- 0.92, and 1.66 +/- 0.96, respectively, all P<0.05 vs. baseline [1.47 +/- 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin. CONCLUSIONS: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response.

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Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans

Hosoya, K., Minakuchi, H., Wakino, S., Fujimura, K., Hasegawa, K., Komatsu, M., Yoshifuji, A., Futatsugi, K., Shinozuka, K., Washida, N., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Kidney Int 87 （ 4 ） 749 - 60 2015年04月

ISSN 0085-2538

In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.

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Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin

Homma, K., Homma, Y., Yoshida, T., Ozawa, H., Shiina, Y., Wakino, S., Hayashi, K., Itoh, H. and Hori, S.

J Clin Lipidol 9 （ 2 ） 210 - 6 2015年03月

ISSN 1933-2874

BACKGROUND: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. OBJECTIVE: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). MATERIALS AND METHODS: Atorvastatin was administered to patients with PHC (n = 11), FCHL (n = 16), and FH (n = 13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. RESULTS: The average daily dosage of atorvastatin was 10, 27, and 40 mg in patients with PHC, FCHL, and FH, respectively; after 12 months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P < .0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P < .0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P </= .0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. CONCLUSION: Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.

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Serum total bilirubin concentration is negatively associated with increasing severity of retinopathy in patients with type 2 diabetes mellitus

Sekioka, R., Tanaka, M., Nishimura, T. and Itoh, H.

J Diabetes Complications 29 （ 2 ） 218 - 21 2015年03月

ISSN 1056-8727

AIMS: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy. METHODS: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c. RESULTS: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without. Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy. CONCLUSIONS: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes.

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Impact of Peritoneal Dialysis Catheter Insertion by a Nephrologist: Results of a Questionnaire Survey of Patients and Nurses

Washida, N., Aikawa, K., Inoue, S., Kasai, T., Shinozuka, K., Morimoto, K., Hosoya, K., Hayashi, K. and Itoh, H.

Adv Perit Dial 31 59 - 68 2015年

ISSN 1197-8554

Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 +/- 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes

Tanaka, K., Saisho, Y., Kawai, T., Tanaka, M., Meguro, S., Irie, J., Imai, T., Shigihara, T., Morimoto, J., Yajima, K., Atsumi, Y., Takei, I. and Itoh, H.

Endocr J 62 （ 5 ） 399 - 409 2015年

ISSN 0918-8959

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 +/- 0.80% vs. -0.80 +/- 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

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伊藤 裕

論文 - 伊藤 裕

伊藤　裕

論文 - 伊藤　裕