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Papers - ITOH Hiroshi

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Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice

Hirata, T., Kawai, T., Hirose, H., Tanaka, K., Kurosawa, H., Fujii, C., Fujita, H., Seto, Y., Matsumoto, H. and Itoh, H.

Endocr Res 41 ( 1 ) 8 - 15 2016

ISSN 0743-5800

The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive beta-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

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DNA Damage and Epigenetic Changes in Kidney Diseases - Focused on Transcription Factors in Podocytes

Hayashi, K., Hishikawa, A. and Itoh, H.

Curr Hypertens Rev 12 ( 2 ) 105 - 11 2016

ISSN 1573-4021

Recently it has been shown that epigenetic mechanisms are involved in initiation and progression of caridiovascular and metabolic diseases, including diabetes, obesity, atherosclerosis, heart failure, hypertension and kidney diseases. In these chronic diseases, various exogenous and endogenous stresses cause DNA damage, followed by DNA repair process. Accumulation of DNA damages and impaired repair process can lead to epigenetic changes, which may contribute to onset and progression of diseases. Recently we have shown that therapeutic effect of transcription factor KLF4 (Kruppel-like factor 4) in kidney glomerular epithelial cells (podocytes) on proteinuric kidney diseases through epigenetic mechanisms. Our result suggests the possibility of transcription factors as a target of selective epigenetic therapy. Moreover, we have reported that renin-angiotensin system (RAS) blockers, which are widely prescribed for the treatment of cardiovascular diseases, can restore epigenetic changes through KLF4 in part. These results suggest that activation of RAS causes epigenetic changes in disease states, and elucidation of the precise mechanism may lead to establishment of novel therapeutic target of kidney diseases. In this review we focus on DNA damage repair system and epigenetic modulators in disease states, and speculate a candidate for epigenetic therapy of kidney diseases.

Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism

Hasegawa, K., Wakino, S., Sakamaki, Y., Muraoka, H., Umino, H., Minakuchi, H., Yoshifuji, A., Naitoh, M., Shinozuka, K., Futatsugi, K., Urai, H., Kanda, T., Tokuyama, H., Hayashi, K. and Itoh, H.

Curr Hypertens Rev 12 ( 2 ) 95 - 104 2016

ISSN 1573-4021

We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship "proximal tubule-podocyte communication". In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule-podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN.

Adrenal Insufficiency under Standard Dosage of Glucocorticoid Replacement after Unilateral Adrenalectomy for Cushing's Syndrome

Fujii, K., Miyashita, K., Kurihara, I., Hiratsuka, K., Sato, S., Yokota, K., Kobayashi, S., Shibata, H. and Itoh, H.

Case Rep Endocrinol 2016 2347528 2016

ISSN 2090-6501

Glucocorticoid replacement is needed for patients after adrenal surgery for Cushing's syndrome; however, the adequate dosage is not easily determined. The patient was a 62-year-old woman who has had hypertension for 5 years and presented with heart failure due to hypertrophic cardiomyopathy. She consulted with us because of general fatigue, facial edema, and muscle weakness and was diagnosed with Cushing's syndrome. A laparoscopic left adrenalectomy was performed, standard dosage of postoperative replacement was administered, and she was discharged with 30 mg/day of hydrocortisone (cortisol). However, she suffered from loss of appetite and was transferred to an emergency unit with the symptoms of adrenal insufficiency on postoperative day 15. After initial hydrocortisone replacement with 200 mg/day, the dosage was gradually decreased during hospitalization; however, reduction of hydrocortisone dosage lower than 60 mg/day was difficult because of nausea and fatigue. Her circadian cortisol profile after hydrocortisone administration showed delayed and lowered peaks, which suggested that hydrocortisone absorption in the intestine was impaired. Therefore, complicated heart failure may have led to the adrenal insufficiency in the patient. In such cases, we should consider postoperative administration of more than the standard dosage of hydrocortisone to avoid adrenal insufficiency after surgery for Cushing's syndrome.

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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 2015.11

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 2015.11

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 2015.11

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 2015.10

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 2015.10

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 2015.10

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 2015.10

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 2015.10

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 2015.10

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 2015.08

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 2015.08

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 2015.07

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 2015.06

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 2015.06

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 2015.06

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 2015.04

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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