Papers - FURUHASHI Masato

Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension

M Furuhashi, N Ura, K Higashiura, H Murakami, M Tanaka, N Moniwa, D Yoshida, K Shimamoto

HYPERTENSION ( LIPPINCOTT WILLIAMS & WILKINS )  42 ( 1 ) 76 - 81  2003.07  [Refereed]

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Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-angiotensin system (RAS) on adiponectin concentrations. EHT were divided into 12 insulin-resistant EHT (EHT-R) and 18 non-insulin-resistant EHT (EHT-N) using mean-1 SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an angiotensin-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an angiotensin II receptor blocker (candesartan, 8 mg/d; n=7) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.

DOI PubMed

The effect of tumor necrosis factor-alpha on tissue specificity and selectivity to insulin signaling

K Yamaguchi, K Higashiura, N Ura, H Murakami, M Hyakukoku, M Furuhashi, K Shimamoto

HYPERTENSION RESEARCH ( JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE )  26 ( 5 ) 389 - 396  2003.05  [Refereed]

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Recent studies have indicated that tumor necrosis factor (TNF)-alpha plays a significant role in insulin resistance. It has been proposed that selective impairment of insulin signaling in glucose metabolism is related to the development of atherosclerosis, although the mechanisms are not clear. The aim of this study was to elucidate the effect of TNF-alpha on tissue specificity and selectivity to insulin signaling. L6 myotubes and rat aortic vascular smooth muscle cells (VSMC) were cultured. Cells were stimulated with insulin pretreated with or without TNF-alpha. The protein extracts were used for electrophoresis and immunoblotting studies to examine phosphorylation of insulin receptor (IR)-beta, insulin receptor substrate (IRS)-1 and extracellular signal-regulated kinase (ERK). IR-beta phosphorylation was not affected by TNF-alpha in L6 or in VSMC. TNF-alpha significantly (p<0.05) inhibited IRS-1 phosphorylation by insulin but had no effect on ERK in L6. TNF-alpha had no effect on either IRS-1 phosphorylation or ERK in VSMC. Insulin induced ERK phosphorylation in a dose-dependent manner in VSMC. These results suggests that TNF-alpha plays a significant role in the tissue specificity and signal selectivity of insulin resistance. The pathway related to glucose metabolism is selectively impaired by TNF-alpha in skeletal muscle, and this impairment may induce compensatory hyperinsulinemia, which in turn would stimulate the pathway related to the cell proliferation in vascular tissues and possibly enhance the progression of atherosclerosis.

DOI PubMed

Tissue-specific impairment of insulin signaling in vasculature and skeletal muscle of fructose-fed rats

M Hyakukoku, K Higashiura, N Ura, H Murakami, K Yamaguchi, L Wang, M Furuhashi, N Togashi, K Shimamoto

HYPERTENSION RESEARCH ( JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE )  26 ( 2 ) 169 - 176  2003.02  [Refereed]

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The relation between insulin resistance/hyperinsulinemia and cardiovascular diseases has attracted much attention. Insulin affects not only glucose metabolism, but also protein synthesis and cell growth. Insulin stimulates both the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways, but the relationship between cardiovascular disease and selective insulin signal pathways is unclear. We investigated the tissue specificity and intracellular signal transduction selectivity of insulin resistance in the vasculature and skeletal muscle of fructose-fed rats (FFR). Sprague-Dawley rats were fed either normal rat chow (control rats) or fructose-rich chow. Normal saline with or without 1,000 (mug/kg) insulin was injected, and then the thoracic aorta or soleus muscle was removed under anesthetization. Insulin-induced tyrosine phosphorylation of insulin receptor beta subunit (IRbeta) and insulin receptor substrate-1 (IRS-1) and tyrosine/threonine phosphorylation of p44/42 MAPK (ERK-1/2) were evaluated. There were no significant differences in the degree of phosphorylation of IRbeta or ERK-1/2 in the thoracic aorta or in the soleus muscle between FFR and controls. However, tyrosine phosphorylation of IRS-1 in the soleus muscle of FFR was significantly reduced to 80% (p<0.001) of that in controls. The results suggest that PI3-K pathway in skeletal muscle is selectively impaired in FFR, and this impairment may induce hyperinsulinemia, which in turn may stimulate the MAPK pathway and lead to atherosclerosis. Thus PI3-K pathway may be one of the factors underlying the onset of cardiovascular disease in patients with insulin resistance.

DOI PubMed

Insulin sensitivity and lipid metabolism in human CD36 deficiency

M Furuhashi, N Ura, T Nakata, K Shimamoto

DIABETES CARE ( AMER DIABETES ASSOC )  26 ( 2 ) 471 - 474  2003.02  [Refereed]

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OBJECTIVE - CD36 has been proposed as a fatty acid translocase and a receptor for HDL and oxidized LDL. The association between CD36 deficiency and insulin resistance remains controversial. We investigated glucose and lipid metabolism in human CD36 deficiency. RESEARCH DESIGN AND METHODS - A total of 61 type I CD36-deficient patients and 25 control subjects were examined. Diabetes was defined as fasting glucose level greater than or equal to7 mmol/l or use of hypoglycemic agents. A homeostasis model assessment (HOMA) index was evaluated in patients without diabetes. Insulin resistance was defined as a HOMA index greater than or equal to1.73 (sensitivity 64.3%, specificity 78.9%; J Japan Diab Soc, 2000). RESULTS - Diabetes was identified in 12 (20%) of the 61 CD36-deficient patients. Fasting glucose, HbA(1c), and total cholesterol levels in the diabetic CD36-deficient patients were significantly higher than in the control subjects and the nondiabetic CD36-deficient patients. Regardless of diabetes, HDL cholesterol concentrations in the CD36-deficient patients were significantly higher than in the control subjects. The nondiabetic CD36-deficient patients had higher triglyceride concentrations than the control subjects, and triglyceride concentrations were higher in the diabetic CD36-deficient patients than in the nondiabetic CD36-deficient patients. The prevalence of insulin resistance in the nondiabetic CD36-deficient patients was similar to that in the control subjects. CONCLUSIONS - Human CD36 deficiency is not necessarily responsible for insulin resistance. Lipid abnormalities in CD36 deficiency may partly depend on the presence of diabetes, and increased levels of triglyceride and HDL cholesterol may be due to impaired binding of fatty acids and HDL to CD36 and subsequent clearance.

DOI PubMed

Serum ratio of heart-type fatty acid-binding protein to myoglobin - A novel marker of cardiac damage and volume overload in hemodialysis patients

M Furuhashi, N Ura, K Hasegawa, H Yoshida, K Tsuchihashi, T Nakata, K Shimamoto

NEPHRON CLINICAL PRACTICE ( KARGER )  93 ( 2 ) C69 - C74  2003.02  [Refereed]

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Background: The concentration of heart-type fatty acid-binding protein (hFABP), a promising novel marker for detection of acute or persistent myocardial damage, is significantly influenced by renal clearance and thus has limitations to its usefulness in patients with renal dysfunction. We evaluated whether the serum ratio of hFABP to myoglobin (F/M) might be a useful marker for assessing cardiac damage in hemodialysis patients. Methods: Serum hFABP and myoglobin were measured, and the value of F/M was calculated in 21 hemodialysis patients. Cardiac markers (cardiac troponin T [cTnT], atrial natriuretic peptide [ANP], and brain natriuretic peptide [BNP]) and echocardiographic indices (left ventricular end-diastolic dimension [LVDd], left ventricular mass index [LVMI], and inferior vena cava [IVC] dimension) were examined and compared with hFABP, myoglobin, and F/M ratios. Results: Serum hFABP and myoglobin levels were significantly elevated in hemodialysis patients and reduced by 30-40% during hemodialysis. The value of F/M after hemodialysis, but not the concentration of hFABP or myoglobin, had significant linear correlations with ANP, BNP, cTnT, LVDd, LVMI, and IVC. Conclusion: The value of F/M after hemodialysis, but not the concentration of hFABP itself, might be a newly useful marker for estimation of cardiac damage and volume overload in hemodialysis patients. Copyright (C) 2003 S. Karger AG, Basel.

DOI

Serum ratio of heart-type fatty acid-binding protein to myoglobin. A novel marker of cardiac damage and volume overload in hemodialysis patients.

Furuhashi M, Ura N, Hasegawa K, Yoshida H, Tsuchihashi K, Nakata T, Shimamoto K

Nephron. Clinical practice ( 2 )  93   C69 - 74  2003  [Refereed]

PubMed

本態性高血圧におけるレジスチンとインスリン抵抗性

古橋 眞人, 浦 信行, 吉田 大輔, 田中 希尚, 茂庭 仁人, 萩原 誠, 村上 英之, 吉田 英昭, 東浦 勝浩, 島本 和明

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  78 ( 2 ) 459 - 459  2002.09

Sonoclot coagulation analysis: new bedside monitoring for determination of the appropriate heparin dose during haemodialysis

M Furuhashi, N Ura, K Hasegawa, H Yoshida, K Tsuchihashi, T Miura, K Shimamoto

NEPHROLOGY DIALYSIS TRANSPLANTATION ( OXFORD UNIV PRESS )  17 ( 8 ) 1457 - 1462  2002.08  [Refereed]

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Background. Thrombotic and haemorrhagic complications affect cardiovascular morbidity and mortality in haemodialysis patients. We investigated whether a new bedside Sonoclot analysis is useful for determining an appropriate heparin dose during haemodialysis. Methods. Twenty-two haemodialysis patients (15 males and seven females) treated with unfractionated heparin were recruited. Sonoclot parameters, including activated clotting time (ACT), clot rate (CR), time to peak (TP) and peak amplitude (PA), were examined before and after haemodialysis, coupled with conventional coagulable variables, platelet count and fibrinogen level. Some indices were determined and verified to control heparin dose. Thrombotic and haemorrhagic complications were observed for 3 months. Sonoclot analysis was subsequently performed before initiation, 1 h later, 2.5 or 3 h later (before cessation of heparin infusion), and at the end of haemodialysis. Results. Both CR and PA were positively correlated with platelet count and fibrinogen level. Sonoclot parameters except for PA were significantly correlated with heparin dose. Heparin dose was reduced without causing complications in 12 patients with DeltaACT greater than or equal to40 s and/or CR after haemodialysis (CRpost) <20 U/min. Thrombotic complications occurred in five patients who had CRpost >30 U/min. ACT and TP increased during heparin treatment. ACT was reversed but TP did not change after cessation of heparin. CR significantly decreased after initiation of heparin and was reversed, although not completely, after cessation of heparin. PA showed no significant changes during haemodialysis. Conclusions. Sonoclot analysis can monitor accurate coagulable states and determine an appropriate heparin dose during haemodialysis.

PubMed

Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle

M Furuhashi, N Ura, H Murakami, M Hyakukoku, K Yamaguchi, K Higashiura, K Shimamoto

JOURNAL OF ENDOCRINOLOGY ( SOC ENDOCRINOLOGY )  174 ( 2 ) 321 - 329  2002.08  [Refereed]

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We investigated the effect of fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, on insulin sensitivity including lipid metabolism in skeletal muscle. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) or a fructose-rich chow (fructose-fed rats (FFRs)) for 6 weeks. FFRs were treated either with a vehicle or with 30 mg/kg per day of fenofibrate for the last 2 weeks. Insulin sensitivity (NI-value) was estimated by the euglycemic hyperinsulinernic glucose clamp method. Fatty acid-binding protein (FABP) in skeletal muscle was measured by ELISA, and the expression of FABP mRNA was analyzed by semi-quantitative RT-PCR. The serum and muscle triglyceride (sTG and mTG) levels and the activity of 3-hydroxyacyl-CoA dehydrogenase (HADH), a beta-oxidation enzyme, in muscle were also determined. FFRs showed a lower NI-value and higher blood pressure, sTG and mTG than did the control group. The mTG was correlated positively with sTG and negatively with the NI-value. Fenofibrate treatment for 2 weeks did not change blood pressure but significantly improved the M-value, sTG and mTG. FABP content and mRNA in the soleus muscle were significantly elevated in FFRs compared with those in the control group. Fenofibrate treatment further increased FABP. The HADH activity was comparable between the control group and FFRs, but significantly increased by fenofibrate treatment. These results suggest that fenofibrate improves insulin sensitivity not only by lowering serum lipids and subsequent influx of fatty acids into muscles but also by reducing intramuscular lipid content via further induction of FABP and stimulation of beta-oxidation in muscles.

DOI PubMed

Prevalence of asymptomatic ST segment elevation in right precordial leads with right bundle branch block (Brugada-type ST shift) among the general Japanese population

M Furuhashi, K Uno, K Tsuchihashi, D Nagahara, M Hyakukoku, T Ohtomo, S Satoh, T Nishimiya, K Shimamoto

HEART ( BRITISH MED JOURNAL PUBL GROUP )  86 ( 2 ) 161 - 166  2001.08  [Refereed]

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Objective-To examine the modality and morbidity of asymptomatic ST segment elevation in leads V1 to V3 with right bundle branch block (Brugada-type ST shift). Methods-8612 Japanese subjects (5987 men and 2625 women, mean age 49.2 years) who underwent a health check up in 1997 were investigated. Those with Brugada-type ST shift underwent the following further examinations over a two year period after the initial check up: ECG, echocardiogram, 24 hour Holter monitoring, treadmill exercise testing, signal averaged ECG, and slow kinetic sodium channel blocker loading test (cibenzoline, 1.4 mg/kg). Results-Asymptomatic Brugada-type ST sh-ift was found in 12 of 8612 (0.14%) subjects. Eleven of these 12 subjects were followed up. Follow up ECG exhibited persistent Brugada-type ST shift in seven of 11 (63.6%) subjects. ST shift was transformed from a saddle back to a coved type in three subjects. None of the subjects had morphological abnormalities or abnormal tachyarrhythmias. Positive late potentials were found in seven of 11 (63.6%) subjects. Augmentation of ST shift was shown by both submaximal exercise and drug administration in one of the 11 subjects (9.1%). Conclusions-Asymptomatic subjects with Brugada-type ST shift were not unusual, at a rate of 0.14% in the general Japanese population. Almost all of the subjects had some abnormalities in non-invasive secondary examinations. Additional and prospective studies are needed to confirm the clinical significance and the prognosis of asymptomatic Brugada-type ST shift.

PubMed