研究者詳細 - 古橋　眞人

論文 - 古橋　眞人

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Double-Stranded RNA-Dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis

Takahisa Nakamura, Masato Furuhashi, Ping Li, Haiming Cao, Gurol Tuncman, Nahum Sonenberg, Cem Z. Gorgun, Goekhan S. Hotamisligil

CELL ( CELL PRESS ) 140 ( 3 ) 338 - U41 2010年02月 [査読有り]

As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.

A Predominant Role for Parenchymal c-Jun Amino Terminal Kinase (JNK) in the Regulation of Systemic Insulin Sensitivity

Sara N. Vallerie, Masato Furuhashi, Raquel Fucho, Goekhan S. Hotamisligil

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 3 ( 9 ) e3151 2008年09月 [査読有り]

It has been established that c-Jun N-terminal kinase 1 (JNK1) is essential to the pathogenesis of insulin resistance and type 2 diabetes. Although JNK influences inflammatory signaling pathways, it remains unclear whether its activity in macrophages contributes to adipose tissue inflammation and ultimately to the regulation of systemic metabolism. To address whether the action of this critical inflammatory kinase in bone marrow-derived elements regulates inflammatory responses in obesity and is sufficient and necessary for the deterioration of insulin sensitivity, we performed bone marrow transplantation studies with wild type and JNK1-deficient mice. These studies illustrated that JNK1-deficiency in the bone marrow-derived elements (BMDE) was insufficient to impact macrophage infiltration or insulin sensitivity despite modest changes in the inflammatory profile of adipose tissue. Only when the parenchymal elements lacked JNK1 could we demonstrate a significant increase in systemic insulin sensitivity. These data indicate that while the JNK1 activity in BMDE is involved in metabolic regulation and adipose milieu, it is epistatic to JNK1 activity in the parenchymal tissue for regulation of metabolic homeostasis.

Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice

Masato Furuhashi, Raquel Fucho, Cem Z. Gorgun, Guerol Tuncman, Haiming Cao, Goekhan S. Hotamisligil

JOURNAL OF CLINICAL INVESTIGATION ( AMER SOC CLINICAL INVESTIGATION INC ) 118 ( 7 ) 2640 - 2650 2008年07月 [査読有り]

Adipose tissue inflammation is a characteristic of obesity. However, the mechanisms that regulate this inflammatory response and link adipose inflammation to systemic metabolic consequences are not fully understood. In this study, we have taken advantage of the highly restricted coexpression of adipocyte/macrophage fatty acid-binding proteins (FABPs) aP2 (FABP4) and mal1 (FABP5) to examine the contribution of these lipid chaperones in macrophages and adipocytes to local and systemic inflammation and metabolic homeostasis in mice. Deletion of FABPs in adipocytes resulted in reduced expression of inflammatory cytokines in macrophages, whereas the same deletion in macrophages led to enhanced insulin signaling and glucose uptake in adipocytes. Using radiation chimerism through bone marrow transplantation, we generated mice with FABP deficiency in bone marrow and stroma-derived elements in vivo and studied the impact of each cellular target on local and systemic insulin action and glucose metabolism in dietary obesity. The results of these experiments indicated that neither macrophages nor adipocytes individually could account for the total impact of FABPs on systemic metabolism and suggest that interactions between these 2 cell types, particularly in adipose tissue, are critical for the inflammatory basis of metabolic deterioration.

Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets

Masato Furuhashi, Goekhan S. Hotamisligil

NATURE REVIEWS DRUG DISCOVERY ( NATURE PUBLISHING GROUP ) 7 ( 6 ) 489 - 503 2008年06月 [査読有り]

Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages. Here, we discuss the central role of lipid chaperones-the fatty acid-binding proteins (FABPs)-in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals, and highlight their therapeutic significance. Pharmacological agents that modify FABP function may provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, potentially providing a new class of drugs for diseases such as obesity, diabetes and atherosclerosis.

Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

Masato Furuhashi, Guerol Tuncman, Cem Z. Goerguen, Liza Makowski, Genichi Atsumi, Eric Vaillancourt, Keita Kono, Vladimir R. Babaev, Sergio Fazio, MacRae F. Linton, Richard Sulsky, Jeffrey A. Robl, Rex A. Parker, Goekhan S. Hotamisligil

NATURE ( NATURE PUBLISHING GROUP ) 447 ( 7147 ) 959 - U2 2007年06月 [査読有り]

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis

Kathryn E. Wellen, Raquel Fucho, Margaret F. Gregor, Masato Furuhashi, Carlos Morgan, Torstein Lindstad, Eric Vaillancourt, Cem Z. Gorgun, Fahri Saatcioglu, Gokhan S. Hotamisligil

CELL ( CELL PRESS ) 129 ( 3 ) 537 - 548 2007年05月 [査読有り]

Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.

Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes

Umut Oezcan, Erkan Yilmaz, Lale Oezcan, Masato Furuhashi, Eric Vaillancourt, Ross O. Smith, Cem Z. Goerguen, Goekhan S. Hotamisligil

SCIENCE ( AMER ASSOC ADVANCEMENT SCIENCE ) 313 ( 5790 ) 1137 - 1140 2006年08月 [査読有り]

Endoplasmic reticulum ( ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

Acute renal failure likely due to acute nephritic syndrome associated with typhoid fever

M Hayashi, H Kouzu, M Nishihara, T Takahashi, M Furuhashi, K Sakamoto, N Satoh, T Nishitani, Y Shikano

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 44 ( 10 ) 1074 - 1077 2005年10月 [査読有り]

A 45-year-old woman was admitted to our hospital because of high fever and malaise. She also presented abnormal urine findings including macrohematuria and proteinuria with transient renal insufficiency. Salmonella Typhi was isolated from her blood and stool culture, and then she was diagnosed as having typhoid fever. Salmonella enterica serotype typhi infection can be complicated by renal involvement, although rare. In Japan, few cases have been reported about acute nephritic syndrome in typhoid fever. Here, we report a case of endemic acquired typhoid fever associated with acute renal failure probably due to acute nephritic syndrome successfully treated with levofloxacin.

Low adiponectin level in young normotensive men with a family history of essential hypertension

Masato Furuhashi, Nobuyuki Ura, Katsuhiro Higashiura, Yoshinori Miyazaki, Hideyuki Murakami, Masaya Hyakukoku, Kazuaki Shimamoto

HYPERTENSION RESEARCH ( JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE ) 28 ( 2 ) 141 - 146 2005年02月 [査読有り]

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperin-sulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, non-obese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.

Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes

K Maeda, HM Cao, K Kono, CZ Gorgun, M Furuhashi, KT Uysal, Q Cao, G Atsumi, H Malone, B Krishnan, Y Minokoshi, BB Kahn, RA Parker, GS Hotamisligil

CELL METABOLISM ( CELL PRESS ) 1 ( 2 ) 107 - 119 2005年02月 [査読有り]

Fatty acid binding proteins (FABPs) are cytosolic fatty acid chaperones whose biological role and mechanisms of action are not well understood. Here, we developed mice with targeted mutations in two related adipocyte FABPs, aP2 and mal1, to resolve their role in systemic lipid, glucose, and energy metabolism. Mice lacking aP2 and mail exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance, type 2 diabetes, and fatty liver disease. These mice have altered cellular and systemic lipid transport and composition, leading to enhanced insulin receptor signaling, enhanced muscle AMP-activated kinase (AMP-K) activity, and dramatically reduced liver stearoyl-CoA desaturase-1 (SCD-1) activity underlying their phenotype. Taken together with the previously reported strong protection against atherosclerosis, these results demonstrate that adipocyte/macrophage FABPs have a robust impact on multiple components of metabolic syndrome, integrating metabolic and inflammatory responses in mice and constituting a powerful target for the treatment of these diseases.

Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit

M Furuhashi, K Kitamura, M Adachi, T Miyoshi, N Wakida, N Ura, Y Shikano, Y Shinshi, K Sakamoto, M Hayashi, N Satoh, T Nishitani, K Tomita, K Shimamoto

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM ( ENDOCRINE SOC ) 90 ( 1 ) 340 - 344 2005年01月 [査読有り]

Liddle's syndrome is an autosomal dominant form of salt-sensitive hypertension and has been shown to be caused by missense or frameshift mutations in the amiloride-sensitive epithelial sodium channel (ENaC), which is composed of three subunits: alpha, beta, and gamma. All disease mutations either remove or alter amino acids of the target proline-rich PPPxY sequence (PY motif) of beta- or gamma-ENaC and result in increased channel activity. In this report, we present a family with Liddle's syndrome whose abnormality is caused by a novel missense mutation, P616R, in the PY motif of the betaENaC. Functional studies using the P616R mutant expressed in Xenopus oocytes showed an approximately 6-fold increase in the amiloride-sensitive sodium channel activity compared with that of the wild type. These findings provide additional clinical evidence that a conserved PY motif is critically important for the regulation of ENaC activity.

Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity

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

JOURNAL OF HYPERTENSION ( LIPPINCOTT WILLIAMS & WILKINS ) 22 ( 10 ) 1977 - 1982 2004年10月 [査読有り]

Objective Based on results of in vitro studies, it has been hypothesized that blockade of the renin-angiotensin system (RAS) promotes the recruitment and differentiation of pre-adipocytes and that increased formation of small insulin-sensitive adipocytes counteracts ectopic deposition of lipids, thereby improving insulin sensitivity. We investigated the effect of RAS blockade on insulin sensitivity, adipocyte size, and intramuscular lipid content in fructose-fed rats (FFR) as a model of insulin-resistant hypertension. Design and methods Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (control) and those fed a fructose-rich chow for 6 weeks. FFR were treated with a vehicle or with 1 mg/kg per day of temocapril, an angiotensin-converting enzyme inhibitor, or 0.1 mg/kg per day of olmesartan, an angiotensin II type 1 receptor blocker, for the last 2 weeks. Insulin sensitivity (M value: mg/kg per min) was estimated by the euglycemic hyperinsulinemic glucose clamp method. Sizes of adipocytes derived from epididymal fat and triglyceride content in the soleus muscle were determined. Results FFR had lower M value, higher blood pressure, larger adipocyte size, higher ratio of epididymal fat pads over body weight (%fat pads), and higher intramuscular triglyceride than did the control rats. Both temocapril and olmesartan significantly improved the M value and decreased blood pressure and adipocyte size without change in %fat pads in FFR. Adipocyte size was negatively correlated with the M value. Treatment for 2 weeks decreased, but not significantly, intramuscular triglyceride. Conclusions RAS blockade decreases adipocyte size without change in epididymal %fat pads accompanied by improvement in insulin sensitivity.

Possible impairment of transcardiac utilization of adiponectin in patients with type 2 diabetes

M Furuhashi, N Ura, N Moniwa, Y Shinshi, H Kouzu, M Nishihara, N Kokubu, T Takahashi, K Sakamoto, M Hayashi, N Satoh, T Nishitani, Y Shikano, K Shimamoto

DIABETES CARE ( AMER DIABETES ASSOC ) 27 ( 9 ) 2217 - 2221 2004年09月 [査読有り]

OBJECTIVE - Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS - A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS - The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic Patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS - Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.

Utility of serum ratio of heart-type fatty acid-binding protein to myoglobin for cardiac damage regardless of renal dysfunction

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

CIRCULATION JOURNAL ( BLACKWELL PUBLISHING ASIA ) 68 ( 7 ) 656 - 659 2004年07月 [査読有り]

Background The serum ratio of heart-type fatty acid-binding protein to myoglobin (F/M) has been shown to be a new marker for cardiac damage and volume overload in hemodialysis patients. We evaluated the utility of F/M in hemodialysis patients compared to control subjects. Methods and Results Twenty-one hemodialysis patients and 17 control subjects with normal renal function were investigated. Using a cutoff point of mean + 2SD of the F/M in the controls (value: 0.147), the hemodialysis patients were divided into 2 groups. The concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide after hemodialysis in the high F/M group were higher than those in the low F/M group. The mean level of ANP in the low F/M group was almost the upper limit of normal range. The values of left ventricular end-diastolic dimension and left ventricular mass index in the high F/M group were higher than those in the low F/M group, and the mean levels of those in the low F/M group were almost the same as those in the controls. Conclusions The F/M can be evaluated by the absolute value regardless of renal dysfunction, and the value of 0.147 might be useful for determining the cutoff level of cardiac involvement.

血液透析患者におけるアディポネクチンの意義

林学, 古橋眞人, 西谷隆宏, 神津英至, 西原昌宏, 高橋亨, 坂本賢一, 佐藤直利, 鹿野泰邦, 茂庭仁人, 浦信行, 島本和明

日本透析医学会雑誌 ( (一社)日本透析医学会 ) 37 ( Suppl.1 ) 909 - 909 2004年05月

血液透析及び腹膜透析患者におけるアディポネクチン濃度

西谷隆宏, 古橋眞人, 林学, 神津英至, 西原昌宏, 高橋亨, 坂本賢一, 佐藤直利, 鹿野泰邦, 茂庭仁人, 浦信行, 島本和明

日本透析医学会雑誌 ( (一社)日本透析医学会 ) 37 ( Suppl.1 ) 796 - 796 2004年05月

糖尿病患者におけるアディポネクチン利用障害(Impaired Utilization of Adiponectin in Patients with Diabetes Mellitus)

Furuhashi Masato, Ura Nobuyuki, Takagawa Yoshitoki, Moniwa Norihito, Kouzu Hidemichi, Takahashi Toru, Sakamoto Ken-ichi, Hayashi Manabu, Satoh Naotoshi, Nishitani Takahiro, Shikano Yasukuni, Shinshi Yashuyuki, Kokubu Nobuaki, Shimamoto Kazuaki

Circulation Journal ( (一社)日本循環器学会 ) 68 ( Suppl.I ) 241 - 241 2004年03月

Circulating resistin levels in essential hypertension

Masato Furuhashi, Nobuyuki Ura, Katsuhiro Higashiura, Hideyuki Murakami, Kazuaki Shimamoto

CLINICAL ENDOCRINOLOGY ( BLACKWELL PUBLISHING ) 59 ( 4 ) 507 - 510 2003年10月 [査読有り]

OBJECTIVE Resistin, a novel cysteine-rich protein secreted by adipocytes, has been proposed to serve as a link between obesity and insulin resistance in rodents, but this has remained controversial. Most of the data obtained in previous studies are restricted to mRNA levels in tissues. DESIGN AND PATIENTS We examined the association between insulin resistance and circulating protein levels of resistin in 33 essential hypertensive patients (EHT) and 18 normotensive subjects (NT). insulin sensitivity (M-value) was evaluated by the euglycaemic hyperinsulinaemic glucose clamp technique. RESULTS Using a cutoff point of mean - 1 SD of the M-value in the NT, the EHT were divided into two groups: one group of 12 insulin-resistant patients (EHT-R) and one group of 21 noninsulin-resistant patients (EHT-N). There were no intergroup differences in age, gender, body mass index (BMI; range: 20.1-30.4 kg/m(2)), fasting glucose and total cholesterol. The EHT-R had significantly higher levels of fasting insulin and triglyceride than did the NT and the EHT-N. The EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein cholesterol than did the EHT-N. The M-value was negatively correlated with fasting insulin, free fatty acid, and triglyceride. Circulating resistin levels were not significantly different among the three groups and were not correlated with the M-value, BMI, blood pressure, or lipid variables. CONCLUSIONS Our results suggest that circulating resistin levels are not related to insulin resistance, at least in patients with essential hypertension, although disturbance of lipid metabolism may be associated with insulin resistance.

Right bundle branch block and coved-type ST-segment elevation mimicked by acute cholecystitis

M Furuhashi, K Uno, S Satoh, K Hoshikawa, E Sakai, K Tsuchihashi, K Shimamoto

CIRCULATION JOURNAL ( BLACKWELL PUBLISHING ASIA ) 67 ( 9 ) 802 - 804 2003年09月 [査読有り]

A 69-year-old woman had acute cholecystitis that mimicked right bundle branch block with coved-type ST-segment elevation in the precordial electrocardiogram leads (Brugada-type ST shift). The patient did not have obvious heart disease, syncope, or a family history of sudden death. The coved-type ST-segment elevation disappeared as the acute inflammation subsided. Intravenous administration of pilsicainide, a pure sodium channel blocker, could reproduce the Brugada-type ST shift. This is the first report of the Brugada-type ST shift occurring in association with acute cholecystitis.

Role of adiponectin in insulin-resistant hypertension and atherosclerosis

H Murakami, N Ura, M Furuhashi, K Higashiura, T Miura, K Shimamoto

HYPERTENSION RESEARCH ( JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE ) 26 ( 9 ) 705 - 710 2003年09月 [査読有り]

Insulin resistance is one of the major risk factors associated with development of hypertension and atherosclerosis. Recent studies have shown that adiponectin, an adipocyte-derived hormone, may be involved in insulin resistance and development of atherosclerosis in diabetes patients. The aim of this study was to examine adiponectin levels in patients with essential hypertension to determine the relationships between adiponectin levels and insulin sensitivity and to examine the relationship of adiponectin with pulse wave velocity (PWV) in a general population based on the results of an epidemiological survey in Japan. In a clinical study, 20 normotensives (NT) and 30 non-treated essential hypertensives (EHT) were hospitalized, and euglycemic hyperinsulinemic glucose clamp (GC) was performed to evaluate insulin sensitivity defined as M value. EHT were divided into insulin-resistant EHT (EHT-R) and insulin-nonresistant EHT (EHT-N) according to the mean -1 SD of the M value of NT as a cut-off point. Fasting plasma glucose (FPG), immunoreactive insulin (IRI), and adiponectin concentrations were measured. There were no significant differences in body mass index (BMI) or FPG among the NT, EHT-N, and EHT-R groups. The M value and adiponectin concentration in EHT-R were significantly lower than those in the NT or EHT-N. The IRI level in the EHT-R was significantly higher than those in the other groups. A positive correlation between adiponectin concentration and M value was found in all subjects, and adiponectin concentration and M value were found to be significant determinants of each other in multiple regression analysis. In an epidemiological study, we studied 391 male inhabitants of rural communities in Hokkaido, Japan. Systolic blood pressure (SBP), BMI, FPG, IRI, and adiponectin were measured in all subjects early in the morning. Homeostasis model assessment (HOMA) values were calculated as an index of insulin sensitivity, and PWV was used as an index of atherosclerosis. A negative correlation between HOMA values and adiponectin concentration was found in all of the subjects. Multiple regression analysis revealed that adiponectin was a significant determinant for PWV in subjects less than 70 years of age. The results of the clinical study indicate that EHT-R had not only hyperinsulinemia but also a low concentration of adiponectin. The results of multiple regression analysis for determinants of degree of PWV using data obtained in the epidemiological study suggest that adiponectin plays a role in antiatherosclerosis, partly through improvement of insulin resistance.

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