Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model.

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.

Specificity assessment of immunoassay kits for determination of urinary free cortisol concentrations.

BACKGROUND: In immunoassay kits for determination of urinary free cortisol (UFC) concentrations, the results vary markedly from kit to kit, so we compared in this study the reaction specificity among 4 commercially available immunoassay kits to determine the applicability of these assays in routine determination of UFC concentrations. METHOD: Using 4 commercially available kits, cross-reaction was investigated. In addition, urine samples were fractionated by HPLC to investigate endogenous immunoreactive cortisol responses. HPLC fractions were subjected to gas chromatography-mass spectrometry (GCMS) to identify substances causing inter-kit assay discrepancies. RESULTS: Among the 4 kits, cortisol Kit "TFB" (Immunotech; IOT-RIA method) showed the lowest cross-reaction (2.5%) for prednisolone. Furthermore, on HPLC, 87.8% of the reaction of the entire fraction was seen in the fractions corresponding to the elution position of standard cortisol with the IOT-RIA method; this was the highest percentage among the 4 kits. GCMS revealed that the substance that showed a cross-reaction with the other 3 kits was 5alpha-tetrahydrocortisol (5alpha-THF) glucuronide. CONCLUSIONS: The IOT-RIA method was found to be the most specific for UFC. The other 3 commercially available kits showed cross-reaction with a conjugate of 5alpha-THF, found to be one of the causes of inter-kit assay discrepancies.

Anti-albuminuric effect of losartan versus amlodipine in hypertensive Japanese patients with type 2 diabetes mellitus: A prospective, open-label, randomized, comparative study.

UNLABELLED: Abstract. BACKGROUND: The antiproteinuric effect of the angiotensin II receptor-antagonist losartan has been observed in patients with type 2 diabetes mellitus (T2DM). Proteinuria is considered to be a predictor of the progression of kidney disease. OBJECTIVE: The aims of the present study were to compare and examine the ability of losartan and amlodipine to ameliorate albuminuria in hypertensive Japanese patients (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) with T2DM and whether the change in albuminuria was associated with a change in glomerular filtration rate (GFR). METHODS: This prospective, open-label, randomized, comparative study was conducted over 3 months at the Kinki University School of Medicine, Osaka-Sayama, Japan. Hypertensive patients with T2DM were enrolled and randomly assigned to 1 of 2 study groups receiving either losartan (25-100 mg/d) or the calcium channel-blocker amlodipine (2.5-5 mg/d). Urinary albumin excretion (UAE), creatinine clearance, and GFR were recorded at study initiation (baseline) and study end (month 3). The GFR was measured from the fractional renal accumulation of (99m)Tc-diethylenetriaminepentaacetic acid. Adverse events (AEs) were monitored by a clinical research nurse during the examination. RESULTS: Fifty patients were asked to enroll and 38 returned the informed written consent. Thirty-five Japanese patients were included in the final study analysis. Seventeen patients were assigned to the losartan group (male sex, 10 [58.8%]; mean [SD] age, 58.1 [8.2] years) and 18 were assigned to the amlodipine group (male sex, 10 [55.6%]; mean [SD] age, 57.4 [8.9] years); no significant between-group difference in demographics was observed. A significant decrease from baseline to month 3 of mean (SD) UAE was observed in the losartan group (352.5 [556.6] mg/d vs 275.7 [466.1] mg/d; P = 0.048). No significant difference in mean (SD) UAE was observed in the amlodipine group for the same time period (298.2 [416.6] mg/d vs 322.7 [415.4] mg/d). There was a statistically significant difference found in the mean (SD) percent change of UAE from baseline to month 3 in the losartan group compared with the amlodipine group (-23.52 [28.42] vs +27.90 [63.51]; P = 0.004). Neither group was associated with a significant change in GFR during the course of the study. No patient discontinued the study due to AEs that were considered, by the investigator, to be possibly or probably associated with study treatment. CONCLUSIONS: Treatment with losartan, but not amlodipine, was associated with a reduction in albuminuria in these hypertensive Japanese patients with T2DM within a period as short as 3 months. Neither drug was associated with a significant change in GFR. Therefore, the reduction of UAE was independent of a change in the GFR.

Genetic variation in the renin-angiotensin system and autonomic nervous system function in young healthy Japanese subjects.

CONTEXT: The renin-angiotensin system (RAS) interacts with the autonomic nervous system (ANS) in the regulation of blood pressure and cardiovascular function. Several genetic polymorphisms in the RAS have been identified and have been implicated as a cause of hypertension and cardiovascular disease. OBJECTIVE: The aim of the present study was to evaluate the relation between genetic polymorphisms of the RAS (M235T of AGT gene, insertion/deletion of ACE gene, A1166C of AT1R gene, and A1675G of AT2R gene) and ANS function. SUBJECTS: One hundred forty-nine young healthy Japanese males were genotyped for each RAS polymorphism. MAIN OUTCOME MEASURES: ANS function was evaluated by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. RESULTS: In a supine position, subjects homozygous for the AGT 235T allele had a higher HRV sympathetic index than 235M allele carriers, whereas the orthostatic change in this index was relatively blunted in AGT 235TT carriers. In the analysis of gene-gene interaction, these effects of the AGT 235T homozygotes on HRV sympathetic index were more apparent in the presence of the ACE D allele. Meanwhile, the AT1R 1166C allele was significantly associated with higher HRV low-frequency power and sympathetic index in a standing position. These data suggest that the AGT M235T polymorphism is associated with sympathetic predominance at rest, and AT1R 1166C allele carriers have potentially increased sympathetic response. CONCLUSIONS: Cardiac autonomic function can be modulated by genetic variation in the RAS even in young and healthy states.

Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity.

Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.

Sucrase-isomaltase gene expression is inhibited by mutant hepatocyte nuclear factor (HNF)-1alpha and mutant HNF-1beta in Caco-2 cells.

Hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta are concerned in sucrase-isomaltase (SI) gene expression, and directly bind two sites (SIF2, SIF3) of the promoter of the SI gene. However, it is not completely clear that HNF-1alpha and HNF-1beta play a role in regulation of SI gene expression. To clarify mechanisms of SI gene expression regulated by HNF-1alpha and HNF-1beta, we established four stable cell lines based on enterocyte-like cell line Caco-2, in which wild HNF-1alpha or wild HNF-1beta, or else mutant HNF-1alphaT539fsdelC or mutant HNF-1betaR177X was overexpressed. In the HNF-1alphaT539fsdelC cells and HNF-1betaR177X cells, but not in the wild HNF-1alpha cells and wild HNF-1beta cells, SI gene expression and enzyme activity were significantly diminished compared with that in Caco-2 cells. Moreover, to clarify whether or not stable cell differentiation was influenced by overexpression of these transgenes, alkaline phosphatase (ALP) gene expression and enzyme activity were measured. There were no changes in ALP gene expression or enzyme activity in these cells. These observations suggest that mutant HNF-1alphaT539fsdelC and mutant HNF-1betaR177X inhibits SI gene at the transcriptional level, resulting in decreased SI enzyme activity in Caco-2 cells. We propose that both HNF-1alpha and HNF-1beta would contribute to constitutive expression of the SI gene in the differentiated state in Caco-2 cells.

Renal rupture associated with a poorly differentiated follicular thyroid carcinoma metastasizing to the thigh muscle, lung and kidney.

A 76-year-old woman with a history of total thyroidectomy for a thyroid carcinoma at the age of 63 was admitted to our hospital for the treatment of a renal rupture induced by a tumor of about 3 cm in diameter. High levels of blood thyroglobulin (Tg>1,000 ng/ml) led us to suspect a recurrence of thyroid carcinoma. Strong accumulation in whole-body 123I and 201Tl scintigraphy scans after the nephrectomy revealed tumors in the right lung and left thigh muscle measuring 5 cm and 9 cm in diameter, respectively. The tumors of the kidney and thigh muscle were pathologically diagnosed as poorly differentiated follicular thyroid carcinoma, and the lung tumor was also suggested to be a metastasis of the thyroid carcinoma based on the scintigraphy findings. We report this rare case of follicular thyroid carcinoma associated with metastases to the thigh muscle and kidney leading to a rupture 13 years after a total thyroidectomy. Care should be taken to determine whether unknown tumors are thyroid carcinoma metastases.

Type 1 diabetes associated with asymptomatic acromegaly successfully treated with surgery after pregnancy: a case report.

We report a rare case of type 1 diabetes in a woman associated with acromegaly who was treated with surgery after pregnancy. An 18-year-old woman came to our hospital in April, 1998, complaining of thirst, polydipsia, polyuria, appetite loss, body weight loss of 8 kg in a month, and amenorrhea beginning 2 months earlier. Based on laboratory data, she was diagnosed as having type 1 diabetes mellitus. Although we suspected her of having acromegaly because of high growth hormone (GH) levels (6.9 or 8.5 ng/ml), blood levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were within normal range and the circadian rhythm of her blood GH levels was normally maintained. Her blood GH level was elevated to 12.6 ng/ml 15 minutes after a TRH administration. Blood GH levels were suppressed from 49 ng/ml to 1.5 ng/ml 4 hours after an oral administration of 2.5 mg of bromocriptine. A magnetic resonance images (MRIs) showed pituitary swelling, but no nodules were found in the pituitary. Therefore, we diagnosed her as having acromegaly and observed her without surgery, while prescribing diet therapy and intensive insulin therapy for diabetes. We started a treatment of oral administration of 7.5 mg of bromocriptine per day for the acromegaly from April 28, 2000, because her elevated GH was suspected of causing her diabetes to be poorly controlled. During a pregnancy from October, 2000 to September, 2001, diabetic control was improved with increased administration of insulin under a constant dose of bromocriptine. She delivered a normal full-term infant. After the bromocriptine therapy was stopped as she hoped to breastfeed, blood levels of GH and IGF-1 became elevated and her diabetic control deteriorated. As her pituitary tumor observed in pituitary MRIs became larger during the course, a transsphenoidal surgery was performed on March 8, 2002. After the surgery, blood levels of GH and IGF-1 lowered and diabetic control improved again. We concluded as follows: to rule out acromegaly in patients with poorly controlled diabetes, 1) measurements of serum GH and IGF-1 should be performed, and 2) pituitary MRIs should be performed if blood levels of GH or IGF-1 are high.

Gonadal hormones and gonadal function in type 2 diabetes model OLETF (Otsuka Long Evans Tokushima Fatty) rats.

Gonadal functions, with special reference to blood levels of sex-related markers such as 17beta-estradiol (E2), free testosterone (free Te) and lutenizing hormone (LH), were examined in male OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats, a model of human type 2 diabetes mellitus. Male rats of the OLETF strain and male rats of the LETO strain, which act as a control of OLETF, both supplied by Otsuka Pharmaceutical Co., Ltd. (Tokushima, Japan), were periodically examined for blood levels of E2, free Te and LH at the age of 4, 5, 32, 40 and 64 weeks. The weight of the testis, the number of sperm contained within and histological findings of the testis were comparatively studied in both strains. Glucose and insulin (IRI) at fasting were examined to evaluate the homeostasis model assessment (HOMA) index. In order to investigate any sex hormone imbalance, sex hormone-binding globulin (SHBG) was measured by a dextran- charcoal assay. All of the OLETF rats became diabetic at the age of 32 weeks. There were no significant differences between OLETF and LETO rats regarding free Te, E2, LH or SHBG during the observation period from 4 to 64 weeks. Testis weight was significantly decreased in OLETF rats at 32 and 64 weeks and sperm counts at 64 weeks of age were also significantly decreased. Histologically, there was seminiferous tubule atrophy in the OLETF rats at 64 weeks of age. A significant negative correlation between testis weight and fasting blood glucose, as well as HOMA index, was observed in OLETF rats. In male diabetic OLETF rats, with a variety of hypogonadisms such as atrophy of the testis and low sperm count, the serum levels of E2, free Te, LH and SHBG were normally preserved.

Association of C825T polymorphism of G protein beta3 subunit with the autonomic nervous system in young healthy Japanese individuals.

BACKGROUND: The T allele of the C825T polymorphism of the G protein beta3 subunit gene (GNB3) is reported to be associated with increased intracellular signal transduction and the prevalence of essential hypertension. Because the two major receptors in the autonomic nervous system (ANS), the adrenergic and muscarinic acetylcholine receptors, are G protein-coupled receptors, it was expected that the GNB3 C825T polymorphism was associated with ANS function. In the present study, we have investigated the association of this polymorphism with ANS in young, healthy Japanese male individuals. METHODS: A total of 94 young, healthy subjects underwent the genotyping for the GNB3 C825T polymorphism and electrocardiogram R-R interval power spectral analysis in supine rest and standing positions. RESULTS: There were no significant differences among genotypes in any of the characteristics investigated (body mass index, blood pressure, plasma glucose, insulin, lipids, and family history of hypertension, diabetes, or obesity). However, in power spectral analysis of heart rate variability, the very-low-frequency component when standing was higher in TT carriers than in CC carriers, and TT and CT carriers had a significantly higher sympathetic nervous system (SNS) index and lower parasympathetic nervous system (PNS) index when standing than CC carriers. In addition, we found that TT carriers showed no chronological variations in either SNS or PNS index after postural change. CONCLUSIONS: These observations suggested that GNB3 C825T polymorphism is associated with ANS in youth. These findings raise the possibility that individuals who are T allele carriers are at increased risk for developing hypertension in relation to ANS function.

Promoting insulin secretion in pancreatic islets by means of bisphenol A and nonylphenol via intracellular estrogen receptors.

In this study, we investigated the effects of endocrine disrupters bisphenol A (BPA) and nonylphenol (NP) on insulin secretion from rat pancreatic islets. Following acute exposure to BPA and NP, neither BPA nor NP (0.1, 1, 10, 100 and 1000 microg/l) affected insulin secretion in concentrations of 16.7 mM glucose. However, insulin secretion following long-term exposure to BPA or NP for 24 h in 16.7 mM glucose was significantly higher than without exposure. To determine whether increased insulin secretion resulting from long-term exposure to BPA and NP is induced via intracellular estrogen receptors, we blocked the cytosolic/nuclear estrogen receptors, using actinomycin-D (Act-D), an inhibitor of RNA synthesis, and ICI 182,780 (ICI), an estrogen receptor inhibitor. Following long-term exposure to BPA (10 microg/l) or NP (10 microg/l), Act-D or ICI treatment eliminated the facilitation of insulin secretion. In conclusion, we have demonstrated for the first time that long-term exposure to endocrine disrupters, such as BPA and NP, promotes in vitro insulin secretion from the pancreatic islets, via cytosolic/nuclear estrogen receptors.

Effect of mutations in HNF-1alpha and HNF-1beta on the transcriptional regulation of human sucrase-isomaltase in Caco-2 cells.

Mutations in transcription factors hepatocyte nuclear factors (HNF)-1alpha and HNF-1beta cause maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. HNF-1alpha and HNF-1beta mutations are well studied in some tissues, but the mechanism by which HNF-1alpha and HNF-1beta mutations affect sucrase-isomaltase (SI) transcription in the small intestine is unclear. We studied the effects of 13 HNF-1alpha mutants and 2 HNF-1beta mutants on human SI gene transcription, which were identified in subjects with MODY3 and MODY5, respectively. Transactivation activity of 11 HNF-1alpha and 2 HNF-1beta mutants was significantly lower than that of wild (wt)-HNF-1alpha and wt-HNF-1beta. Furthermore, in co-expression studies with mutant (mu)-HNF-1alpha/ wt-HNF-1beta and wt-HNF-1alpha/mu-HNF-1beta, the combination of mu-HNF-1alpha (P379fsdelCT and T539fsdelC)/wt-HNF-1beta impaired SI transcription, but the others were not remarkably different from wt-HNF-1alpha/wt-HNF-1beta. Although wt-HNF-1beta inhibited the transactivation activity of wt-HNF-1alpha on SI transcription, the inhibitory effect was reduced by 2 HNF-1beta mutants. These results suggest that SI transcription might tend to be unchanged or lower in MODY3, while occurring more in MODY5.

T393C polymorphism of GNAS1 associated with the autonomic nervous system in young, healthy Japanese subjects.

1. T393C polymorphism of the gene encoding the Gs-protein alpha-subunit (GNAS1) has been reported recently to be associated with hypertension in which dysfunctions of the autonomic nervous system (ANS) are closely involved. In the present study, the association of this polymorphism with ANS activity was investigated in young, healthy Japanese males. 2. Four hundred and one subjects were genotyped for the T393C polymorphism of GNAS1 by polymerase chain reaction-restriction fragment length polymorphism. Autonomic nervous system activity during supine rest and when standing was assessed in 137 subjects by electrocardiogram R-R interval power spectral analysis. 3. One hundred and fifty-four subjects (38.4%) were homozygous for the T allele (TT), 188 (46.9%) were heterozygous (TC) and 59 (14.7%) were homozygous for the C allele (CC). There were no significant differences as to genotype among the clinical characteristics investigated. In power spectral analysis of heart rate variability, the high-frequency component and parasympathetic nervous system (PNS) index during supine rest were significantly lower in TT and TC carriers than in CC carriers. Furthermore, the increase in heart rate and the responsiveness of sympathetic nervous system index and PNS index to postural change from supine rest to standing were significantly lower in TT and TC carriers than in CC carriers. 4. These observations suggest that the GNAS1 T393C polymorphism is associated with ANS activity in youth, so that it may be useful as a genetic marker for future pathogenesis of hypertension. Follow-up studies are necessary to clarify the prevalence rates of hypertension among 393T allele carriers in the present study.

Anaplastic thyroid carcinoma with humoral hypercalcemia of malignancy (HHM): an autopsy case report.

An 84-year-old woman was admitted to our hospital for the examination and treatment of painful right thyroid swelling on August 2, 2002. Thyroid ultrasonography showed a mass of about 6 cm in diameter at the right thyroid lobe. Aspiration biopsy cytology (ABC) of her mass showed a thyroid carcinoma. Her neck mass was cold on (123)I scintigraphy and hot on both early- and delayed- phase (201)Tl scintigraphy. Whole body (67)Ga scintigraphy scan showed a strong hot accumulation in the area from the right thyroid lobe to the right lateral lobe. Multiple lung tumors were observed from chest computed tomography (CT) scans. She was diagnosed as having an anaplastic thyroid carcinoma with metastatic lung tumors. As her thyroid carcinoma was inoperable, percutaneous injection therapy of lipiodol and ethanol (lip-PEIT) against the primary thyroid carcinoma was performed twice a week. However, the thyroid carcinoma gradually enlarged and oppressed her trachea. Two months after the initiation of lip-PEIT, parathyroid hormone-related protein (PTHrP)-dependent hypercalcemia was diagnosed because serum levels of calcium, phosphate and intact-PTHrP were 2.72 mmol/l (10.9 mg/dl), 0.71 mmol/l (2.2 mg/dl), 3.2 pmol/l, respectively. The hypercalcemia was reduced by the use of pamidronate. After one week she died of an airway obstruction caused by the developing thyroid carcinoma. Carcinoma cells with a mixed papillary and squamoid pattern were positively stained immunohistochemically by anti-PTHrP(1-34) antisera. Herein, we report a rare autopsy case of a PTHrP-producing thyroid carcinoma.

Two cases of monostotic Paget's disease: effects of bisphosphonate.

We report two cases of monostotic Paget's disease which were effectively treated with bisphosphonate. Case 1 was a 60-year-old female. Medical examination revealed high alkaline phosphatase (ALP) levels making her visit our clinic. Hematological examination showed high levels of ALP isozyme 3 and bone metabolism markers, and bone scintigraphy demonstrated strong accumulation of 99mTc on the skull. With the diagnosis of monostotic Paget's disease of the skull, treatment with bisphosphonate (etidronate) was started. The response to etidronate was good and after 12 weeks of treatment, the ALP levels decreased to about 26% of the levels before treatment, without the appearance of any symptoms or lesion development. One year and three months later, ALP increased again, and etidronate administration was resumed. However, four years after the diagnosis of the disease, etidronate became ineffective and oral administration of alendronate, a stronger bisphosphonate, was started at 5 mg/day. The patient responded favorably to the bisphosphonate and is still under observation. Case 2 was a 71-year-old female. High ALP levels were found during the follow-up of type 2 diabetes, and the case was diagnosed as monostotic Paget's disease of the pelvis based on bone metabolism markers and bone scintigraphy. Etidronate treatment at 200 mg/day resulted in the improvement of bone metabolism markers and bone scintigraphy findings. When she died of colon cancer twelve months later, with no marked progress of the Paget's disease of bone observed clinically.

The effect of leptin, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production on insulin resistance in Otsuka Long-Evans fatty rats.

Adipocytokines and nitric oxide (NO) play important roles in type 2 diabetes; however, the regulatory mechanism has not been fully clarified. To investigate the role of adipocytokines and NO production on insulin resistance in type 2 diabetes, the LETO rats and the OLETF rats were fed a control diet or a high-fat diet for 4 weeks. After 4 weeks the blood levels of leptin, tumor necrosis factor-alpha (TNF-alpha), and NO were measured. As an indicator of insulin resistance, the homeostasis model assessment for insulin resistance (HOMA-R) was applied. Food intake in high-fat diet group rats was lower than in control diet group rats. The high fat diet increased body weight (BW), but did not significantly affect the HOMA-R and blood pressure (BP). Leptin and TNF-alpha levels were significantly higher in the OLETF rats than in the LETO rats, while NO levels did not change between the two groups. The high-fat diet elevated blood leptin levels, but not TNF-alpha and NO levels. The HOMA-R in the OLETF rats was correlated with leptin, but not with BP, BW, TNF-alpha or NO. NO showed an inverse correlation with BP. In conclusion, leptin, TNF-alpha, and NO may each regulate insulin sensitivity through their own unique pathways. The elucidation of the regulatory mechanism of adipocytokines and NO may give a clue to clarify the pathophysiology of insulin resistance.