Michio Otsuki

Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients.

Abnormal glucose tolerance is often demonstrated in acromegalic patients. Although insulin resistance is a common feature of acromegaly, it remains unclear whether the extent of insulin resistance per se determines the abnormal glucose tolerance. In order to elucidate this issue, we investigated insulin sensitivity and β‐cell function in acromegalic patients.

Characterization of premature atherosclerosis of carotid arteries in acromegalic patients

OBJECTIVE Acromegalic patients have increased mortality from vascular diseases. Although atherosclerotic risk factors such as hypertension, diabetes mellitus and dyslipoproteinaemia are highly associated with acromegaly, the prevalence of premature atherosclerosis in acromegalic patients and its relationship to these risk factors have not been reported.

Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-κB binding to its recognition sequence

Cilostazol is a specific inhibitor of cAMP phosphodiesterase, which is used for treatment of ischemic symptoms of peripheral vascular disease. Although cilostazol has antiplatelet and vasodilator properties, its effect on the expression of adhesion molecules in vascular endothelium is not known. In the present investigation, we examined the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured vascular endothelial cells. Cilostazol strongly inhibited tumor necrosis factor (TNF)-alpha-induced expression of VCAM-1 protein and its mRNA. In addition, cilostazol reduced TNF-alpha-induced U937 cell adhesion to the vascular endothelial cells. In transient transfection studies, cilostazol inhibited TNF-alpha-induced transcriptional activation of VCAM-1 promoter. Electrophoretic mobility shift assays revealed that cilostazol repressed TNF-alpha-induced increase in binding of the transcription nuclear factor-kappaB (NF-kappaB) to its recognition site of VCAM-1 promoter. Cilostazol, however, failed to prevent nuclear translocation of the NF-kappaB p65 protein. These data indicate that cilostazol repressed VCAM-1 gene transcription in cultured vascular endothelial cells, via inhibiting NF-kappaB binding to its recognition sequence. Since the expression of the adhesion molecule is one of the earliest events occurred in atherogenic process, cilostazol might have the potential to prevent atherosclerosis at least via inhibition of the expression of the adhesion molecule.

PPARα and GR Differentially Down-Regulate the Expression of Nuclear Factor-κB-Responsive Genes in Vascular Endothelial Cells

The antiinflammatory action of glucocorticoids is mediated partly by the inhibition of the expression of several cytokines and adhesion molecules. Some activators for nuclear receptors other than the GR have also been shown to inhibit the expression of these inflammatory molecules, although their molecular mechanisms remain unidentified. We therefore examined the effects of the PPARα activator fenofibrate and the GR activator dexamethasone on TNFα-stimulated expression of IL-6 and vascular cell adhesion molecule-1 in vascular endothelial cells. Both fenofibrate and dexamethasone reduced TNFα-induced IL-6 production in human vascular endothelial cells, but only fenofibrate reduced TNFα-stimulated vascular cell adhesion molecule-1 expression in these cells. Transient transfection of bovine aortic endothelial cells with an IL-6 promoter construct or a vascular cell adhesion molecule-1 promoter construct revealed that fenofibrate inhibited TNFα-induced IL-6 promoter as well as vascular cell adhesion molecule-...

Progesterone, but Not Medroxyprogesterone, Inhibits Vascular Cell Adhesion Molecule-1 Expression in Human Vascular Endothelial Cells

Abstract —It has been shown that ovarian steroid hormones can reduce the incidence of cardiovascular disease in postmenopausal women. As hormone replacement therapy for postmenopausal women, progestins are added to estrogens to eliminate the increased risk of endometrial cancer. However, the effects of progestins on the atherogenic process have not been well understood. In the present study, we examined the effects of progestins on the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Immunocytochemical analysis revealed the presence of progesterone receptors in HUVECs. Progesterone clearly inhibited tumor necrosis factor-&agr;–activated expression of VCAM-1 protein and its mRNA in HUVECs. Synthetic progesterone receptor agonist R5020 also inhibited the tumor necrosis factor-&agr;–activated VCAM-1 expression, whereas medroxyprogesterone acetate (MPA) failed to do so. Electrophoretic mobility shift assays demonstrated that progesterone, but not MPA, inhibited DNA binding of the transcription nuclear factor-&kgr;B, which is critical for the inducible expression of VCAM-1. Because the expression of VCAM-1 is one of the earliest events that occurs in the atherogenic process, this adhesion molecule might be a target molecule for progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of hormone replacement therapy.

Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves' disease.

It has been shown that vitamin D deficiency is associated with autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS) and type 1 diabetes (T1DM), and that vitamin D supplementation prevents the onset and/or development of these autoimmune diseases [1]. Furthermore, it was reported more recently that patients with Hashimoto’s thyroiditis, an autoimmune thyroid disease had lower vitamin D levels [2]. However, there are few studies examining vitamin D status in patients with newly onset Graves’ disease. In the present study, we evaluated the vitamin D status in female patients with newly onset GD and the association of serum vitamin D levels with the clinical factors related to GD.

Relationship between circulating vascular cell adhesion molecule‐1 and microvascular complications in Type 2 diabetes mellitus

The soluble form of the vascular cell adhesion molecule‐1 (VCAM‐1) is detectable in human sera and is elevated in diabetic patients, with unknown clinical significance. In the present study, the relationship between serum soluble VCAM‐1 and diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) was evaluated in 95 Japanese patients with Type 2 diabetes mellitus (DM). Serum soluble VCAM‐1 concentration was higher in patients with more advanced stages of retinopathy as well as nephropathy. There was a significant correlation between soluble VCAM‐1 and log10 (urinary albumin excretion) in 69 patients with normal serum creatinine levels (r = 0.51, p<0.0001) and a significant correlation between soluble VCAM‐1 and log10 (serum creatinine) in all the patients (r = 0.83, p<0.0001). Soluble VCAM‐1 concentration was also elevated in patients with neuropathy. There was a significant correlation between soluble VCAM‐1 concentration and the number of microvascular complications (r = 0.59, p<0.0001). However, multivariate regression analysis revealed that only diabetic nephropathy, was associated with the soluble VCAM‐1 concentration. The elevation of circulating VCAM‐1 level in diabetic nephropathy may result from underlying systemic endothelial dysfunction, increased VCAM‐1 production in damaged renal tubular or glomerular epithelial cells and/or decreased renal clearance of this molecule, depending on the stage of nephropathy.

Menopause, but not age, is an independent risk factor for fasting plasma glucose levels in nondiabetic women.

Objective:Glucose metabolism is influenced by various genetic and environmental factors. In women the prevalence of abnormal glucose metabolism is known to increase around and after age 50. The aim of this study was to determine whether menopause augments fasting plasma glucose (FPG) levels in women. Design:Of 672 Japanese women who underwent health examinations, we studied 505 nondiabetic participants who had no history of hysterectomy and had never used estrogens or progestins. All participants were administered an oral glucose tolerance test, and their blood measurements and information about their menopause status were obtained. Results:Of these 505 women, 208 were premenopausal and 297 were postmenopausal. Age, body mass index, triglycerides level, total cholesterol level, low-density lipoprotein cholesterol level, blood pressure, and homeostasis model assessment insulin sensitivity index rose across quintiles of FPG levels, whereas high-density lipoprotein cholesterol level and homeostasis model assessment pancreatic &bgr;-cell function index did not. The number of premenopausal women declined and the number of postmenopausal women increased across quintiles of FPG levels. Univariate regression analysis demonstrated that age, body mass index, triglycerides level, low-density lipoprotein cholesterol level, and menopause status were associated with FPG level, whereas high-density lipoprotein cholesterol level was not. Stepwise multivariate regression analysis showed that the independent risk factors for elevated FPG levels were body mass index, menopause, and triglycerides level, whereas age and low-density lipoprotein cholesterol level did not contribute to FPG levels. Conclusions:Menopause, but not age, is directly involved in augmented FPG levels in nondiabetic women.

Serum vitamin D levels are decreased in patients without remission of Graves’ disease

Graves’ disease (GD) is an autoimmune thyroid disease in which thyrotropin receptor autoantibodies (TRAb) cause hyperthyroidism. Although medical treatment with antithyroid drugs (ATD) is the first choice treatment for GD in Japan and Europe, a remission rate of GD with ATD is not satisfactory, and many patients need long-term treatment with ATD or further treatments such as radioactive iodine therapy or thyroidectomy [1]. Therefore, it is very important to identify the factors relating to the remission of GD. It has been recently shown that vitamin D deficiency is associated with the onset and/or development of several autoimmune diseases, including multiple sclerosis (MS), inflammatory bowel disease (IBD), and type 1 diabetes (T1DM) [2]. Furthermore, it has been reported more recently that patients with autoimmune thyroid diseases including GD have lower vitamin D status [3, 4]. However, there is no study comparing vitamin D status between the patients with and without remission of GD. In the present study, we examined vitamin D status in female patients with and without remission of GD and discussed the role of vitamin D in the pathogenesis and/or prognosis of GD.

Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell death-inducing DNA fragmentation factor, α-subunit-like effector A

Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor alpha target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.