Akira Shimatsu

Lymphocytic Infundibuloneurohypophysitis as a Cause of Central Diabetes Insipidus

BACKGROUND Central diabetes insipidus may be familial, secondary to hypothalamic or pituitary disorders, or idiopathic. Idiopathic central diabetes insipidus is characterized by selective hypofunction of the hypothalamic-neurohypophysial system, but its cause is unknown. METHODS We studied 17 patients with idiopathic diabetes insipidus, in whom the duration of the disorder ranged from 2 months to 20 years. Only four patients had been treated with vasopressin before the study began. All the patients underwent endocrinologic studies and magnetic resonance imaging (MRI) with a 1.5-T superconducting unit, and two patients had biopsies of the neurohypophysis or the pituitary stalk. RESULTS Nine of the 17 patients had thickening of the pituitary stalk, enlargement of the neurohypophysis, or both and lacked the hyperintense signal of the normal neurohypophysis. In the remaining eight patients, the pituitary stalk and the neurohypophysis were normal, although the hyperintense signal was absent. The abnormalities of thickening and enlargement were seen on MRI only in the patients who had had diabetes insipidus for less than two years, and the abnormalities disappeared during follow-up, suggesting a self-limited process. In addition to vasopressin deficiency, two patients had mild hyperprolactinemia and nine had impaired secretory responses of growth hormone to insulin-induced hypoglycemia. The two biopsies revealed chronic inflammation, with infiltration of lymphocytes (mainly T lymphocytes) and plasma cells. CONCLUSIONS Diabetes insipidus can be caused by lymphocytic infundibuloneurohypophysitis, which can be detected by MRI. The natural course of the disorder is self-limited.

Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet

MicroRNAs (miRNAs) are short non-coding RNA that post-transcriptionally regulates gene expression. miR-143 has been proposed to play a role in the differentiation of adipocytes in culture. However, the mechanism regulating the expression of miR-143 in adult adipose tissue during the development of obesity in vivo is unknown. Here in, we showed that the expression of miR-143 in the mesenteric fat was up-regulated in mice fed a high-fat diet. Increased miR-143 expression was associated with an elevated body weight and mesenteric fat weight. Furthermore, miR-143 levels were closely correlated with expression levels of adipocyte differentiation markers such as PPARgamma and aP2 as well as plasma levels of leptin, one of the important adipocytokines involved in insulin resistance. These findings provide the first evidence for the up-regulated expression of miR-143 in the mesenteric fat of high-fat diet-induced obese mice, which might contribute to the regulated expression of adipocyte genes involved in the pathophysiology of obesity.

Molecular Mechanism of the Inhibitory Effect of Aldosterone on Endothelial NO Synthase Activity

Although the proinflammatory and profibrotic actions of aldosterone (Aldo) on the vasculature have been reported, the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined. We investigated how Aldo regulates endothelial NO synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hours with Aldo 10−7 mol/L. The concentration of reactive oxygen species was estimated by measuring 2′,7′-dichlorodihydrofluorescein diacetate chemiluminescence. Signal transduction was estimated by Western immunoblots. Real-time RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 and components of reduced nicotinamide-adenine dinucleotide phosphate oxidase. To eliminate the possible effect of the glucocorticoid receptor (GR) and to emphasize the role of mineralocorticoid receptor, we used GR small interfering RNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. Reactive oxygen species production increased significantly in Aldo-treated HUVECs but was abolished by pretreatment with eplerenone. Transcripts of p47phox were increased by Aldo treatment. Vascular endothelial growth factor–induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with Aldo. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in Aldo-treated cells, suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor. The decrease in NO output caused by Aldo pretreatment was reversed significantly by 5,6,7,8-tetrahydrobiopterin, GTP cyclohydrolase-1 overexpression, or p47phox knockdown. These results suggest that Aldo inhibits eNOS function through bimodal mechanisms of 5,6,7,8-tetrahydrobiopterin deficiency and protein phosphatase 2A activation.

Immunoreactive growth hormone (GH) secretion by human lymphocytes: Augmented release by exogenous GH

Peripheral blood mononuclear cells (PBMCs) from normal adults secreted small amounts of human growth hormone (GH; 0.2-0.6 pg/10(5) cells/7 days culture) as measured by a highly sensitive enzyme immunoassay. Stimulation of PBMCs with phytohemagglutinin (PHA) consistently showed a 4-6 fold increase in GH secretion. Transformed B-lymphocytes by Epstein-Barr virus also secreted GH (0.8-4.8 pg/5 x 10(4) cells/7 days culture). GH secreted by lymphocytes comigrated with pituitary GH on an Ultrogel AcA44 column. Addition of GH during the culture augmented endogenous GH secretion from PHA-stimulated PBMCs. GH-releasing hormone and a somatostatin analogue, SMS 201-995, did not affect GH secretion from non-stimulated and PHA-stimulated PBMCs. These findings suggest that both T and B lymphocytes secrete immunoreactive GH in a different manner from that in the anterior pituitary.

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors

BackgroundWe conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004.MethodsData on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed.ResultsNonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively.ConclusionsThe incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

Evaluation of the Cardio-Ankle Vascular Index, a New Indicator of Arterial Stiffness Independent of Blood Pressure, in Obesity and Metabolic Syndrome

Aortic stiffness is predictive of cardiovascular diseases (CVD) and mortality in lifestyle-related diseases. The cardio-ankle vascular index (CAVI), a new index of arterial stiffness, was recently developed by measuring of pulse wave velocity (PWV) and blood pressure (BP). CAVI is adjusted for BP based on stiffness parameter β and is less influenced by BP, suggesting its superiority over brachial-ankle PWV (baPWV). However, there are currently no reports on the usefulness of CAVI as an atherogenic index in obesity and metabolic syndrome (MS). Among the 325 obese Japanese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study, 216 patients (67%) met the criteria of MS according to the modified National Cholesterol Education Program–Adult Treatment Panel III. CAVI values were significantly higher in MS than in non-MS patients, whereas there was no significant difference in body mass index, total cholesterol, and low-density lipoprotein-cholesterol between both groups. CAVI values were weakly correlated with BP but closely correlated with the severity of MS and MS-related parameters such as hypoadiponectinemia, relative to baPWV. Furthermore, weight-reduction therapy through diet and exercise over a 3-month period significantly decreased CAVI values in parallel with increasing adiponectin. This study demonstrates for the first time that CAVI is a good indicator of arterial stiffness. It is closely correlated with the severity of MS and CVD risks in obesity and independent of BP, and is thus superior to baPWV. Therefore, the determination of arterial stiffness by CAVI may be useful for evaluating and managing the CVD risks of MS patients.

A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients

AIMS/HYPOTHESIS Glucagon-like peptide-1 (GLP-1) exerts beneficial effects on the cardiovascular system. Here, we examined the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on systemic inflammation and pro-inflammatory (M1)/anti-inflammatory (M2)-like phenotypes of peripheral blood monocytes in diabetic patients. METHODS Forty-eight type 2 diabetic patients were divided into the following two groups: sitagliptin-treatment (50mg daily for 3months) (n=24) and untreated control (n=24) groups. Measurements were undertaken to assess changes in glucose-lipid metabolism, serum levels of inflammatory cytokines such as serum amyloid A-LDL (SAA-LDL), C-reactive protein (CRP), interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α). Furthermore, the effects of sitagliptin treatment on M1/M2-like phenotypes in peripheral blood monocytes were examined. RESULTS Treatment with sitagliptin significantly decreased fasting plasma glucose, hemoglobin A1c (HbA1c), serum levels of inflammatory markers, such as SAA-LDL, CRP, and TNF-α. In contrast, sitagliptin increased serum IL-10, an anti-inflammatory cytokine, as well as plasma GLP-1. In addition, sitagliptin increased monocyte IL-10 expression and decreased monocyte TNF-α expression. Multivariate regression analysis revealed that the sitagliptin treatment was the only factor independently associated with an increase in monocyte IL-10 (β=0.499; R(2)=0.293, P<0.05). However, other factors including the improvement of glucose metabolism were not associated with the increase. CONCLUSIONS/INTERPRETATION This study is the first to show that a DPP-4 inhibitor, sitagliptin, reduces inflammatory cytokines and improves the unfavorable M1/M2-like phenotypes of peripheral blood monocytes in Japanese type 2 diabetic patients.

Highly purified eicosapentaenoic acid reduces cardio-ankle vascular index in association with decreased serum amyloid A-LDL in metabolic syndrome.

A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, reduces the incidence of cardiovascular diseases. However, the detailed mechanism underlying the anti-atherogenic effect of EPA is still poorly understood. In this study, we examined the effect of EPA on cardio-ankle vascular index (CAVI), a new index of arterial stiffness that is less influenced by blood pressure (BP), as well as on serum amyloid A-low-density lipoprotein (SAA–LDL), an oxidized LDL (oxLDL), in the metabolic syndrome. Ninety-two obese Japanese subjects with metabolic syndromes were randomly divided into two groups (n=46): the EPA-treated group (1.8 g administered daily for 3 months) and the control group. Measurements were taken to assess the changes in glucose-lipid metabolism, SAA–LDL, C-reactive protein (CRP), leptin, adiponectin and pulse wave velocity (PWV), and CAVI. EPA treatment significantly reduced the levels of immunoreactive insulin, triglycerides, SAA–LDL, CRP, PWV and CAVI and increased the levels of adiponectin relative to the control group for 3 months (P<0.05). Stepwise multivariate linear regression analysis revealed that the only significant determinant for a decrease in CAVI by EPA is a reduction in SAA–LDL (P<0.05). Moreover, the EPA-induced reduction of SAA–LDL was only significantly correlated with a decrease in total cholesterol and an increase in adiponectin (P<0.05). This study is the first demonstration that EPA improves arterial stiffness and is less influenced by BP, possibly through the suppression of SAA–LDL, thereby leading to a reduction in the frequency of cardiovascular disease development in metabolic syndrome.

DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

CONTEXT Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fishers exact test). CONCLUSIONS This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

Effects of VIP, TRH, GABA and dopamine on prolactin release from superfused rat anterior pituitary cells

Effects of VIP, TRH, dopamine and GABA on the secretion of prolactin (PRL) from rat pituitary cells were studied in vitro with a sensitive superfusion method. Dispersed anterior pituitary cells were placed on a Sephadex G-25 column and continuously eluted with KRBG buffer. Infusion of TRH (10(-11) - 10(-8)M) and VIP (10(-9) - 10(-6)M) resulted in a dose-related increase in PRL release. LHRH (10(-8) - 10(-5)M) had no effect on PRL release. On the other hand, infusion of dopamine (10(-9) - 10(-6)M) and GABA (10(-8) - 10(-4)M) suppressed not only the basal PRL release from dispersed pituitary cells but also the PRL response to TRH and VIP. The potency of TRH to stimulate PRL release is greater than that of VIP, and the potency of dopamine to inhibit PRL secretion is stronger than that of GABA on a molar basis. These results indicate that TRH and VIP have a stimulating role whereas dopamine and GABA have an inhibitory role in the regulation of PRL secretion at the pituitary level in the rat.