The islets of Langerhans is the endocrine function region of pancreas, which exist in five cell types. The majority of endocrine cells are insulin-secreting β cells, mixed up with glucagon-secreting α-cells. The islets of Langerhans are highly vascularized, and the capillary network around the islet is about five times denser than that in the exocrine tissues. It guarantees endocrine cells adequately contact with the capillary networks. Above mentioned is the basis of deep study the interaction between β cells and capillary. Increasing number of studies contribute to the consensus that endothelial cells have positive effects in the islet microenvironment. Endothelial cells can act as endocrine cells which release many active substances, such as hepatocyte growth factors (HGF), thrombospondin-1(TSP-1), laminins, and collagens by means of different molecule pathways, inducing β cells differentiation, proliferation, survivor, and insulin release next to the vessels. Apart from the effect of endothelial cells on β cells by paracrine fashion, the islets can utilize VEGF-A, angiopoietin-1 and insulin signaling to increase the interaction with endothelial cells. As the endocrine role of endothelial cells to β cells, it may be a novel target to stimulate β cells regeneration, promote vascularization post islet transplantation strategy in the treatment of diabetes mellitus.
Effective treatment strategies that help tackle the complex problems associated with managing endocrine cancers are in great demand. Because of the shortcomings in current treatments and the problems associated with the treatment strategies used in the cure and/or management of endocrine cancers, considerable effort must be devoted to developing new and effective therapeutic strategies. Gene therapy represents an area of both basic and clinical research that can potentially be considered a therapeutic option in treating endocrine cancers. Therefore, we consider it timely to summarize the studies related to gene-therapy interventions that are available for treating endocrine cancers and to highlight the major limitations of and the recent progress made in these therapies. After systematically reviewing the literature, we provide a comprehensive overview of distinct studies conducted to evaluate gene-therapy approaches in various endocrine cancers. Some of these successful studies have been extended toward translational investigations. The emerging view is that an integrative approach is required to combat the pitfalls associated with gene-therapy studies, especially in endocrine cancers.
Measuring the levels of the plasma free metanephrines (PFMs) represents a recently developed and promising test for the diagnosis of pheochromocytoma in the United States and Europe. As this test has not yet been evaluated in Japan, it is necessary to evaluate the diagnostic efficacy of measuring the levels of PFMs compared with the standard measurement of the urinary excretion of metanephrines (uMNs) whose reliability is well established to detect of pheochromocytoma. A total of 101 Japanese subjects clinically suspected of having pheochromocytoma in were included in this study. Subsequently, we prospectively measured the PFMs levels in all patients, compared with those of biochemical markers of the catecholamine secretion and metabolisms in the plasma and urine. All subjects with adrenal tumors underwent tumor excision. Data were available for 84 of the 101 patients, 47 of whom had histopathologically proven pheochromocytoma and 37 were finally diagnosed with non-pheochromocytoma. The results of comparisons in the accuracy of measurement for diagnosis of pheochromocytoma between PFMs and the urinary excretion of metanephrines (uMNs) were 0.980 VS 0.951 for AUC of receiver operatorating characteristic (ROC) curve, 0.957 VS 0.894 for sensitivity, and 0.973 VS 0.946 for specificity, respectively. Although the differences were small, the results of our study definitely demonstrated that measurement of PFMs was not inferior to standard urinary metanephrines (uMNs) measurement, which is established to be the most reliable biochemical method to detect pheochromocytoma. This study clearly shows measuring the PFMs levels to be a reliable and efficient method for diagnosing pheochromocytoma in Japanese patients, as demonstrated in previous reports.
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P<0.05). 11β-HSD1 mRNA levels in cells treated with GH in the presence of 1 μM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 μM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 μM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 μM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11β-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I.
In several genome-wide association studies, nonalcoholic fatty liver disease and alanine aminotransferase susceptibility variants have been identified in several genes, including LYPLAL1, ZP4, GCKR, HSD17B13, PALLD, PPP1R3B, FDFT1, TRIB1, COL13A1, CPN1, ERLIN1, CWF19L1, EFCAB4B, PZP, and NCAN. To investigate the relationship between these genes and nonalcoholic fatty liver disease in the Japanese population, we genotyped 540 patients and 1012 control subjects for 18 variations. We performed logistic regression analyses to characterize the association between the tested variations and nonalcoholic fatty liver disease. Metabolic syndrome and histological traits were also analyzed by linear regression. We also examined GCKR rs780094, TRIB1 rs2954021, and PNPLA3 rs738409 for epistatic effects. The A-allele of rs780094 in GCKR (P = 0.0024) and the A-allele of rs2954021 TRIB1 (P = 4.5×10-5) were significantly associated with nonalcoholic fatty liver disease. GCKR rs780094 was also associated with decreased plasma glucose, and increased triglycerides in the patient and control groups. GCKR rs780094 was also associated with an increased ratio of visceral to subcutaneous fat area in the patients with nonalcoholic fatty liver disease. Variations in GCKR, TRIB1, and PNPLA3 independently influenced nonalcoholic fatty liver disease and had no epistatic effects. Our data suggest variations in GCKR and TRIB1 are involved in the development of nonalcoholic fatty liver disease.
Thyroid storm (TS) is a life-threatening endocrine emergency. However, the pathogenesis of TS is poorly understood. A 40-year-old man was admitted to a nearby hospital with body weight loss and jaundice. Five days after a contrasted abdominal computerized tomography (CT) scan, he exhibited high fever and disturbance of consciousness. He was diagnosed with TS originating from untreated Graves’ disease and was transferred to the intensive care unit (ICU) of our hospital. The patient exhibited impaired consciousness (E4V1M4 in Glasgow coma scale), high fever (39.3°C), and atrial flutter with a pulse rate 162/min, and was complicated by heart failure, acute hepatic failure, and disseminated intravascular coagulation syndrome (DIC). His circulating level of soluble interleukin-2 receptor (sIL-2R), a serum marker of an activated immune response, was highly elevated (7,416 U/mL, reference range: 135-483). Multiple organ failure (MOF) and DIC were successfully managed by multimodality treatments using inorganized iodide, glucocorticoids, anti-thyroid drugs, beta-blockers, and diuretics as well as an anticoagulant agent and the transfusion of platelet concentrate and fresh frozen plasma. sIL-2R levels gradually decreased during the initial treatment, but were still above the reference range even after thyroidectomy. Mild elevations in serum levels of sIL-2R have previously been correlated with thyroid hormone levels in non-storm Graves’ disease. The present study demonstrated, for the first time, that circulating sIL-2R levels could be markedly elevated in TS. The marked increase in sIL-2R levels was speculated to represent an inappropriate generalized immune response that plays an unknown role in the pathogenesis of TS.
Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The American Thyroid Association and the Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2011 and 2012, respectively; however, impact of the guidelines in routine clinical practice is unknown. We therefore carried out a survey to study current practices in the screening and management of hypothyroidism in pregnancy. We collected completed questionnaire survey based on clinical case scenarios from 321 members of the Asia-Oceania Thyrpid Association (AOTA). Responses from 310 clinician members (from 21 Asian countries) were analyzed. For a woman with hypothyroidism planning pregnancy, 54% favored testing thyroid function before adjusting the dose, whilst 32% recommended increasing the dose of L-thyroxine (L-T4) as soon as pregnancy is confirmed. For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of L-T4. One half of responders used serum TSH and free T4 to monitor the dose of L-T4. Although the target of thyroid function tests that responders aimed to achieve with L-T4 was inconsistent, but a majority aim to keep TSH within recommended trimester specific range. Twenty-one % responders or their institutions screened all pregnant women for thyroid dysfunction, 66% performed targeted screening of only the high-risk group, whilst 13% did not carry out systemic screening. Majority of responders practices within recommendations of major professional societies; however, there is wide variation in the clinical practice in the treatment and screening of hypothyroidism during pregnancy in Asia.
Vascular endothelial (VE)-cadherin and claudin-5 are major components of the adherens and tight junctions of vascular endothelial cells, respectively, and decreases in their expression are associated with increases in endothelial paracellular permeability. In the uterus, estrogen induces endometrial edema. However, the in vivo effect of estrogen on endothelial paracellular permeability is unknown. Therefore, we studied the expression of VE-cadherin and claudin-5 in vascular endothelial cells in murine uteri stimulated by estrogen or progesterone. Ovariectomized mature mice were injected with estradiol-17β (1 μg/mouse) or progesterone (1 mg/mouse) at intervals of 24 hours for 6 days. The frozen transverse sections of the uteri of these mice and untreated mice were stained for CD31 (vascular endothelial cell marker) plus VE-cadherin or claudin-5 using a double-immunofluorescence method. Then, the percentages of VE-cadherin- or claudin-5-positive vessels among CD31-positive vessels were examined in the uterine endometria. VE-cadherin and claudin-5 were expressed in most CD31-positive vessels in the endometria of the untreated mice. Progesterone did not affect the expression of both VE-cadherin and claudin-5 and estradiol-17β also did not affect the VE-cadherin expression, but estradiol-17β significantly decreased the claudin-5 expression. This decreasing effect of estradiol-17β was detected from 24 hours later when the water content per a uterus significantly increased. The present study indicates that estrogen, but not progesterone, decreases the expression of claudin-5 in vascular endothelial cells in the murine uterine endometrium from 24 hours later, suggesting that the decrease in the claudin-5 expression contributes to the endometrial edema late after the estrogen stimulation.
Methylenetetrahydrofolate reductase plays an important role in folate metabolism. Individuals who are type 2 diabetes mellitus have greatest risk for the development of vascular complications. The results of studies which assessed the association between MTHFR C677T polymorphism and T2DM with vascular complications were inconsistent in the Chinese Han population. The purpose of this meta-analysis was to assess the associations between MTHFR C677T polymorphism and T2DM with vascular complications in the Chinese Han population. We collected all relevant articles on MTHFR C677T polymorphisms and T2DM with vascular complications in the Chinese Han population in multiple electronic databases which were searched to December 2013. Fixed-effects and random-effects meta-analyses were performed to assess the odds ratios (ORs). Stratified Analysis, sensitivity Analysis and publication bias were examined. A total of 1984 diabetic patients with vascular complications and 1703 single diabetic patients were found in meta-analysis. There was a significant association between MTHFR C677T polymorphisms and T2DM with vascular complications under recessive genetic model, dominant genetic model, homozygous genetic model, heterozygous genetic model and allele comparison. Sensitivity analysis indicated that the overall result was dependable. Our meta-analysis suggests the MTHFR C677T polymorphisms is associated with T2DM with vascular complications in the Chinese Han population.
Excess parathyroid hormone (PTH), known as primary hyperparathyroidism (pHPT), results in hypercalcemia and bone loss. Recent studies have shown that PTH is associated with the occurrence of hypertension in Western countries; however, controversy remains regarding high serum levels of PTH and calcium as risk factors for hypertension in Japanese patients. We retrospectively enrolled 114 consecutive Japanese patients who visited our hospital for examination and treatment of hypercalcemia and/or hypertension with serum calcium levels ≥9.8 mg/dL. To estimate the prevalence of hypertension, the patients were categorized according to calcium levels into hypercalcemic (10.2-13.4 mg/dL) and normocalcemic (9.8-10.1 mg/dL) groups, which were further categorized into high PTH (50-440 pg/mL) and low PTH (8-49 pg/mL) groups. The prevalence of hypertension was higher in patients with hypercalcemia than in patients with normocalcemia in both the high and low PTH groups. The prevalence of hypertension was higher in patients with high serum PTH levels than in patients with low serum PTH levels in both the hypercalcemic and normocalcemic groups. Logistic multiple regression analysis determined that serum calcium (P < 0.05) and PTH (P < 0.01) levels were positive contributors to hypertension. In conclusion, high serum levels of PTH and calcium are risk factors for hypertension in Japanese patients.
The majority of patients with systemic sclerosis (SSc) have gastrointestinal (GI) tract involvement, but therapies using prokinetic agents are usually unsatisfactory. Ghrelin stimulates gastric motility in healthy human volunteers. In this study, we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc. The study was performed in a randomized, double-blind, placebo-controlled crossover fashion on two occasions. Ten SSc patients with GI tract involvement received an infusion of either ghrelin (5.0 μg/kg) or saline, and gastric emptying rate was evaluated by 13C-acetic acid breath test. Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc (ghrelin vs. saline: 43.3 ± 11.4 min vs. 53.4 ± 5.4 min, P=0.03). No serious adverse effects were observed. Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc.