Endocrine journal最新文献

Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [¹⁸F]FB(ePEG12)12-exendin-4 (¹⁸F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by ¹⁸F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).

Although growth hormone (GH) and prolactin (PRL) are usually recognized as pituitary hormones, their expression is not restricted to the adenohypophysis and can also be found in extra-pituitary tissues including placenta. Furthermore, GH, PRL, and their receptors structurally belong to the cytokine family of proteins, and indeed they have remarkable pleiotropic effects. In this review, we analyzed the biological roles of GH/PRL from an evolutionary perspective. We have recognized that the biological significance of GH/PRL can be summarized as follows: cytokines (metabokines) that regulate the shift of nutrients and even of whole bodies to live in the most appropriate environment(s) for conducting growth and reproduction. In this sense, the common keyword of the two metabokines is "shift" for environmental adaptation. Considering that these metabokines flexibly changed their biological roles, GH/PRL may have played important roles during vertebrate evolution.

This umbrella review was conducted aiming to assess the association between genetic variations and the development of diabetic retinopathy (DR) by collecting and evaluating available systematic reviews and meta-analysis results. We evaluated the methodological quality using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2.0, estimated the summary effect size by using the random effects model and calculated the 95% prediction intervals (PIs). Evidence from the included meta-analyses was graded according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant. This umbrella review included 32 meta-analyses of 52 candidate SNPs. The 12 selected meta-analyses were rated as "high," 2 studies were rated as "moderate," 11 studies were graded as "low," and the remaining 7 studies were graded as "critically low" in terms of methodological quality. Carriers of specific genotypes and alleles of the transcription Factor 7-like 2 C/T (TCF7L2 C/T) polymorphism (rs7903146, p < 0.001) might be more susceptible to the occurrence of DR in the homozygous and recessive models, and these associations were supported by "convincing" evidence. Significant associations were also found between interleukin-6 (IL-6) -174 G/C (rs1800795; p < 0.05) or vascular endothelial growth factor (VEGF) polymorphisms (rs2010963, rs699947, rs1570360, rs2010963, rs699947, rs2146323; all p values <0.05) and DR risk, but these associations were supported by "weak" evidence. The TCF7L2 C/T variant could be identified as a definitive genetic risk factor for the development and progression of DR. Data from additional in-depth studies are needed to establish robust evidence for the associations between polymorphisms of IL-6 or VEGF and DR.

Interleukin-2-inducible tyrosine kinase (ITK) is a crucial cytoplasmic protein in the T-cell signaling pathway. Here, we aimed to demonstrate the anti-inflammatory effect of the selective IL-2-induced tyrosine kinase inhibitor BMS-509744 (BMS) on Graves' orbitopathy (GO) in an in vitro model. ITK mRNA expression in orbital tissues from GO and normal controls was compared using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary cultured orbital fibroblasts from each group were pretreated with BMS and stimulated with interleukin (IL)-1β to induce inflammatory reaction. ITK mRNA expression was evaluated using western blotting, and inflammatory cytokine production and downstream transcription factor expression were analyzed after pretreatment with BMS. ITK mRNA expression in GO tissues was significantly higher than that in normal control tissues. After stimulation with IL-1β, ITK phosphorylation significantly increased in both GO orbital and normal control tissues. BMS inhibited IL-1β-induced IL-8 expression in the GO orbital fibroblasts. BMS pretreatment significantly suppressed NF-κB phosphorylation in both GO and normal controls. The selective ITK inhibitor attenuates proinflammatory cytokine production and proinflammatory transcription factor phosphorylation in in vitro model of GO.

In Japan, the traditional method for measuring plasma aldosterone concentration (PAC) was radioimmunoassay (RIA), which had several challenges, including poor traceability of certified reference materials and reduced detection sensitivity at low concentrations. To overcome these issues, a chemiluminescent enzyme immunoassay (CLEIA) for PAC measurement was introduced in April 2021 and the Japan Endocrine Society published new guidelines for primary aldosteronism (PA). This study aimed to evaluate the impact of the transition from RIA to CLEIA for PAC measurement on PA diagnosis. Data from 190 patients admitted to the Second Department of Internal Medicine, University of the Ryukyus Hospital, between April 2012 and March 2021 were analyzed. Patients who were diagnosed with PA underwent adrenal venous sampling. The PAC measured by RIA (PAC(RIA)) was converted to the estimated PAC measured by CLEIA (ePAC(CLEIA)) using a conversion formula. The present study evaluated the discordance rates in diagnoses based on screening (SC), captopril challenge test (CCT), saline infusion test (SIT), and diagnosis of PA between results judged by PAC(RIA) according to the previous guidelines and those judged by ePAC(CLEIA) according to the new guidelines. The results revealed discordant diagnosis rates of 6.4% for SC and 10.1% for CCT, with no discordance for SIT. The discordant diagnosis rate for PA was 3.7%. Our study reveals the challenges in establishing appropriate diagnostic criteria for PA using PAC(CLEIA) and highlights the demand for further research on provisionally positive categories.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2, and various complications have been reported. Furthermore, there have been increasing reports of endocrinopathy related to COVID-19 following the pandemic. We report a 49-year-old healthy woman who developed rapid onset of polydipsia and polyuria three weeks after COVID-19. Laboratory tests indicated low urine osmolarity and increased serum osmolarity, and antidiuretic hormone (ADH) was undetectable. Urine osmolality remained low with water deprivation. Similarly, plasma ADH responses to hypertonic-saline infusion were blunted and urine osmolality increased in response to desmopressin. There was no clear evidence of anterior pituitary dysfunction. T1-weighted magnetic resonance imaging (MRI) showed pituitary stalk thickening and absence of posterior pituitary bright signal spots, suggesting the presence of hypophysitis. Based on these results, we made a probable diagnosis of lymphocytic infundibulo-neurohypophysitis (LINH) which have caused central diabetes insipidus. Positive findings for serum anti-rabphilin-3A antibodies, reported as a potential diagnostic marker for LINH, were also noted. Following oral desmopressin administration, polydipsia and polyuria were quickly improved, though treatment with desmopressin was still required over four months. This is the first report of a patient with a probable diagnosis of LINH after COVID-19 who tested positive for anti-rabphilin-3A antibodies. Positive findings for those antibodies suggest that pituitary dysfunction associated with COVID-19 is hypophysitis involving an abnormal immune mechanism. The presence of anti-rabphilin-3A antibodies may be useful as a non-invasive diagnostic marker of LINH and potentially serve as a valuable diagnostic aid in cases of LINH associated with COVID-19.

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism (H), deafness (D), and renal dysplasia (R) caused by genetic variants of the GATA3 gene. We present the case of a 38-year-old Japanese man with HDR syndrome who exhibited hypoparathyroidism, sensorineural deafness, renal dysfunction, severe symptomatic hypocalcemia with Chvostek's and Trousseau's signs, and QT prolongation on electrocardiography. He had a family history of deafness and hypocalcemia. Genetic testing revealed a novel GATA3 gene variant at exon 2 (c.48delC), which induces a frameshift resulting in termination at codon 178, causing HDR syndrome. We summarized 45 Japanese cases of HDR syndrome with regard to the mode of onset (familial or sporadic) and the age at diagnosis. In addition, we summarized all previous cases of HDR syndrome with GATA3 gene variants. Mapping of previously reported genetic variants in HDR syndrome revealed that most missense variants were observed at exons 4 and 5 regions in the GATA3 gene. These two regions contain zinc finger domains, demonstrating their functional importance in GATA3 transcription. This review of literature provides a useful reference for diagnosing HDR syndrome and predicting the related future manifestations.

Cushing's disease is associated with increased morbidity and mortality. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid, sustained mean urinary free cortisol (mUFC) normalization in Cushing's disease patients in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734). Here, we evaluate the efficacy and safety of osilodrostat in Cushing's disease in patients of Asian origin compared with patients of non-Asian origin. Pooled data from LINC 3 and LINC 4 were analyzed. Outcomes were evaluated separately for Asian and non-Asian patients. For the analysis, 210 patients were included; 56 (27%) were of Asian origin. Median (minimum-maximum) osilodrostat dose was 3.8 (1-25) and 7.3 (1-47) mg/day in Asian and non-Asian patients, respectively. mUFC control was achieved at weeks 48 and 72 in 64.3% and 68.1% of Asian and 68.2% and 75.8% of non-Asian patients. Improvements in cardiovascular and metabolic-related parameters, physical manifestations of hypercortisolism, and quality of life were similar in both groups. Most common adverse events (AEs) were adrenal insufficiency (44.6%) in Asian and nausea (45.5%) in non-Asian patients. AEs related to hypocortisolism and pituitary tumor enlargement occurred in more Asian (58.9% and 21.4%) than non-Asian patients (40.3% and 9.1%). Of Asian and non-Asian patients, 23.2% and 13.6%, respectively, discontinued because of AEs. Asian patients with Cushing's disease generally required numerically lower osilodrostat doses than non-Asian patients to achieve beneficial effects. Hypocortisolism-related AEs were reported in more Asian than non-Asian patients. Together, these findings suggest that Asian patients are more sensitive to osilodrostat than non-Asian patients.

Elevated Fulminant Index (FI), [plasma glucose (PG)/glycosylated hemoglobin A1c (HbA1c)], was reportedly a sensitive index to differentiate fulminant type 1 diabetes (FT1D) from non-fulminant T1D (nFT1D). Aim of this study was to describe a better, but simpler index of FT1D. 49 and 52 patients with FT1D and nFT1D, respectively, were registered, and the discriminating ability of the rounded, normalized ratio, [PG (mmol/L) – 5.0]/[HbA1c (%) – 5.0], and the original ratio, [PG (mmol/L)]/[HbA1c (%)], was compared. Normalizing the ratio significantly raised its accuracy: area under the curve for receiver operating curve, AUROC (95%CI), 0.927 (0.858–0.964) and 0.851 (0.763–0.910), respectively, with and without the normalization (p < 0.01). Rounding of the figure into [PG (mmol/L) – 5.0]/[HbA1c (%) – 5.0] did not significantly sacrifice the discriminating ability of the index. Namely, the optimal cut point of rounded and normalized GAR, 10.0, showed 89.8% sensitivity. In conclusion, rounded, normalized (rn) GAR ≥10 (the rounded optimal cut-off) could be used for the snap diagnosis of FT1D.

The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors associated with them. The study included 6 subjects with adrenocortical adenoma (ACA), 7 subjects with adrenocortical carcinoma (ACC), and 13 control subjects with a normal adrenal cortex. The status of VEGF and endocan expression was determined by the proportions of cells staining on a scale ranging from negative (not staining at all) to strongly positive. VEGF expression was detected in 1 (16.7%) of 6 subjects in the ACA group and in 6 (85.7%) of 7 subjects in the ACC group. VEGF expression was not detected in any of the subjects in the control group. Endocan expression was detected in 6 (100%) of 6 subjects in the ACA group and in 7 (100%) of 7 subjects in the ACC group, while it was detected in only 4 (30.7%) of 13 subjects in the control group. VEGF was expressed with a high frequency in subjects with ACC and with a low frequency in subjects with ACA, but it was not expressed in subjects with normal adrenal cortex tissue. Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.