Publications by authors named "Eun Jig Lee"

226 Publications

Altered Glucose Metabolism and Glucose Transporters in Systemic Organs After Bariatric Surgery.

Front Endocrinol (Lausanne) 2022 14;13:937394. Epub 2022 Jul 14.

Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea.

The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.
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http://dx.doi.org/10.3389/fendo.2022.937394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329688PMC
July 2022

Therapeutic Potential of Targeting Periostin in the Treatment of Graves' Orbitopathy.

Front Endocrinol (Lausanne) 2022 30;13:900791. Epub 2022 May 30.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.

Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves' orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts . POSTN (gene encoding periostin) expression in Graves' orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves' orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves' orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides evidence that periostin may be a novel potential therapeutic target for the treatment of GO.
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http://dx.doi.org/10.3389/fendo.2022.900791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189304PMC
May 2022

Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves' Orbitopathy.

Invest Ophthalmol Vis Sci 2022 06;63(6)

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.

Purpose: We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.

Methods: Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.

Results: The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.

Conclusions: BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.
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http://dx.doi.org/10.1167/iovs.63.6.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187939PMC
June 2022

Revisiting growth hormone nadir cut-offs for remission in patients with acromegaly.

Eur J Endocrinol 2022 Apr 25;186(6):657-665. Epub 2022 Apr 25.

Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Objective: Over the past decade, the growth hormone (GH) nadir cut-off during the oral glucose tolerance test for remission in patients with acromegaly was changed from 0.4 to 1.0 μg/L due to the limited use of ultrasensitive detection kits to measure GH levels. However, the optimal cut-off level for GH nadir remains unclear. This retrospective study aimed to investigate the association between different GH nadir cut-offs and prognosis in patients with acromegaly.

Design And Methods: A total of 285 patients with acromegaly with a glucose-suppressed GH nadir <1 μg/L at 3-6 months after trans-sphenoidal adenomectomy were divided into two groups according to the glucose-suppressed GH nadir levels at 3-6 months post-operatively (group A: <0.4 μg/L; group B: 0.4-1.0 μg/L). GH levels were measured using an ultrasensitive IRMA. The clinical, hormonal, metabolic, and neuroradiological data of the two groups were compared.

Results: Female sex, as well as confirmed macroadenomas, was significantly overrepresented in group B. The 5-year rate of patients who achieved nadir GH < 1.0 μg/L and age- and sex-matched normal IGF-1 was significantly higher in group A than that in group B. However, there was no significant difference between the two groups in metabolic parameters at 12 months post-operatively.

Conclusion: Different GH nadir cut-offs were associated with different 5-year rates of patients who achieved nadir GH <1.0 μg/L and age- and sex-matched normal IGF-1, suggesting that a strict GH nadir threshold of 0.4 μg/L correlates better with remission.
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http://dx.doi.org/10.1530/EJE-21-1094DOI Listing
April 2022

Efficacy and Cerebrospinal Fluid Rhinorrhea after Cabergoline Treatment in Patients with Bioactive Macroprolactinoma.

Cancers (Basel) 2021 Oct 26;13(21). Epub 2021 Oct 26.

Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea.

Predicting dopamine agonist resistance in patients with macroprolactinoma is essential for clinicians to prevent treatment failure and subsequent complications such as medication-induced cerebrospinal fluid (CSF) rhinorrhea. We evaluated the features of patients with cabergoline resistance and CSF rhinorrhea in patients with prolactinomas with prolactin levels ≥1000 ng/mL. A total of 140 patients who were newly diagnosed with prolactinoma secreting only prolactin ≥1000 ng/mL and treated with cabergoline for the first time were included in this study. Based on the hormonal and radiologic response of the prolactinoma, the patients were divided into responders and non-responders. Non-responders (36/140, 25.8%) included a higher number of patients receiving hormone replacement than responders (responders, (%) = 12(11.5) vs. non-responders = 13(36.1), = 0.001). In propensity score matching analysis, patients who developed CSF rhinorrhea presented more frequent hormone deficiency than responders regardless of initial cabergoline dose. Hormone deficiency was associated with a greater odds ratio for the risk of non-responders (adjusted odds ratio = 5.13, 95% CI 1.96-13.46, = 0.001). Cabergoline was effective in bioactive macroprolactinoma. Furthermore, initial cabergoline dose was not significantly associated with long-term responsiveness and development of CSF rhinorrhea but the hypopituitarism was independently associated with an increased risk of cabergoline resistance and CSF rhinorrhea.
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http://dx.doi.org/10.3390/cancers13215374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582509PMC
October 2021

Serum Selenium Levels in Patients with Graves Disease: Associations with Clinical Activity and Severity in a Retrospective Case-control Study.

Korean J Ophthalmol 2022 02 8;36(1):36-43. Epub 2021 Nov 8.

Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.

Purpose: To compare serum selenium levels in Graves patients and non-Graves control participants and to evaluate associations between serum selenium levels and clinical features of Graves orbitopathy (GO).

Methods: We conducted a single-center, retrospective case-control study among 33 patients with Graves disease without GO (GD), 31 patients with diagnosed GO, and 27 unaffected healthy participants enrolled between 2013 and 2020 at Severance Hospital. We compared serum selenium concentrations between the GD, GO, and healthy control groups, and analyzed associations between serum selenium and GO patients' clinical activity scores, severity (assessed through modified NOSPECS scores), and other clinical features using multivariate linear regression analysis.

Results: Mean serum selenium levels were 109.30 ± 16.39, 111.39 ± 14.04, and 126.09 ± 21.09 ng/mL in GO patients, GD patients, and healthy control participants, respectively. Mean serum selenium levels in Graves patients with and without orbitopathy were significantly lower than those in the healthy control group (p < 0.05), and mean selenium levels were slightly lower in GO than those in GD patients (p = 0.594). Serum selenium levels were significantly lower in GO patients with eyelid retraction than in patients without retraction (p = 0.038). However, serum selenium levels were not associated with clinical activity scores and modified NOSPECS scores (p = 0.241 and 0.801, respectively).

Conclusions: Serum selenium levels were significantly lower in Graves patients with or without GO, compared to non-Graves control participants. Selenium levels were not associated with clinical activity scores or NOSPECS scores, though we observed an association with eyelid retraction.
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http://dx.doi.org/10.3341/kjo.2021.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849989PMC
February 2022

Downregulation of miR-216a-5p and miR-652-3p is associated with growth and invasion by targeting JAK2 and PRRX1 in GH-producing pituitary tumours.

J Mol Endocrinol 2021 11 26;68(1):51-62. Epub 2021 Nov 26.

Endocrinology, Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea.

Expression of aberrant microRNA (miRNA) is associated with tumour formation, migration, and invasion. However, there is limited information about the epigenetics of pituitary tumorigenesis. This study investigated the role of miRNA expression during the tumorigenesis of growth hormone (GH)-secreting pituitary tumours. miRNA profiling and real-time PCR were used to analyse the mRNA expression profile in sequential pituitary tissues of a unique animal model with a GH-producing pituitary tumour. Selected miRNAs were further validated in GH-producing cell lines and human pituitary tumour samples. The expression of significantly altered miRNAs and their predicted targets, as detected by microarray, was evaluated by real-time PCR, Western blotting, and immunohistochemistry using samples from mouse models and human pituitary tumours. The effect of miRNAs on tumour proliferation and invasion was examined in GH3 cells using the MTS and Matrigel invasion assays. Among the 14 miRNAs whose expression was significantly changed, miR-216a-5p (fold change = -5.638, P -value = 0.014) and miR-652-3p (fold change = -3.482, P -value = 0.010) were constantly and significantly downregulated. Transfection with mimics of miR-216a-5p and miR-652-3p inhibited GH3 proliferation and invasion, whereas inhibitors promoted them. The direct target genes of miR-216a-5p and miR-652-3p were Jak2 and Prrx1, respectively, which were downregulated in GH3 cells transfected with mimics and in serial pituitary gland tissues, including hyperplasic tissues and tumours of acromegalic animal models and pituitary tumour tissues of acromegalic patients. Downregulated miR-216a-5p and miR-652-3p expression may contribute to tumour progression by targeting JAK2 and PRRX1 on GH-producing pituitary tumours.
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http://dx.doi.org/10.1530/JME-21-0070DOI Listing
November 2021

Clinical Relevance of New World Health Organization Classification System for Pituitary Adenomas: A Validation Study With 2-Year Experience.

Front Oncol 2021 13;11:739290. Epub 2021 Sep 13.

Department of Neurosurgery, Yonsei University College of Medicine, Seoul, South Korea.

Background: The new World Health Organization (WHO) classification system proposed a cell lineage-based classification scheme for pituitary adenomas in which transcription factors (TFs) play a major role as key classifiers. We aimed to evaluate clinical relevance of the new classification system in a clinical setting.

Methods: TF staining was retrospectively performed for 153 clinically and histologically well characterized pituitary adenomas. Then, 484 pituitary adenomas were prospectively stained for TFs and then for relevant pituitary hormones. TF and hormone stain-based diagnoses were compared, and differences in clinical manifestations were evaluated.

Results: The accuracies of antibodies for three TFs were successfully validated and had an overall matching rate was 89.6%. We identified 50 (10.4%) cases with discrepancies between TF and pituitary hormone stains. Gonadotroph adenomas lacking follicle-stimulating hormone and luteinizing hormone stains account for most discrepancies. Null cell adenomas may be more prevalent than reported and may be clinically more aggressive than gonadotroph adenomas.

Conclusion: The new WHO classification is mostly well matched with the traditional classification. However, until the new classification is further validated and interpreted in the context of long-term clinical outcomes, routine histological examination should include full slate of immunostains for pituitary hormones as well as TFs.
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http://dx.doi.org/10.3389/fonc.2021.739290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476031PMC
September 2021

Treatment of acromegaly by rosiglitazone via upregulating 15-PGDH in both pituitary adenoma and liver.

iScience 2021 Sep 14;24(9):102983. Epub 2021 Aug 14.

Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.

Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligand, has been reported to reduce growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in 10 patients with acromegaly. However, the mechanisms remain unknown. Here, we reveal that PPARγ directly enhances 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, whose expression is decreased and negatively correlates with tumor size in acromegaly. Rosiglitazone decreases GH production and promotes apoptosis and autophagy in GH3 and primary somatotroph adenoma cells and suppresses hepatic GH receptor (GHR) expression and IGF-1 secretion in HepG2 cells. Activating the PGE2/cAMP/PKA pathway directly increases GHR expression. Rosiglitazone suppresses tumor growth and decreases GH and IGF-1 levels in mice inoculated subcutaneously with GH3 cells. The above effects are all dependent on 15-PGDH expression. Rosiglitazone as monotherapy effectively decreases GH and IGF-1 levels in all nineteen patients with active acromegaly. Evidence suggests that rosiglitazone may be an alternative pharmacological approach for acromegaly by targeting both pituitary adenomas and liver.
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http://dx.doi.org/10.1016/j.isci.2021.102983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403734PMC
September 2021

Novel somatic variants involved in biochemical activity of pure growth hormone-secreting pituitary adenoma without GNAS variant.

Sci Rep 2021 08 16;11(1):16530. Epub 2021 Aug 16.

Institute of Endocrine Research, Pituitary Tumor Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.

We aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.
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http://dx.doi.org/10.1038/s41598-021-95829-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368009PMC
August 2021

Association of fibroblast growth factor 10 with the fibrotic and inflammatory pathogenesis of Graves' orbitopathy.

PLoS One 2021 12;16(8):e0255344. Epub 2021 Aug 12.

Department of Ophthalmology, Severance Hospital, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, Republic of Korea.

Purpose: The role of fibroblast growth factor (FGF) in orbital fibroblasts (OFs) is rarely known. In this study, we investigated the effect of FGF10 on fibrosis and the inflammation mechanism of Graves' orbitopathy (GO).

Methods: Orbital tissue from GO (n = 15) and non-GO (n = 15) was obtained for this study. The mRNA and protein expression levels of FGF10 and FGF receptor 2b (FGFR2b) in orbital tissue were determined by real-time polymerase chain reaction, western blot analysis, and confocal microscopy. The effects of FGF10 on transforming growth factor (TGF)-β1 induced fibrotic proteins and interleukin (IL)-1β- or tumor necrosis factor (TNF)-α- induced inflammatory proteins were investigated using recombinant human (rh) FGF10 and small interfering (si) RNA transfection against FGF10.

Results: FGF10 and FGFR2b mRNA expression levels were significantly lower in GO orbital tissues than in non-GO orbital tissues (p = 0.009 and 0.005, respectively). Immunostaining of FGF10 in orbital adipose tissues showed differences in FGF10 expression between GO and control samples. Immunostaining of FGF10 was very weak in the orbital tissues of GO patients. TGF-β1-induced fibronectin, collagen Iα, α-smooth muscle actin protein expression in GO OFs was attenuated by rhFGF10 treatment and increased by knockdown of FGF10 via siFGF10 transfection. Similarly, IL-1β- or TNF-α-induced IL-6, IL-8, and cyclooxygenase-2 protein production in GO OFs was either blocked by rhFGF10 treatment or further upregulated by inhibition of FGF10 via siFGF10 transfection.

Conclusions: Our data demonstrate that FGF10 has beneficial effects on the inflammatory and fibrotic mechanisms of GO in primary cultured OFs, providing new insights into GO pathology and the discovery of FGF10 as a promising novel therapeutic application for the treatment of GO.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360584PMC
November 2021

Potential of an Enzyme Mixture of Glucose Oxidase, Glucosyl Transferase, and Fructosyl Transferase as an Antidiabetic Medicine.

Biomedicines 2021 Jun 28;9(7). Epub 2021 Jun 28.

Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea.

An enzyme mixture (EM) of glucose oxidase, glucosyl transferase, and fructosyl transferase can regulate glucose absorption into the body by converting carbohydrates in food to indigestible oligosaccharides. We evaluated the antidiabetic effects of repeated oral administration of EM in db/db mice. Seven-week-old db/db mice were divided into control, voglibose, and EM groups. Drugs were administered orally mixed with limited feed for one month. Glucose levels were measured every week. A meal tolerance test was conducted after overnight fasting, before the mice were sacrificed. There were no differences in body weight or food intake between the groups. EM treatment reduced blood glucose levels compared with those in the control group. Blood glucose levels during the meal tolerance test were significantly lower in the EM group than those in the control group. A significant decrease in triglyceride level and a tendency for decreased low-density lipoprotein were observed in the EM group compared with in the control group. The Bacteroidetes-to-Firmicutes ratio was higher in the EM group than that in the control group. EM may be useful for people at risk of hyperglycemia or diabetes who need to safely regulate their blood glucose levels. EM may also improve lipid and gut microbiota profiles.
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http://dx.doi.org/10.3390/biomedicines9070745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301424PMC
June 2021

Signal transducer and activator of transcription 3 as a potential therapeutic target for Graves' orbitopathy.

Mol Cell Endocrinol 2021 08 9;534:111363. Epub 2021 Jun 9.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, 03722, South Korea. Electronic address:

The roles of signal transducer and activator of transcription 3 (STAT3) in inflammation, oxidative stress, and adipogenesis during Graves' orbitopathy (GO) are incompletely understood. Here, STAT3 expression in orbital tissues (from individuals with GO and healthy control subjects) was studied, and the role of STAT3 in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in primary orbital fibroblasts. STAT3 mRNA expression was higher in GO orbital tissues than in non-GO tissues. Treatment with proinflammatory cytokines, thyroid-stimulating hormone, or insulin-like growth factor-1 induced STAT3 mRNA in GO orbital fibroblasts, but not in non-GO cells. STAT3 silencing inhibited interleukin-1β-induced inflammatory cytokines and oxidative stress-induced haem oxygenase-1 expression. STAT3 siRNA-transfected GO orbital fibroblasts showed decreased adipocyte differentiation. STAT3 affected proinflammatory cytokine production, oxidative stress responses, and adipogenesis in an in vitro model of GO, suggesting that STAT3 mediates GO pathology, and that modulating STAT3 expression may have therapeutic potential against GO.
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http://dx.doi.org/10.1016/j.mce.2021.111363DOI Listing
August 2021

PERK mediates oxidative stress and adipogenesis in Graves' orbitopathy pathogenesis.

J Mol Endocrinol 2021 05 11;66(4):313-323. Epub 2021 May 11.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.

We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves' orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress-related genes in orbital tissue harvested from individuals with or without GO was studied using real-time PCR. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through Wwestern blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein (CHOP) mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.
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http://dx.doi.org/10.1530/JME-21-0057DOI Listing
May 2021

Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force.

Endocrinol Metab (Seoul) 2021 04 6;36(2):322-338. Epub 2021 Apr 6.

Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.

Pheochromocytoma and paraganglioma (PPGLs) are rare catecholamine-secreting neuroendocrine tumors but can be life-threatening. Although most PPGLs are benign, approximately 10% have metastatic potential. Approximately 40% cases are reported as harboring germline mutations. Therefore, timely and accurate diagnosis of PPGLs is crucial. For more than 130 years, clinical, molecular, biochemical, radiological, and pathological investigations have been rapidly advanced in the field of PPGLs. However, performing diagnostic studies to localize lesions and detect metastatic potential can be still challenging and complicated. Furthermore, great progress on genetics has shifted the paradigm of genetic testing of PPGLs. The Korean PPGL task force team consisting of the Korean Endocrine Society, the Korean Surgical Society, the Korean Society of Nuclear Medicine, the Korean Society of Pathologists, and the Korean Society of Laboratory Medicine has developed this position statement focusing on the comprehensive and updated diagnosis for PPGLs.
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http://dx.doi.org/10.3803/EnM.2020.908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090459PMC
April 2021

Associations of GNAS Mutations with Surgical Outcomes in Patients with Growth Hormone-Secreting Pituitary Adenoma.

Endocrinol Metab (Seoul) 2021 04 23;36(2):342-350. Epub 2021 Mar 23.

Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background: The guanine nucleotide-binding protein, alpha stimulating (GNAS) gene has been associated with growth hormone (GH)-secreting pituitary adenoma. We investigated the prevalence of GNAS mutations in Korean patients with acromegaly and assessed whether mutation status correlated with biochemical or clinical characteristics.

Methods: We studied 126 patients with acromegaly who underwent surgery between 2005 and 2014 at Severance Hospital. We performed GNAS gene analysis and evaluated age, sex, hormone levels, postoperative biochemical remission, and immunohistochemical staining results of the tumor.

Results: GNAS mutations were present in 75 patients (59.5%). Patients with and without GNAS mutations showed similar age distribution and Knosp classification. The proportion of female patients was 76.5% and 48.0% in the GNAS-negative and GNAS-mutation groups, respectively (P=0.006). In immunohistochemical staining, the GNAS-mutation group showed higher GH expression in pituitary tumor tissues than the mutation-negative group (98.7% vs. 92.2%, P=0.015). Patients with GNAS mutations had higher preoperative insulin-like growth factor-1 levels (791.3 ng/mL vs. 697.0 ng/mL, P=0.045) and lower immediate postoperative basal (0.9 ng/mL vs. 1.0 ng/mL, P=0.191) and nadir GH levels (0.3 ng/mL vs. 0.6 ng/mL, P=0.012) in oral glucose tolerance tests. Finally, the GNAS-mutation group showed significantly higher surgical remission rates than the mutation-negative group, both at 1 week and 6 months after surgical resection (70.7% vs. 54.9%, P=0.011; 85.3% vs. 82.4%, P=0.007, respectively).

Conclusion: GNAS mutations in GH-secreting pituitary tumors are associated with higher preoperative insulin-like growth factor-1 levels and surgical remission rates and lower immediate postoperative nadir GH levels. Thus, GNAS mutation status can predict surgical responsiveness in patients with acromegaly.
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http://dx.doi.org/10.3803/EnM.2020.875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090461PMC
April 2021

Revisiting the Role of Insulin-like Growth Factor-1 Measurement After Surgical Treatment of Acromegaly.

J Clin Endocrinol Metab 2021 06;106(7):e2589-e2599

Department of Neurosurgery, Yonsei University College of Medicine, Seoul,Republic of Korea.

Context: In the management of growth hormone (GH)-secreting pituitary adenomas, the oral glucose tolerance test (OGTT) has been the gold standard not only for diagnoses but also for the determination of biochemical remission. Insulin-like growth factor-1 (IGF-1) is an essential biomarker, although it should be adjusted for both age and sex.

Objective: We evaluated whether IGF-1 levels could serve as a reliable alternative to an OGTT for disease monitoring after the surgical treatment of acromegaly. We retrospectively reviewed the medical records of 320 patients who underwent surgical resection of their GH-secreting pituitary tumors at the Severance hospital. Receiver operator characteristic (ROC) analyses were performed to validate the accuracy of IGF-1 levels for the assessment of remission. In addition, regression analyses were performed to identify factors associated with discrepancy between OGTT and IGF-1 levels.

Results: Except for 1 week after surgery, ROC analyses showed an area under the curve of greater than 0.8 for IGF-1 at all time points. Of 320 patients, 270 achieved endocrine remission after surgery alone. Among these patients, IGF-1 levels were normalized in 250 patients. The mean duration from surgery to IGF-1 normalization was 4.7 months. Regression analyses demonstrated that risk of failed IGF-1 normalization was increased by 3.1-fold when the tumor invaded the cavernous sinus and increased by 9.0-fold in patients with incomplete tumor removal.

Conclusion: IGF-1 level is a reliable alternative to OGTT and plays a valuable role in monitoring acromegaly status.
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http://dx.doi.org/10.1210/clinem/dgab186DOI Listing
June 2021

Radiomics With Ensemble Machine Learning Predicts Dopamine Agonist Response in Patients With Prolactinoma.

J Clin Endocrinol Metab 2021 07;106(8):e3069-e3077

Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea.

Context: Early identification of the response of prolactinoma patients to dopamine agonists (DA) is crucial in treatment planning.

Objective: To develop a radiomics model using an ensemble machine learning classifier with conventional magnetic resonance images (MRIs) to predict the DA response in prolactinoma patients.

Design: Retrospective study.

Setting: Severance Hospital, Seoul, Korea.

Patients: A total of 177 prolactinoma patients who underwent baseline MRI (109 DA responders and 68 DA nonresponders) were allocated to the training (n = 141) and test (n = 36) sets. Radiomic features (n = 107) were extracted from coronal T2-weighed MRIs. After feature selection, single models (random forest, light gradient boosting machine, extra-trees, quadratic discrimination analysis, and linear discrimination analysis) with oversampling methods were trained to predict the DA response. A soft voting ensemble classifier was used to achieve the final performance. The performance of the classifier was validated in the test set.

Results: The ensemble classifier showed an area under the curve (AUC) of 0.81 [95% confidence interval (CI), 0.74-0.87] in the training set. In the test set, the ensemble classifier showed an AUC, accuracy, sensitivity, and specificity of 0.81 (95% CI, 0.67-0.96), 77.8%, 78.6%, and 77.3%, respectively. The ensemble classifier achieved the highest performance among all the individual models in the test set.

Conclusions: Radiomic features may be useful biomarkers to predict the DA response in prolactinoma patients.
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http://dx.doi.org/10.1210/clinem/dgab159DOI Listing
July 2021

Danshen Extracts Prevents Obesity and Activates Mitochondrial Function in Brown Adipose Tissue.

Endocrinol Metab (Seoul) 2021 02 24;36(1):185-195. Epub 2021 Feb 24.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Background: Danshen has been widely used in oriental medicine to improve body function. The purpose of this study is to investigate the effect of water-soluble Danshen extract (DE) on weight loss and on activation proteins involved in mitochondrial biogenesis in brown adipose tissue (BAT) in obese mice.

Methods: BAT was isolated from 7-week-old male Sprague-Dawley rats, and expression of proteins related to mitochondrial biogenesis was confirmed in both brown preadipocytes and mature brown adipocytes treated with DE. For the in vivo study, low-density lipoprotein receptor knock out mice were divided into three groups and treated for 17 weeks with: standard diet; high fat diet (HFD); HFD+DE. Body weight was measured every week, and oral glucose tolerance test was performed after DE treatment in streptozotocin-induced diabetic mice. To observe the changes in markers related to thermogenesis and adipogenesis in the BAT, white adipose tissue (WAT) and liver of experimental animals, tissues were removed and immediately frozen in liquid nitrogen.

Results: DE increased the expression of uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in brown preadipocytes, and also promoted the brown adipocyte differentiation and mitochondrial function in the mature brown adipocytes. Reactive oxygen species production in brown preadipocytes was increased depending on the concentration of DE. DE activates thermogenesis in BAT and normalizes increased body weight and adipogenesis in the liver due to HFD. Browning of WAT was increased in WAT of DE treatment group.

Conclusion: DE protects against obesity and activates mitochondrial function in BAT.
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http://dx.doi.org/10.3803/EnM.2020.835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937848PMC
February 2021

Role of Proprotein Convertase Subtilisin/Kexin Type 9 in the Pathogenesis of Graves' Orbitopathy in Orbital Fibroblasts.

Front Endocrinol (Lausanne) 2020 8;11:607144. Epub 2021 Jan 8.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea.

Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in the pathogenesis of inflammatory diseases. We sought to investigate the role of PCSK9 in the pathogenesis of Graves' orbitopathy (GO) and whether it may be a legitimate target for treatment.

Methods: The was compared between GO (n=11) and normal subjects (n=7) in orbital tissue explants using quantitative real-time PCR, and in cultured interleukin-1β (IL-1β)-treated fibroblasts using western blot. Western blot was used to identify the effects of PCSK9 inhibition on IL-1β-induced pro-inflammatory cytokines production and signaling molecules expression as well as levels of adipogenic markers and oxidative stress-related proteins. Adipogenic differentiation was identified using Oil Red O staining. The plasma PCSK9 concentrations were compared between patients with GO (n=44) and healthy subjects (n=26) by ELISA.

Results: The transcript level was higher in GO tissues. The depletion of PCSK9 blunted IL-1β-induced expression of intercellular adhesion molecule 1 (ICAM-1), IL-6, IL-8, and cyclooxygenase-2 (COX-2) in GO and non-GO fibroblasts. The levels of activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphorylated forms of Akt and p38 were diminished when PCSK9 was suppressed in GO fibroblasts. Decreases in lipid droplets and attenuated levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and leptin as well as hypoxia-inducible factor 1α (HIF-1α), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), and heme oxygenase-1 (HO-1) were noted when PCSK9 was suppressed during adipocyte differentiation. The plasma PCSK9 level was significantly higher in GO patients and correlated with level of thyrotropin binding inhibitory immunoglobulin (TBII) and the clinical activity score (CAS).

Conclusions: PCSK9 plays a significant role in GO. The PCSK9 inhibition attenuated the pro-inflammatory cytokines production, oxidative stress, and fibroblast differentiation into adipocytes. PCSK9 may serve as a therapeutic target and biomarker for GO.
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http://dx.doi.org/10.3389/fendo.2020.607144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821242PMC
May 2021

Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment.

Gut 2021 10 18;70(10):1847-1856. Epub 2020 Nov 18.

Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

Objective: The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery.

Design: 2-Deoxy-2-[F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis.

Results: The AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation.

Conclusion: Bariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.
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http://dx.doi.org/10.1136/gutjnl-2020-321402DOI Listing
October 2021

Role of binding immunoglobulin protein (BiP) in Graves' orbitopathy pathogenesis.

J Mol Endocrinol 2021 01;66(1):71-81

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.

Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves' orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by Western blotting and ELISA. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by Western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.
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http://dx.doi.org/10.1530/JME-20-0155DOI Listing
January 2021

Biochemical Remission after Cabergoline Withdrawal in Hyperprolactinemic Patients with Visible Remnant Pituitary Adenoma.

J Clin Endocrinol Metab 2021 01;106(2):e615-e624

Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Context: Dopamine agonists (DAs) are the first-line therapy for prolactinomas. Although pituitary tumors often do not completely disappear, discontinuing DAs in patients with no visible tumor on magnetic resonance imaging is advised.

Objective: To analyze biochemical remission after cabergoline (CAB) withdrawal in patients with visible remnant pituitary tumors.

Design: Retrospective cohort study.

Setting: Severance Hospital.

Subjects: We identified 734 patients with prolactinomas undergoing CAB therapy for at least 12 months from 2005 to 2018. We selected 44 patients with prolactinomas who discontinued CAB with normal prolactin levels; they were receiving a minimal CAB dose but had visible remnant tumors.

Results: Median age at diagnosis was 32 (18-58) years, and most patients were women (95.45%). Median treatment duration was 32 (12-120) months. Of 44 patients, 33 continued to have normoprolactinemia, but 11 patients developed hyperprolactinemia after drug withdrawal within 26 (12-97) months. Age, sex, maximal and remnant tumor size, and treatment duration were similar between the groups. The initial prolactin level and chances of cavernous sinus (CS) invasion were higher in the recurrence group. CS invasion at diagnosis was associated with an increased recurrence rate. Although treatment response did not correlate with the initial and final signal intensity assessments, a significant decrease in T2 intensity ratio after 6 months of CAB therapy was observed in the remission group (P = .043).

Conclusion: In patients with visible tumors, the presence of CS invasion at diagnosis may be an unfavorable predictor for biochemical remission after CAB discontinuation.
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http://dx.doi.org/10.1210/clinem/dgaa744DOI Listing
January 2021

Hemoglobin glycation index is associated with incident chronic kidney disease in subjects with impaired glucose metabolism: A 10-year longitudinal cohort study.

J Diabetes Complications 2021 01 7;35(1):107760. Epub 2020 Oct 7.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang 14068, Republic of Korea; Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju 26426, Republic of Korea. Electronic address:

Aim: We investigated the associations between hemoglobin glycation index (HGI) and incident chronic kidney disease (CKD) in treatment-naïve subjects with prediabetes or diabetes.

Methods: We conducted a prospective cohort study comprising 2187 subjects with prediabetes or diabetes. HGI was calculated as the difference between the measured and predicted values of HbA1c using the linear relationship between HbA1c level and fasting plasma glucose levels. Incident CKD was considered if eGFR decreased to <60 mL/min/1.73 m and by >25% from the baseline value during follow up. The hazard ratios (HRs) for incident CKD were calculated using Cox proportional hazards regression models.

Results: The overall prevalence of CKD was 15.3% (n = 335) during the 10-year follow-up period. The prevalence of CKD increased significantly from the low to the high HGI groups. In the multivariate analysis, the highest HGI group showed the highest adjusted HR for incident CKD (HR, 1.57; 95% confidence interval, 1.06-2.34), and this remained significant even after adjusting for the HbA1c level.

Conclusions: High HGI was associated with an increased risk of incident CKD among treatment-naïve subjects with prediabetes or diabetes, suggesting that HGI may be used to predict CKD in these patients regardless of HbA1c levels.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107760DOI Listing
January 2021

Radiomics model predicts granulation pattern in growth hormone-secreting pituitary adenomas.

Pituitary 2020 Dec;23(6):691-700

Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea.

Purpose: To investigate whether radiomic features from magnetic resonance image (MRI) can predict the granulation pattern of growth hormone (GH)-secreting pituitary adenoma patients.

Methods: Sixty-nine pathologically proven acromegaly patients (densely granulated [DG] = 50, sparsely granulated [SG] = 19) were included. Radiomic features (n = 214) were extracted from contrast-enhancing and total tumor portions from T2-weighted (T2) MRIs. Imaging features were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression model with fivefold cross-validation. Diagnostic performance for predicting granulation pattern was compared with that for qualitative T2 signal intensity assessment and T2 relative signal intensity (rSI) using the area under the receiver operating characteristics curve (AUC).

Results: Four significant radiomic features from the contrast-enhancing tumor (1 from shape, 1 from first order feature, and 2 from second order features) were selected by LASSO for model construction. The radiomics model showed an AUC, accuracy, sensitivity, and specificity of 0.834 (95% confidence interval [CI] 0.738-0.930), 73.7%, 74.0%, and 73.9%, respectively. The radiomics model showed significantly better performance than the model using qualitative T2 signal intensity assessment (AUC 0.597 [95% CI 0.447-0.747], P = 0.009) and T2 rSI (AUC 0.647 [95% CI 0.523-0.759], P = 0.037).

Conclusion: Radiomic features may be useful biomarkers to differentiate granulation pattern of GH-secreting pituitary adenoma patients, and showed better performance than qualitative assessment or rSI evaluation.
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http://dx.doi.org/10.1007/s11102-020-01077-5DOI Listing
December 2020

Association Between Serum Bilirubin and the Progression of Carotid Atherosclerosis in Type 2 Diabetes.

J Lipid Atheroscler 2020 Jan 13;9(1):195-204. Epub 2020 Jan 13.

Huh's Diabetes Center and the 21st Century Diabetes and Vascular Research Institute, Seoul, Korea.

Objective: This study investigated whether serum bilirubin levels can predict the progression of carotid atherosclerosis in individuals with type 2 diabetes mellitus (T2DM).

Methods: This observational study included 1,381 subjects with T2DM in whom serial measurements of carotid intima-media thickness (CIMT) were made at 1- to 2-year intervals for 6-8 years. The progression of carotid atherosclerosis was defined as newly detected plaque lesions on repeat ultrasonography. After dividing total serum bilirubin levels into tertiles, the association between total serum bilirubin at baseline and plaque progression status was analyzed.

Results: Among 1,381 T2DM patients, 599 (43.4%) were categorized as having plaque progression in their carotid arteries. Those with plaque progression were significantly older; showed a higher prevalence of hypertension, abdominal obesity, and chronic kidney disease; and had a longer duration of T2DM, higher levels of total cholesterol (TC), triglycerides, and insulin resistance, and lower total bilirubin concentrations than those with no plaque progression. When total serum bilirubin levels were divided into tertiles, the highest tertile group was younger than the lowest tertile group, with higher levels of TC and high-density lipoprotein cholesterol. Multiple logistic regression analysis demonstrated that higher serum bilirubin levels were associated with a significantly lower risk of CIMT progression (odds ratio, 0.584; 95% confidence interval, 0.392-0.870; =0.008). Age (<0.001), body mass index (=0.023), and TC (=0.019) were also associated with the progression of carotid atherosclerosis in T2DM patients.

Conclusion: Total serum bilirubin is independently associated with progression of atherosclerosis in the carotid arteries in T2DM patients.
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http://dx.doi.org/10.12997/jla.2020.9.1.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379078PMC
January 2020

Protein tyrosine phosphatase 1B as a therapeutic target for Graves' orbitopathy in an in vitro model.

PLoS One 2020 6;15(8):e0237015. Epub 2020 Aug 6.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1β, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-β stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1β, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1β-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-β-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410323PMC
October 2020

Glycogen Synthase Kinase-3β Mediates Proinflammatory Cytokine Secretion and Adipogenesis in Orbital Fibroblasts from Patients with Graves' Orbitopathy.

Invest Ophthalmol Vis Sci 2020 07;61(8):51

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Purpose: We sought to determine the role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Graves' orbitopathy(GO).

Methods: Expression of the GSK-3β gene in whole orbital tissue explants was compared between GO and non-GO donors using quantitative real-time PCR (RT-PCR). The expression of proinflammatory molecules in the presence of the GSK-3β inhibitor CHIR 99021 was analyzed using RT-PCR, western blot, and ELISA. Adipogenic differentiation was identified using Oil Red O staining, and the levels of peroxisome proliferator activator gamma (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) α and β were determined by western blot.

Results: The expression of GSK-3β was significantly higher in GO tissues than in control tissues. The addition of CHIR 99021 led to a decrease in the active form of the kinase in which the Y216 residue is phosphorylated. When GO and non-GO fibroblasts were stimulated with IL-1β or TNF-α, IL-6, IL-8, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-1 (COX-1), and monocyte chemoattractant protein 1 (MCP-1) showed increased production, which was blunted when CHIR 99021 was added. The activation of Akt, PI3K, nuclear factor (NF)-κB, Erk, Jnk, and p38 kinase by IL-1β and TNF-α was diminished with CHIR 99021 in GO cells. A decrease in lipid droplets and expression of PPARγ and c/EBPα and -β was noted in fibroblasts treated with CHIR 99021 during adipocyte differentiation. The inhibition of Wnt and β-catenin in adipogenesis was reversed by CHIR 99021.

Conclusions: GSK-3β plays a significant role in GO pathogenesis. The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. GSK-3β may be a potential target for anti-inflammatory and anti-adipogenic treatment of GO.
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http://dx.doi.org/10.1167/iovs.61.8.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426624PMC
July 2020

Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase.

Lancet Diabetes Endocrinol 2020 09 27;8(9):748-761. Epub 2020 Jul 27.

Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, MA, USA.

Background: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease.

Methods: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete.

Findings: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase.

Interpretation: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1016/S2213-8587(20)30240-0DOI Listing
September 2020

Diagnosis and Treatment of Growth Hormone Deficiency: A Position Statement from Korean Endocrine Society and Korean Society of Pediatric Endocrinology.

Endocrinol Metab (Seoul) 2020 06 24;35(2):272-287. Epub 2020 Jun 24.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea.

Growth hormone (GH) deficiency is caused by congenital or acquired causes and occurs in childhood or adulthood. GH replacement therapy brings benefits to body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life. Before initiating GH replacement, GH deficiency should be confirmed through proper stimulation tests, and in cases with proven genetic causes or structural lesions, repeated GH stimulation testing is not necessary. The dosing regimen of GH replacement therapy should be individualized, with the goal of minimizing side effects and maximizing clinical improvements. The Korean Endocrine Society and the Korean Society of Pediatric Endocrinology have developed a position statement on the diagnosis and treatment of GH deficiency. This position statement is based on a systematic review of evidence and expert opinions.
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http://dx.doi.org/10.3803/EnM.2020.35.2.272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386113PMC
June 2020
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