Endocrinology and Metabolism

Review Articles

Calcium & bone metabolism
Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis: Brendan F. Boyce, Jinbo Li, Zhenqiang Yao, Lianping Xing; Endocrinol Metab. 2023;38(5):504-521. Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.501; Funded: National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute for Aging

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Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

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The Role of Rosavin in the Pathophysiology of Bone Metabolism
Piotr Wojdasiewicz, Paweł Turczyn, Anna Lach-Gruba, Łukasz A. Poniatowski, Daryush Purrahman, Mohammad-Reza Mahmoudian-Sani, Dariusz Szukiewicz
International Journal of Molecular Sciences.2024; 25(4): 2117. CrossRef
The role of monocyte/macrophage chemokines in pathogenesis of osteoarthritis: A review
Hao Luo, Linfeng Li, Song Han, Tao Liu
International Journal of Immunogenetics.2024;[Epub] CrossRef
The effect of low-level laser therapy on osteoclast differentiation: Clinical implications for tooth movement and bone density
Chun-Yi Huang, Huynh Hoai Thuong Le, Hsiao-Chi Tsai, Chih-Hsin Tang, Jian-Hong Yu
Journal of Dental Sciences.2024;[Epub] CrossRef
Genetic Deficiency of the Long Pentraxin 3 Affects Osteogenesis and Osteoclastogenesis in Homeostatic and Inflammatory Conditions
Valentina Granata, Dario Strina, Maria Lucia Schiavone, Barbara Bottazzi, Alberto Mantovani, Antonio Inforzato, Cristina Sobacchi
International Journal of Molecular Sciences.2023; 24(23): 16648. CrossRef

Diabetes, obesity and metabolism
The Emerging Importance of Mitochondria in White Adipocytes: Neither Last nor Least: Juan Cai, Fenfen Wang, Mengle Shao; Endocrinol Metab. 2023;38(5):493-503. Published online October 10, 2023; DOI: https://doi.org/10.3803/EnM.2023.1813; Funded: National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Municipal Science and Technology Project, Shanghai Pujiang Program, China Postdoctoral Science Foundation, Shanghai Postdoctoral Excellence Program, Special Research Assistant Funding Project of Chinese Academy of Sciences

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Abstract PDF PubReader ePub: The growing recognition of mitochondria’s crucial role in the regulation of white adipose tissue remodeling and energy balance underscores its significance. The marked metabolic diversity of mitochondria provides the molecular and cellular foundation for enabling adipose tissue plasticity in response to various metabolic cues. Effective control of mitochondrial function at the cellular level, not only in thermogenic brown and beige adipocytes but also in energy-storing white adipocytes, exerts a profound influence on adipose homeostasis. Furthermore, mitochondria play a pivotal role in intercellular communication within adipose tissue via production of metabolites with signaling properties. A more comprehensive understanding of mitochondrial regulation within white adipocytes will empower the development of targeted and efficacious strategies to enhance adipose function, leading to advancements in overall metabolic health.

Diabetes, obesity and metabolism
The Impact of Taurine on Obesity-Induced Diabetes Mellitus: Mechanisms Underlying Its Effect: Kainat Ahmed, Ha-Neul Choi, Jung-Eun Yim; Endocrinol Metab. 2023;38(5):482-492. Published online October 17, 2023; DOI: https://doi.org/10.3803/EnM.2023.1776; Funded: Financial Program for Self-Directed Research Capacity

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This review explores the potential benefits of taurine in ameliorating the metabolic disorders of obesity and type 2 diabetes (T2D), highlighting the factors that bridge these associations. Relevant articles and studies were reviewed to conduct a comprehensive analysis of the relationship between obesity and the development of T2D and the effect of taurine on those conditions. The loss of normal β-cell function and development of T2D are associated with obesity-derived insulin resistance. The occurrence of diabetes has been linked to the low bioavailability of taurine, which plays critical roles in normal β-cell function, anti-oxidation, and anti-inflammation. The relationships among obesity, insulin resistance, β-cell dysfunction, and T2D are complex and intertwined. Taurine may play a role in ameliorating these metabolic disorders through different pathways, but further research is needed to fully understand its effects and potential as a therapeutic intervention.

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Effect of a Very Low-Calorie Diet on Oxidative Stress, Inflammatory and Metabolomic Profile in Metabolically Healthy and Unhealthy Obese Subjects
Neus Bosch-Sierra, Carmen Grau-del Valle, Christian Salom, Begoña Zaragoza-Villena, Laura Perea-Galera, Rosa Falcón-Tapiador, Susana Rovira-Llopis, Carlos Morillas, Daniel Monleón, Celia Bañuls
Antioxidants.2024; 13(3): 302. CrossRef

Original Articles

Thyroid
Beyond Acute COVID-19: Investigating the Incidence of Subacute Thyroiditis in Long COVID-19 in Korea: Jeongmin Lee, Gi Hyeon Seo, Keeho Song; Endocrinol Metab. 2023;38(4):455-461. Published online August 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1711; Funded: Korean Endocrine Society

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Background
The correlation between acute coronavirus disease 2019 (COVID-19) and subacute thyroiditis (SAT) has not been clearly investigated in “long COVID” patients. We aimed to investigate the incidence of SAT during convalescence and after the acute phase of COVID-19, comparing with that of the general population.
Methods
Data from a total of 422,779 COVID-19 patients and a control group of 2,113,895 individuals were analyzed. The index date was defined as the date 3 months after confirmation of COVID-19. The incidence rate (IR) of SAT and hazard ratios (HRs) were calculated per 100,000 persons. Subgroup analysis included analysis of HRs 90–179 and 180 days post-COVID-19 diagnosis; and additional analysis was conducted according to hospitalization status, sex, and age group.
Results
The IR of SAT was 17.28 per 100,000 persons (95% confidence interval [CI], 12.56 to 23.20) in the COVID-19 group and 8.63 (95% CI, 6.37 to 11.45) in the control group. The HR of COVID-19 patients was 1.76 (95% CI, 1.01 to 3.06; P=0.045). The HR of SAT was 1.39 (95% CI, 0.82 to 2.34; P=0.220) up to 6 months after the index date and 2.30 (95% CI, 1.60 to 3.30; P<0.001) beyond 6 months. The HR for SAT among COVID-19 patients was 2.00 (95% CI, 1.41 to 2.83) in hospitalized patients and 1.76 (95% CI, 1.01 to 3.06) in non-hospitalized patients compared to the control group. The IR of SAT was 27.09 (95% CI, 20.04 to 35.82) for females and 6.47 (95% CI, 3.34 to 11.30) for males. In the 19 to 64 age group, the IR of SAT was 18.19 (95% CI, 13.70 to 23.67), while the IR was 9.18 (95% CI, 7.72 to 10.84) in the 65 to 69 age group.
Conclusion
SAT could be a potential long-term complication of COVID-19. Long-term surveillance for thyroid dysfunction is needed especially in hospitalized, female and young-aged subjects.

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Thyroid dysfunction in COVID-19
David Tak Wai Lui, Chi Ho Lee, Yu Cho Woo, Ivan Fan Ngai Hung, Karen Siu Ling Lam
Nature Reviews Endocrinology.2024;[Epub] CrossRef
Subacute Thyroiditis in the Time of COVID-19
Hwa Young Ahn
Endocrinology and Metabolism.2024; 39(1): 186. CrossRef
Occult endocrine disorders newly diagnosed in patients with post-COVID-19 symptoms
Yasuhiro Nakano, Naruhiko Sunada, Kazuki Tokumasu, Hiroyuki Honda, Yuki Otsuka, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Daisuke Omura, Kanako Ochi, Miho Yasuda, Hideharu Hagiya, Keigo Ueda, Fumio Otsuka
Scientific Reports.2024;[Epub] CrossRef
rRisk of incident thyroid dysfunction in the post-acute phase of COVID-19: a population-based cohort study in Hong Kong
David Tak Wai Lui, Xi Xiong, Ching‐Lung Cheung, Francisco Tsz Tsun Lai, Xue Li, Eric Yuk Fai Wan, Celine Sze Ling Chui, Esther Wai Yin Chan, Franco Wing Tak Cheng, Lanlan Li, Matthew Shing Hin Chung, Chi Ho Lee, Yu Cho Woo, Kathryn Choon Beng Tan, Carlos
Endocrine Practice.2024;[Epub] CrossRef

Thyroid
Different Molecular Phenotypes of Progression in BRAF- and RAS-Like Papillary Thyroid Carcinoma: Jinsun Lim, Han Sai Lee, Jiyun Park, Kyung-Soo Kim, Soo-Kyung Kim, Yong-Wook Cho, Young Shin Song; Endocrinol Metab. 2023;38(4):445-454. Published online July 18, 2023; DOI: https://doi.org/10.3803/EnM.2023.1702; Funded: National Research Foundation of Korea, Ministry of Science and ICT

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Abstract PDF Supplementary Material PubReader ePub: Background
Papillary thyroid carcinoma (PTC) can be classified into two distinct molecular subtypes, BRAF-like (BL) and RASlike (RL). However, the molecular characteristics of each subtype according to clinicopathological factors have not yet been determined. We aimed to investigate the gene signatures and tumor microenvironment according to clinicopathological factors, and to identify the mechanism of progression in BL-PTCs and RL-PTCs.
Methods
We analyzed RNA sequencing data and corresponding clinicopathological information of 503 patients with PTC from The Cancer Genome Atlas database. We performed differentially expressed gene (DEG), Gene Ontology, and molecular pathway enrichment analyses according to clinicopathological factors in each molecular subtype. EcoTyper and CIBERSORTx were used to deconvolve the tumor cell types and their surrounding microenvironment.
Results
Even for the same clinicopathological factors, overlapping DEGs between the two molecular subtypes were uncommon, indicating that BL-PTCs and RL-PTCs have different progression mechanisms. Genes related to the extracellular matrix were commonly upregulated in BL-PTCs with aggressive clinicopathological factors, such as old age (≥55 years), presence of extrathyroidal extension, lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and high metastasis-age-completeness of resection- invasion-size (MACIS) scores (≥6). Furthermore, in the deconvolution analysis of tumor microenvironment, cancer-associated fibroblasts were significantly enriched. In contrast, in RL-PTCs, downregulation of immune response and immunoglobulin-related genes was significantly associated with aggressive characteristics, even after adjusting for thyroiditis status.
Conclusion
The molecular phenotypes of cancer progression differed between BL-PTC and RL-PTC. In particular, extracellular matrix and cancer-associated fibroblasts, which constitute the tumor microenvironment, would play an important role in the progression of BL-PTC that accounts for the majority of advanced PTCs.

Thyroid Big Data Articles (National Health Insurance Service Database)
Prevalence, Treatment Status, and Comorbidities of Hyperthyroidism in Korea from 2003 to 2018: A Nationwide Population Study: Hwa Young Ahn, Sun Wook Cho, Mi Young Lee, Young Joo Park, Bon Seok Koo, Hang-Seok Chang, Ka Hee Yi; Endocrinol Metab. 2023;38(4):436-444. Published online July 12, 2023; DOI: https://doi.org/10.3803/EnM.2023.1684; Funded: Korean Thyroid Association, National Health Insurance Service

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Background
This study aimed to investigate the changes of incidence and treatment of choice for hyperthyroidism from 2003 to 2018 and explore the treatment-related complications and concomitant comorbidities in South Korea using data from the National Health Insurance Service.
Methods
This is a retrospective observational study. Hyperthyroidism was defined as a case having two or more diagnostic codes of thyrotoxicosis, with antithyroid drug intake for more than 6 months.
Results
The average age-standardized incidence of hyperthyroidism from 2003 to 2018 was 42.23 and 105.13 per 100,000 men and women, respectively. In 2003 to 2004, hyperthyroidism was most often diagnosed in patients in their 50s, but in 2017 to 2018, people were most often diagnosed in their 60s. During the entire period, about 93.7% of hyperthyroidism patients were prescribed with antithyroid drugs, and meanwhile, the annual rates of ablation therapy decrease from 7.68% in 2008 to 4.56% in 2018. Antithyroid drug-related adverse events, mainly agranulocytosis and acute hepatitis, as well as complications of hyperthyroidism such as atrial fibrillation or flutter, osteoporosis, and fractures, occurred more often in younger patients.
Conclusion
In Korea, hyperthyroidism occurred about 2.5 times more in women than in men, and antithyroid drugs were most preferred as the first-line treatment. Compared to the general population, hyperthyroid patients may have a higher risk of atrial fibrillation or flutter, osteoporosis, and fractures at a younger age.

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Long-term effect of thyrotropin-binding inhibitor immunoglobulin on atrial fibrillation in euthyroid patients
Jung-Chi Hsu, Kang-Chih Fan, Ting-Chuan Wang, Shu-Lin Chuang, Ying-Ting Chao, Ting-Tse Lin, Kuan-Chih Huang, Lian-Yu Lin, Lung-Chun Lin
Endocrine Practice.2024;[Epub] CrossRef
The Current Status of Hyperthyroidism in Korea
Hyemi Kwon
Endocrinology and Metabolism.2023; 38(4): 392. CrossRef
Is Thyroid Dysfunction Associated with Unruptured Intracranial Aneurysms? A Population-Based, Nested Case–Control Study from Korea
Hyeree Park, Sun Wook Cho, Sung Ho Lee, Kangmin Kim, Hyun-Seung Kang, Jeong Eun Kim, Aesun Shin, Won-Sang Cho
Thyroid®.2023; 33(12): 1483. CrossRef

Diabetes, obesity and metabolism
Risk of Pancreatic Cancer and Use of Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes: A Propensity Score-Matching Analysis: Mee Kyoung Kim, Kyungdo Han, Hyuk-Sang Kwon, Soon Jib Yoo; Endocrinol Metab. 2023;38(4):426-435. Published online July 20, 2023; DOI: https://doi.org/10.3803/EnM.2023.1737; Funded: Korean Society of Endocrinology

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Background
The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors over the course of long-term treatment remain unclear, and concerns have been raised regarding the role of DPP-4 inhibitors in carcinogenesis in the pancreas. Earlier studies of pancreatic adverse events have reported conflicting results.
Methods
This study analyzed Korean National Health Insurance Service data from January 2009 to December 2012. Patients who had type 2 diabetes mellitus and took two or more oral glucose-lowering drugs (GLDs) were included. Patients prescribed DPP-4 inhibitors (n=51,482) or other GLDs (n=51,482) were matched at a 1:1 ratio using propensity score matching. The risk of pancreatic cancer was calculated using Kaplan-Meier curves and Cox proportional-hazards regression analysis.
Results
During a median follow-up period of 7.95 years, 1,051 new cases of pancreatic cancer were identified. The adjusted hazard ratio (HR) for DPP-4 inhibitor use was 0.99 (95% confidence interval [CI], 0.88 to 1.12) compared with the other GLD group. In an analysis limited to cases diagnosed with pancreatic cancer during hospitalization, the adjusted HR for the use of DPP-4 inhibitors was 1.00 (95% CI, 0.86 to 1.17) compared with patients who took other GLDs. Using the other GLD group as the reference group, no trend was observed for elevated pancreatic cancer risk with increased DPP-4 inhibitor exposure.
Conclusion
In this population-based cohort study, DPP-4 inhibitor use over the course of relatively long-term follow-up showed no significant association with an elevated risk of pancreatic cancer.

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Diabetes Duration, Cholesterol Levels, and Risk of Cardiovascular Diseases in Individuals With Type 2 Diabetes
Mee Kyoung Kim, Kyu Na Lee, Kyungdo Han, Seung-Hwan Lee
The Journal of Clinical Endocrinology & Metabolism.2024;[Epub] CrossRef

Diabetes, obesity and metabolism
Triglyceride-Glucose Index Predicts Future Atherosclerotic Cardiovascular Diseases: A 16-Year Follow-up in a Prospective, Community-Dwelling Cohort Study: Joon Ho Moon, Yongkang Kim, Tae Jung Oh, Jae Hoon Moon, Soo Heon Kwak, Kyong Soo Park, Hak Chul Jang, Sung Hee Choi, Nam H. Cho; Endocrinol Metab. 2023;38(4):406-417. Published online August 3, 2023; DOI: https://doi.org/10.3803/EnM.2023.1703; Funded: National Research Foundation of Korea, Korea Health Industry Development Institute, Ministry of Health and Welfare, Korea Centers for Disease Control & Prevention, Ministry of Science and ICT, Medical Research Center

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Background
While the triglyceride-glucose (TyG) index is a measure of insulin resistance, its association with cardiovascular disease (CVD) has not been well elucidated. We evaluated the TyG index for prediction of CVDs in a prospective large communitybased cohort.
Methods
Individuals 40 to 70 years old were prospectively followed for a median 15.6 years. The TyG index was calculated as the Ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. CVDs included any acute myocardial infarction, coronary artery disease or cerebrovascular disease. We used a Cox proportional hazards model to estimate CVD risks according to quartiles of the TyG index and plotted the receiver operating characteristics curve for the incident CVD.
Results
Among 8,511 subjects (age 51.9±8.8 years; 47.5% males), 931 (10.9%) had incident CVDs during the follow-up. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, total cholesterol, smoking, alcohol, exercise, and C-reactive protein, subjects in the highest TyG quartile had 36% increased risk of incident CVD compared with the lowest TyG quartile (hazard ratio, 1.36; 95% confidence interval, 1.10 to 1.68). Carotid plaque, assessed by ultrasonography was more frequent in subjects in the higher quartile of TyG index (P for trend=0.049 in men and P for trend <0.001 in women). The TyG index had a higher predictive power for CVDs than the homeostasis model assessment of insulin resistance (HOMA-IR) (area under the curve, 0.578 for TyG and 0.543 for HOMA-IR). Adding TyG index on diabetes or hypertension alone gave sounder predictability for CVDs.
Conclusion
The TyG index is independently associated with future CVDs in 16 years of follow-up in large, prospective Korean cohort.

Citations

Citations to this article as recorded by

Construction and validation of a nomogram for predicting diabetes remission at 3 months after bariatric surgery in patients with obesity combined with type 2 diabetes mellitus
Kaisheng Yuan, Bing Wu, Ruiqi Zeng, Fuqing Zhou, Ruixiang Hu, Cunchuan Wang
Diabetes, Obesity and Metabolism.2024; 26(1): 169. CrossRef
Association between the triglyceride glucose index and chronic total coronary occlusion: A cross-sectional study from southwest China
Kaiyong Xiao, Huili Cao, Bin Yang, Zhe Xv, Lian Xiao, Jianping Wang, Shuiqing Ni, Hui Feng, Zhongwei He, Lei Xv, Juan Li, Dongmei Xv
Nutrition, Metabolism and Cardiovascular Diseases.2024; 34(4): 850. CrossRef
The association between TyG and all-cause/non-cardiovascular mortality in general patients with type 2 diabetes mellitus is modified by age: results from the cohort study of NHANES 1999–2018
Younan Yao, Bo Wang, Tian Geng, Jiyan Chen, Wan Chen, Liwen Li
Cardiovascular Diabetology.2024;[Epub] CrossRef
Triglyceride-glucose index predicts type 2 diabetes mellitus more effectively than oral glucose tolerance test-derived insulin sensitivity and secretion markers
Min Jin Lee, Ji Hyun Bae, Ah Reum Khang, Dongwon Yi, Mi Sook Yun, Yang Ho Kang
Diabetes Research and Clinical Practice.2024; 210: 111640. CrossRef
Evaluation of the novel three lipid indices for predicting five- and ten-year incidence of cardiovascular disease: findings from Kerman coronary artery disease risk factors study (KERCADRS)
Alireza Jafari, Hamid Najafipour, Mitra Shadkam, Sina Aminizadeh
Lipids in Health and Disease.2023;[Epub] CrossRef

Diabetes, obesity and metabolism
Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells: Cong Thuc Le, Giang Nguyen, So Young Park, Hanh Nguyen Dong, Yun Kyung Cho, Jae-Ho Lee, Seung-Soon Im, Dae-Hee Choi, Eun-Hee Cho; Endocrinol Metab. 2023;38(4):395-405. Published online August 3, 2023; DOI: https://doi.org/10.3803/EnM.2023.1661; Funded: National Research Foundation of Korea

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Abstract PDF PubReader ePub: Background
Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study.
Methods
In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver.
Results
Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis.
Conclusion
Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.

Review Articles

Thyroid
Management of Subclinical Hypothyroidism: A Focus on Proven Health Effects in the 2023 Korean Thyroid Association Guidelines: Eu Jeong Ku, Won Sang Yoo, Hyun Kyung Chung; Endocrinol Metab. 2023;38(4):381-391. Published online August 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1778; Funded: Ministry of Health and Welfare

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Subclinical hypothyroidism (SCH) is characterized by elevated thyroid-stimulating hormone (TSH) and normal free thyroxine levels. The Korean Thyroid Association recently issued a guideline for managing SCH, which emphasizes Korean-specific TSH diagnostic criteria and highlights the health benefits of levothyroxine (LT4) treatment. A serum TSH level of 6.8 mIU/L is presented as the reference value for diagnosing SCH. SCH can be classified as mild (TSH 6.8 to 10.0 mIU/L) or severe (TSH >10.0 mIU/L), and patients can be categorized as adults (age <70 years) or elderly (age ≥70 years), depending on the health effects of LT4 treatment. An initial increase in serum TSH levels should be reassessed with a subsequent measurement, including a thyroid peroxidase antibody test, preferably 2 to 3 months after the initial assessment. While LT4 treatment is not generally recommended for mild SCH in adults, it is necessary for severe SCH in patients with underlying coronary artery disease or heart failure and it may be considered for those with concurrent dyslipidemia. Conversely, LT4 treatment is generally not recommended for elderly patients, regardless of SCH severity. For those SCH patients who are prescribed LT4 treatment, the dosage should be personalized, and serum TSH levels should be regularly monitored to maintain the optimal LT4 regimen.

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Clinical Implications of Different Thyroid-Stimulating Hormone (TSH) Reference Intervals between TSH Kits for the Management of Subclinical Hypothyroidism
Won Sang Yoo
Endocrinology and Metabolism.2024; 39(1): 188. CrossRef

Adrenal Gland
Recent Updates on the Management of Adrenal Incidentalomas: Seung Shin Park, Jung Hee Kim; Endocrinol Metab. 2023;38(4):373-380. Published online August 16, 2023; DOI: https://doi.org/10.3803/EnM.2023.1779; Funded: Korea Health Industry Development Institute, Ministry of Health and Welfare

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Abstract PDF PubReader ePub: Adrenal incidentalomas represent an increasingly common clinical conundrum with significant implications for patients. The revised 2023 European Society of Endocrinology (ESE) guideline incorporates cutting-edge evidence for managing adrenal incidentalomas. This paper provides a concise review of the updated contents of the revised guideline. In the 2023 guideline, in patients without signs and symptoms of overt Cushing’s syndrome, a post-dexamethasone cortisol level above 50 nmol/L (>1.8 μg/dL) should be considered as mild autonomous cortisol secretion. Regarding the criteria of benign adrenal adenomas, a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size. The updated guideline also discusses steroid metabolomics using tandem mass spectrometry to discriminate malignancy. It underscores the importance of high-volume surgeons performing adrenalectomy and emphasizes the pivotal role of a multidisciplinary team approach in deciding the treatment plan for indeterminate adrenal masses. The guideline advocates for more proactive surgical treatment for indeterminate adrenal masses in young patients (<40 years) and pregnant women. This review of the 2023 ESE guideline underscores the ongoing evolution of the adrenal incidentaloma management landscape, emphasizing the need for further research and adaptation of diagnostic and therapeutic strategies.

Diabetes, obesity and metabolism
Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis: Eun Sil Koh, Gheun-Ho Kim, Sungjin Chung; Endocrinol Metab. 2023;38(4):359-372. Published online July 24, 2023; DOI: https://doi.org/10.3803/EnM.2023.1764; Funded: National Research Foundation of Korea, Ministry of Science and ICT

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When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Citations

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Results from a cross-specialty consensus on optimal management of patients with chronic kidney disease (CKD): from screening to complications
Mustafa Arici, Samir Helmy Assaad-Khalil, Marcello Casaccia Bertoluci, Jason Choo, Yau-Jiunn Lee, Magdalena Madero, Guillermo Javier Rosa Diez, Vicente Sánchez Polo, Sungjin Chung, Teerawat Thanachayanont, Carol Pollock
BMJ Open.2024; 14(3): e080891. CrossRef
Chronic Kidney Disease and SGLT2 Inhibitors
Eun Sil Koh, Sungjin Chung
The Journal of Korean Diabetes.2024; 25(1): 16. CrossRef
Genitourinary Tract Infections in Patients Taking SGLT2 Inhibitors
Veraprapas Kittipibul, Zachary L. Cox, Supavit Chesdachai, Mona Fiuzat, JoAnn Lindenfeld, Robert J. Mentz
Journal of the American College of Cardiology.2024; 83(16): 1568. CrossRef
Synopsis of the Korean Society of Nephrology 2023 Practical Recommendations for the Management of Diabetic Kidney Disease
Sungjin Chung
The Korean Journal of Medicine.2023; 98(6): 270. CrossRef

Original Articles

Thyroid
Thyroid Hormone Reference Intervals among Healthy Individuals In Lanzhou, China: Yan Lu, Wen-Xia Zhang, De-Hong Li, Lian-Hua Wei, Yu-Jun Zhang, Fu-Na Shi, Shen Zhou; Endocrinol Metab. 2023;38(3):347-356. Published online June 14, 2023; DOI: https://doi.org/10.3803/EnM.2023.1638; Funded: Gansu Provincial People’s Hospital

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Abstract PDF PubReader ePub: Background
The common reference intervals (RIs) for thyroid hormones currently used in China are provided by equipment manufacturers. This study aimed to establish thyroid hormone RIs in the population of Lanzhou, a city in the subplateau region of northwest China, and compare them with previous reports and manufacturer-provided values.
Methods
In total, 3,123 individuals (1,680 men, 1,443 women) from Lanzhou, an iodine-adequate area of China, perceived as healthy were selected. The Abbott Architect analyzer was used to determine the serum concentration of thyroid hormones. The 95% RI was estimated using the 2.5th and 97.5th percentiles as the lower and upper reference limits, respectively.
Results
The serum levels of thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), antithyroglobulin (ATG) antibody, and antithyroid peroxidase (ATPO) antibody levels were significantly correlated with sex (P<0.05). TSH, total thyroxine (TT4), and ATPO levels were significantly correlated with age (P<0.05). The serum levels of TSH, ATG, and ATPO in men were significantly lower than in women; in contrast, the serum TT3 level was significantly higher in men than in women (P<0.05). Serum TSH, TT3, TT4, and ATG levels differed across age groups (P<0.05), but no such variation was observed for ATG levels (P>0.05). The established RIs of TSH, ATG, and ATPO in this study differed between sexes (P<0.05). The thyroid hormone RIs established herein were inconsistent with the manufacturer-provided values.
Conclusion
The RIs of thyroid hormones in the healthy population of Lanzhou were inconsistent with those in the manufacturer’s manual. Validated sex-specific values are required for diagnosing thyroid diseases.

Diabetes, obesity and metabolism
Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION): Byung Wan Lee, KyungWan Min, Eun-Gyoung Hong, Bon Jeong Ku, Jun Goo Kang, Suk Chon, Won-Young Lee, Mi Kyoung Park, Jae Hyeon Kim, Sang Yong Kim, Keeho Song, Soon Jib Yoo; Endocrinol Metab. 2023;38(3):328-337. Published online June 28, 2023; DOI: https://doi.org/10.3803/EnM.2023.1688; Funded: LG Chem, Ltd.

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Abstract PDF Supplementary Material PubReader ePub: Background
This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin.
Methods
In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks.
Results
The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was –0.66% (0.07) with a 95% confidence interval of –0.80% to –0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted.
Conclusion
Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Diabetes, obesity and metabolism
Effects of Weight Loss and Interaction with Physical Activity on Risks of Cardiovascular Outcomes in Individuals with Type 2 Diabetes: Claudia R. L. Cardoso, Nathalie C. Leite, Gil F. Salles; Endocrinol Metab. 2023;38(3):305-314. Published online May 31, 2023; DOI: https://doi.org/10.3803/EnM.2023.1690; Funded: Conselho Brasileiro de Desenvolvimento Científico e Tecnológico, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

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Background
This study investigated the effects of weight loss during follow-up on cardiovascular outcomes in a type 2 diabetes cohort and tested interactions with clinical and laboratory variables, particularly physical activity, that could impact the associations.
Methods
Relative weight changes were assessed in 651 individuals with type 2 diabetes and categorized as ≥5% loss, <5% loss, or gain. Associations between weight loss categories and incident cardiovascular outcomes (total cardiovascular events [CVEs], major adverse cardiovascular events [MACEs], and cardiovascular mortality) were assessed using multivariable Cox regression with interaction analyses.
Results
During the initial 2 years, 125 individuals (19.2%) lost ≥5% of their weight, 180 (27.6%) lost <5%, and 346 (53.1%) gained weight. Over a median additional follow-up of 9.3 years, 188 patients had CVEs (150 MACEs) and 106 patients died from cardiovascular causes. Patients with ≥5% weight loss had a significantly lower risk of total CVEs (hazard ratio [HR], 0.52; 95% confidence interval, 0.33 to 0.89; P=0.011) than those who gained weight, but non-significant lower risks of MACEs or cardiovascular deaths. Patients with <5% weight loss had risks similar to those with weight gain. There were interactions between weight loss and physical activity. In active individuals, ≥5% weight loss was associated with significantly lower risks for total CVEs (HR, 0.20; P=0.004) and MACEs (HR, 0.21; P=0.010), whereas in sedentary individuals, no cardiovascular protective effect of weight loss was evidenced.
Conclusion
Weight loss ≥5% may be beneficial for cardiovascular disease prevention, particularly when achieved with regular physical activity, even in high-risk individuals with long-standing type 2 diabetes.

Citations

Citations to this article as recorded by

Weight change in patients with new‐onset type 2 diabetes mellitus and its association with remission: Comprehensive real‐world data
Jinyoung Kim, Bongseong Kim, Mee Kyoung Kim, Ki‐Hyun Baek, Ki‐Ho Song, Kyungdo Han, Hyuk‐Sang Kwon
Diabetes, Obesity and Metabolism.2024; 26(2): 567. CrossRef
Cardiovascular Risk Reduction in Type 2 Diabetes: Further Insights into the Power of Weight Loss and Exercise
Seung-Hwan Lee
Endocrinology and Metabolism.2023; 38(3): 302. CrossRef
Effects of body weight variability on risks of macro- and microvascular outcomes in individuals with type 2 diabetes: The Rio de Janeiro type 2 diabetes cohort
Claudia R.L. Cardoso, Nathalie C. Leite, Gil F. Salles
Diabetes Research and Clinical Practice.2023; 205: 110992. CrossRef

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