Endocrinology and Metabolism

Volume 38(5); October 2023

Songwon Lecture 2022

Hypothalamus and pituitary gland
Multiomics Approach to Acromegaly: Unveiling Translational Insights for Precision Medicine: Kyungwon Kim, Cheol Ryong Ku, Eun Jig Lee; Endocrinol Metab. 2023;38(5):463-471. Published online October 13, 2023; DOI: https://doi.org/10.3803/EnM.2023.1820

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Abstract PDF PubReader ePub: The clinical characteristics and prognoses of acromegaly vary among patients. Assessment of current and novel predictors can lead to multilevel categorization of patients, allowing integration into new clinical guidelines and a reduction in the increased morbidity and mortality associated with acromegaly. Despite advances in the diagnosis and treatment of acromegaly, its pathophysiology remains unclear. Recent advancements in multiomics technologies, including genomics, transcriptomics, proteomics, metabolomics, and radiomics, have offered new opportunities to unravel the complex pathophysiology of acromegaly. This review comprehensively explores the emerging role of multiomics approaches in elucidating the molecular landscape of acromegaly. We discuss the potential implications of multiomics data integration in the development of novel diagnostic tools, identification of therapeutic targets, and the prospects of precision medicine in acromegaly management. By integrating diverse omics datasets, these approaches can provide valuable insights into disease mechanisms, facilitate the identification of diagnostic biomarkers, and identify potential therapeutic targets for precision medicine in the management of acromegaly.

Review Articles

Diabetes, obesity and metabolism
The Benefits Of Continuous Glucose Monitoring In Pregnancy: Jee Hee Yoo, Jae Hyeon Kim; Endocrinol Metab. 2023;38(5):472-481. Published online October 11, 2023; DOI: https://doi.org/10.3803/EnM.2023.1805

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Abstract PDF PubReader ePub: Previous studies have consistently demonstrated the positive effects of continuous glucose monitoring (CGM) on glycemic outcomes and complications of diabetes in people with type 1 diabetes. Guidelines now consider CGM to be an essential and cost-effective device for managing type 1 diabetes. As a result, insurance coverage for it is available. Evidence supporting CGM continues to grow and expand to broader populations, such as pregnant people with type 1 diabetes, people with type 2 diabetes treated only with basal insulin therapy, and even type 2 diabetes that does not require insulin treatment. However, despite the significant risk of hyperglycemia in pregnancy, which leads to complications in more than half of affected newborns, CGM indications and insurance coverage for those patients are unresolved. In this review article, we discuss the latest evidence for using CGM to offer glycemic control and reduce perinatal complications, along with its cost-effectiveness in pregestational type 1 and type 2 diabetes and gestational diabetes mellitus. In addition, we discuss future prospects for CGM coverage and indications based on this evidence.

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

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Abstract PDF PubReader ePub: 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.

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

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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.

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

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Abstract PDF PubReader ePub: 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.

Editorial

Diabetes, obesity and metabolism
The Characteristics and Risk of Mortality in the Elderly Korean Population: Sunghwan Suh; Endocrinol Metab. 2023;38(5):522-524. Published online October 23, 2023; DOI: https://doi.org/10.3803/EnM.2023.502

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Original Articles

Diabetes, obesity and metabolism
Risk of Cause-Specific Mortality across Glucose Spectrum in Elderly People: A Nationwide Population-Based Cohort Study: Joonyub Lee, Hun-Sung Kim, Kee-Ho Song, Soon Jib Yoo, Kyungdo Han, Seung-Hwan Lee, Committee of Big Data, Korean Endocrine Society; Endocrinol Metab. 2023;38(5):525-537. Published online September 7, 2023; DOI: https://doi.org/10.3803/EnM.2023.1765

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Background
This study investigated the risk of cause-specific mortality according to glucose tolerance status in elderly South Koreans.
Methods
A total of 1,292,264 individuals aged ≥65 years who received health examinations in 2009 were identified from the National Health Information Database. Participants were classified as normal glucose tolerance, impaired fasting glucose, newly-diagnosed diabetes, early diabetes (oral hypoglycemic agents ≤2), or advanced diabetes (oral hypoglycemic agents ≥3 or insulin). The risk of system-specific and disease-specific deaths was estimated using multivariate Cox proportional hazards analysis.
Results
During a median follow-up of 8.41 years, 257,356 deaths were recorded. Diabetes was associated with significantly higher risk of all-cause mortality (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.57 to 1.60); death due to circulatory (HR, 1.49; 95% CI, 1.46 to 1.52), respiratory (HR, 1.51; 95% CI, 1.47 to 1.55), and genitourinary systems (HR, 2.22; 95% CI, 2.10 to 2.35); and neoplasms (HR, 1.30; 95% CI, 1.28 to 1.32). Diabetes was also associated with a significantly higher risk of death due to ischemic heart disease (HR, 1.70; 95% CI, 1.63 to 1.76), cerebrovascular disease (HR, 1.46; 95% CI, 1.41 to 1.50), pneumonia (HR, 1.69; 95% CI, 1.63 to 1.76), and acute or chronic kidney disease (HR, 2.23; 95% CI, 2.09 to 2.38). There was a stepwise increase in the risk of death across the glucose spectrum (P for trend <0.0001). Stroke, heart failure, or chronic kidney disease increased the risk of all-cause mortality at every stage of glucose intolerance.
Conclusion
A dose-dependent association between the risk of mortality from various causes and severity of glucose tolerance was noted in the elderly population.

Citations

Citations to this article as recorded by

The Characteristics and Risk of Mortality in the Elderly Korean Population
Sunghwan Suh
Endocrinology and Metabolism.2023; 38(5): 522. CrossRef

Diabetes, obesity and metabolism
Intake of Fruit and Glycemic Control in Korean Patients with Diabetes Mellitus Using the Korea National Health and Nutrition Examination Survey: Eunju Yoon, Ji Cheol Bae, Sunghwan Suh; Endocrinol Metab. 2023;38(5):538-544. Published online August 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1730

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Background
Despite the well-recognized health benefits of fresh fruit consumption, there is still substantial uncertainty about its potential effects on glycemic control in patients with type 2 diabetes mellitus (T2DM).
Methods
We examined the association of fresh fruit consumption and glycemic control in patients with T2DM using data from the 6th Korea National Health and Nutrition Examination Survey. The study sample was divided into three groups based on weekly fruit consumption frequency for the analysis.
Results
Patients with the highest fruit intake were older than those in the other two groups, and women were more likely to consume fruits in general. Being a current smoker and weekly alcohol intake also showed negative correlations according to the fruit intake tertiles. Fruit consumption was positively correlated with better hemoglobin A1c (HbA1c) levels. Moreover, patients in the highest tertile of fruit intake were 3.48 times more likely to be in good glycemic control defined as HbA1c <7%.
Conclusion
We observed that fruit consumption can be helpful in glycemic control in Korean patients with T2DM.

Citations

Citations to this article as recorded by

The Relationship between Alcohol Consumption and Diabetes in Korean Adults
Gi Tae Kim, Jae Woong Sull
Biomedical Science Letters.2023; 29(3): 159. CrossRef

Diabetes, obesity and metabolism
Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons: Uisu Hyun, Yoon Young Kweon, Jong-Woo Sohn; Endocrinol Metab. 2023;38(5):545-556. Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.1725

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Abstract PDF Supplementary Material PubReader ePub: Background
Insulin is a peptide hormone that regulates post-prandial physiology, and it is well known that insulin controls homeostasis at least in part via the central nervous system. In particular, insulin alters the activity of neurons within the autonomic nervous system. However, currently available data are mostly from unidentified brainstem neurons of the dorsal motor nucleus of the vagus nerve (DMV).
Methods
In this study, we used several genetically engineered mouse models to label distinct populations of neurons within the brainstem and the spinal cord for whole-cell patch clamp recordings and to assess several in vivo metabolic functions.
Results
We first confirmed that insulin directly inhibited cholinergic (parasympathetic preganglionic) neurons in the DMV. We also found inhibitory effects of insulin on both the excitatory and inhibitory postsynaptic currents recorded in DMV cholinergic neurons. In addition, GABAergic neurons of the DMV and nucleus tractus solitarius were inhibited by insulin. However, insulin had no effects on the cholinergic sympathetic preganglionic neurons of the spinal cord. Finally, we obtained results suggesting that the insulininduced inhibition of parasympathetic preganglionic neurons may not play a critical role in the regulation of glucose homeostasis and gastrointestinal motility.
Conclusion
Our results demonstrate that insulin inhibits parasympathetic neuronal circuitry in the brainstem, while not affecting sympathetic neuronal activity in the spinal cord.

Diabetes, obesity and metabolism
Protective Effects of Melatonin in High-Fat Diet-Induced Hepatic Steatosis via Decreased Intestinal Lipid Absorption and Hepatic Cholesterol Synthesis: Hyungjune Ku, Yeonji Kim, Alvin Lyle Kim, Garam Lee, Youngsik Choi, Bukyung Kim; Endocrinol Metab. 2023;38(5):557-567. Published online September 1, 2023; DOI: https://doi.org/10.3803/EnM.2023.1672

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Abstract PDF PubReader ePub: Background
The preventative effect of melatonin on the development of obesity and the progression of fatty liver under a high-fat diet (HFD) has been well elucidated through previous studies. We investigated the mechanism behind this effect regarding cholesterol biosynthesis and regulation of cholesterol levels.
Methods
Mice were divided into three groups: normal chow diet (NCD); HFD; and HFD and melatonin administration group (HFD+M). We assessed the serum lipid profile, mRNA expression levels of proteins involved in cholesterol synthesis and reabsorption in the liver and nutrient transporters in the intestines, and cytokine levels. Additionally, an in vitro experiment using HepG2 cells was performed.
Results
Expression of hepatic sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) demonstrated that melatonin administration significantly reduces hepatic cholesterol synthesis in mice fed an HFD. Expression of intestinal sodium-glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), GLUT5, and Niemann-pick C1-like 1 (NPC1L1) demonstrated that melatonin administration significantly reduces intestinal carbohydrate and lipid absorption in mice fed an HFD. There were no differences in local and circulatory inflammatory cytokine levels among the NCD, HFD, and HFD+M group. HepG2 cells stimulated with palmitate showed reduced levels of SREBP, LDLR, and HMGCR indicating these results are due to the direct mechanistic effect of melatonin on hepatocytes.
Conclusion
Collectively, these data indicate the mechanism behind the protective effects of melatonin from weight gain and liver steatosis under HFD is through a reduction in intestinal caloric absorption and hepatic cholesterol synthesis highlighting its potential in the treatment of obesity and fatty liver disease.

Diabetes, obesity and metabolism
Coronary Artery Calcium Score as a Sensitive Indicator of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus: A Long-Term Cohort Study: Dae-Jeong Koo, Mi Yeon Lee, Sun Joon Moon, Hyemi Kwon, Sang Min Lee, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki Won Oh, Sung Rae Cho, Young-Hoon Jeong, Eun-Jung Rhee; Endocrinol Metab. 2023;38(5):568-577. Published online October 10, 2023; DOI: https://doi.org/10.3803/EnM.2023.1770

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Abstract PDF Supplementary Material PubReader ePub: Background
Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden.
Methods
We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease.
Results
The relative risk of CVD was significantly higher in patients with CACS ≥10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10≤ CACS <100, 100≤ CACS <400, and CACS ≥400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100.
Conclusion
CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM.

Calcium & bone metabolism
Characteristics Associated with Bone Loss after Spinal Cord Injury: Implications for Hip Region Vulnerability: Sora Han, Sungjae Shin, Onyoo Kim, Namki Hong; Endocrinol Metab. 2023;38(5):578-587. Published online October 10, 2023; DOI: https://doi.org/10.3803/EnM.2023.1795

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Abstract PDF Supplementary Material PubReader ePub: Background
In individuals with spinal cord injury (SCI), bone loss progresses rapidly to the area below the level of injury, leading to an increased risk of fracture. However, there are limited data regarding SCI-relevant characteristics for bone loss and the degree of bone loss in individuals with SCI compared with that in non-SCI community-dwelling adults.
Methods
Data from men with SCI who underwent dual-energy X-ray absorptiometry at the National Rehabilitation Center (2008 to 2020) between 12 and 36 months after injury were collected and analyzed. Community-dwelling men were matched 1:1 for age, height, and weight as the control group, using data from the Korea National Health and Nutrition Examination Survey (KNHANES, 2008 to 2011).
Results
A comparison of the SCI and the matched control group revealed significantly lower hip region T-scores in the SCI group, whereas the lumbar spine T-score did not differ between groups. Among the 113 men with SCI, the paraplegia group exhibited significantly higher Z-scores of the hip region than the tetraplegia group. Participants with motor-incomplete SCI showed relatively preserved Z-scores of the hip region compared to those of the lumbar region. Moreover, in participants with SCI, the percentage of skeletal muscle displayed a moderate positive correlation with femoral neck Z-scores.
Conclusion
Men with SCI exhibited significantly lower bone mineral density of the hip region than community-dwelling men. Paraplegia rather than tetraplegia, and motor incompleteness rather than motor completeness were protective factors in the hip region. Caution for loss of skeletal muscle mass or increased adiposity is also required.

Thyroid
Long-Term Changes in the Mortality Rates of Thyroid Cancer in Korea: Analysis of Korean National Data from 1985 to 2020: Yun Mi Choi, Min-Ju Kim, Jiwoo Lee, Mi Kyung Kwak, Min Ji Jeon, Tae Yong Kim, Eun-Gyoung Hong, Won Bae Kim, Won Gu Kim; Endocrinol Metab. 2023;38(5):588-595. Published online September 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1723

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Abstract PDF Supplementary Material PubReader ePub: Background
Thyroid cancer mortality has been largely overlooked as relatively stable given the large gap between thyroid cancer incidence and mortality. This study evaluated long-term trends in age-standardized mortality rates (ASMRs) throughout Korea and compared them with mortality data reported by the Surveillance, Epidemiology, and End Results (SEER).
Methods
Cancer-specific mortality data from 1985 to 2020 were obtained from Statistics Korea. ASMRs from thyroid cancer were calculated based on the Korean mid-year resident registration population of 2005. We assessed SEER*Explorer and downloaded the mortality data.
Results
The ASMR increased from 0.19 to 0.77/100,000 between 1985 and 2002 but decreased continuously to 0.36/100,000 in 2020. The annual percent change (APC) in the ASMR between 1985 and 2003 and between 2003 and 2020 was 6.204 and −4.218, respectively, with similar patterns observed in both men and women. The ASMR of the SEER showed a modest increase from 1988 to 2016 and then stabilized. In subgroup analysis, the ASMR of the old age group (≥55 years) increased significantly from 0.82 in 1985 to 3.92/100,000 in 2002 (APC 6.917) but then decreased again to 1.86/100,000 in 2020 (APC −4.136). ASMRs according to the age group in the SEER showed a relatively stable trend even in the elderly group.
Conclusion
The ASMR of thyroid cancer in Korea had increased from 1985 to 2002 but has since been steadily decreasing. This trend was mainly attributed to elderly people aged 55 or over. The absolute APC value of Korea was much higher than that of the SEER.

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