Endocrinology and Metabolism

Articles in E-pub version are posted online ahead of regular printed publication.

Review Article

Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis: Brendan F. Boyce, Jinbo Li, Zhenqiang Yao, Lianping Xing; Received July 14, 2023 Accepted August 2, 2023 Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.501 [Epub ahead of print]

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Abstract PDF: 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.

Original Articles

Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons: Uisu Hyun, Yoon Young Kweon, Jong-Woo Sohn; Received May 2, 2023 Accepted August 1, 2023 Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.1725 [Epub ahead of print]

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Abstract PDF: 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.

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; Received May 4, 2023 Accepted July 25, 2023 Published online September 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1723 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: 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.

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; Received June 22, 2023 Accepted July 31, 2023 Published online September 7, 2023; DOI: https://doi.org/10.3803/EnM.2023.1765 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: 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.

Age-Dependent Association of Height Loss with Incident Fracture Risk in Postmenopausal Korean Women: Chaewon Lee, Hye-Sun Park, Yumie Rhee, Namki Hong; Received May 9, 2023 Accepted July 20, 2023 Published online September 1, 2023; DOI: https://doi.org/10.3803/EnM.2023.1734 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: Background
Height loss is a simple clinical measure associated with increased fracture risk. However, limited data exists on the association between height loss and fracture risk in postmenopausal Korean women. It is unknown whether this association varies with age.
Methods
Data on height loss over a 6-year period were collected from a community-based longitudinal follow-up cohort (Ansung cohort of the Korean Genome and Epidemiology Study). Incident fractures were defined based on self-reported fractures after excluding those due to severe trauma or toes/fingers. The association between incident fractures and height loss was investigated using a Cox proportional hazards model.
Results
During a median follow-up of 10 years after the second visit, 259/1,806 participants (median age, 64 years) experienced incident fractures. Overall, a 1 standard deviation (SD) decrease in height (1.6 cm/median 5.8 years) was associated with 9% increased risk of fracture (hazard ratio [HR], 1.09; P=0.037), which lost statistical significance after adjustment for covariates. When stratified into age groups (50–59, 60–69, 70 years or older), a 1 SD decrease in height remained a robust predictor of fracture in the 50 to 59 years age group after adjusting for covariates (adjusted hazard ratio [aHR], 1.52; P=0.003), whereas height loss was not an independent predictor of fracture in the 60 to 69 (aHR, 1.06; P=0.333) or the 70 years or older age groups (aHR, 1.05; P=0.700; P for interaction <0.05, for all).
Conclusion
Height loss during the previous 6 years was associated with an increased 10-year fracture risk in postmenopausal women in their 50s.

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; Received January 30, 2023 Accepted July 27, 2023 Published online September 1, 2023; DOI: https://doi.org/10.3803/EnM.2023.1672 [Epub ahead of print]

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Abstract PDF PubReader ePub Crossref - TDM: 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.

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; Received May 8, 2023 Accepted July 24, 2023 Published online August 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1730 [Epub ahead of print]

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Abstract PDF PubReader ePub Crossref - TDM: 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.

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