Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro.

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 µM palmitic acid (PA), followed by treatment with or without 10 µM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1ß, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7-Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7-Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation.

Enhancing the Reliability of PMP22 Copy Number Variation Detection with an Inherited Peripheral Neuropathy Panel.

The utility of the next-generation sequencing (NGS) panel could be increased in hereditary peripheral neuropathies, given that the duplication of PMP22 is a major abnormality. In the present study, the analytical performance of an algorithm for detecting PMP22 copy number variation (CNV) from the NGS panel data was evaluated. The NGS panel covers 141 genes, including PMP22 and five genes within 1.5-megabase duplicated region at 17p11.2. CNV calling was performed using a laboratory-developed algorithm. Among the 92 cases subjected to targeted NGS panel from March 2018 to January 2021, 26 were suggestive of PMP22 CNV. Multiplex ligation-dependent probe amplification analysis was performed in 58 cases, and the results were 100% concordant with the NGS data (23 duplications, 2 deletions, and 33 negatives). Analytical performance of the pipeline was further validated by another blind data set, including 14 positive and 20 negative samples. Reliable detection of PMP22 CNV was possible by analyzing not only PMP22 but also the adjacent genes within the 1.5-megabase region of 17p11.2. On the basis of the high accuracy of CNV calling for PMP22, the testing strategy for diagnosis of peripheral polyneuropathies could be simplified by reducing the need for multiplex ligation-dependent probe amplification.

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells.

BACKGRUOUND: Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic ß-cells; however, the underlying mechanisms are unknown. METHODS: To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined. RESULTS: DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis. CONCLUSION: These findings indicate that DHA has therapeutic effects on PA-induced pancreatic ß-cells, and that the cellular mechanism of ß-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in ß-cell protection.

Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway.

BACKGRUOUND: Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states. METHODS: Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco's modified Eagle's medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours. RESULTS: SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation. CONCLUSION: These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.

Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification.

BACKGRUOUND: Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system. METHODS: To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide. RESULTS: Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs. CONCLUSION: These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

Nonalcoholic Fatty Liver Disease and the Risk of Thyroid Cancer Among Young Adults in South Korea.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Obesity and metabolic syndrome are known risk factors for thyroid cancer. OBJECTIVE: We investigated the association between NAFLD and thyroid cancer risk in young adults. METHODS: This nationwide cohort study included 1 135 967 participants aged 20 to 39 years who underwent 4 consecutive health screenings in South Korea. NAFLD was categorized using the fatty liver index (FLI), as follows: ≥60, 30 to 60, and <30. The cumulative FLI points were defined as the number of times participants had a FLI of ≥30 (0-4). RESULTS: During a median follow-up of 5.2 years, 4126 participants (0.36%) were newly diagnosed with thyroid cancer. Compared with the participants with an FLI of <30, those with an FLI of 30 to 60 (men: hazard ratio [HR] 1.36 [95% CI, 1.22-1.51] and women: HR 1.44 [1.21-1.70]) and those with an FLI of ≥60 (men: HR 1.71 [1.53-1.92] and women: HR 1.81 [1.46-2.25]) had a significantly higher risk of thyroid cancer. Participants with higher cumulative FLI points had a higher risk of thyroid cancer compared to those with a cumulative FLI point of 0 (P < .001). During the follow-up period, the participants with an increased FLI exhibited an increased risk of thyroid cancer. CONCLUSION: NAFLD was associated with an increased risk of thyroid cancer in young adults. Repeatedly elevated FLI and progression of NAFLD were associated with an increased risk of thyroid cancer in this study.

Evaluation of adrenal masses using 18 F-FDOPA PET/CT in patients suspected with pheochromocytoma.

OBJECTIVE: Pheochromocytomas (PHEOs) are chromaffin cell-derived adrenal tumors. 6-[ 18 F]-L-fluoro-L-3, 4-dihydroxyphenylalanine ( 18 F-FDOPA) is a radiotracer taken up in neuroendocrine chromaffin cells via the L-type amino-acid transporter. 18 F-FDOPA is useful in patients with PHEO. However, more information about the use of 18 F-FDOPA PET/CT scan is needed. Thus, the current study investigated various PET parameters on preoperative 18 F-FDOPA PET/CT scan. METHODS: The 18 F-FDOPA PET/CT scan findings of 29 patients who underwent adrenalectomy after PET/CT scans were evaluated according to their pathologic diagnosis. Thereafter, the patients were classified under different risk groups which were compared based on the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). RESULTS: In terms of histopathologic results after surgery, 24 patients presented with PHEO. The remaining 5 patients were diagnosed with adrenal cortical adenomas or adrenal medullary hyperplasia. The maximum standardized uptake value, mean standardized uptake value, tumor-to-liver ratio, and tumor-to-contralateral adrenal gland ratio of PHEOs on preoperative 18 F-FDOPA PET/CT scan were higher than those of other tumors. The metabolic tumor volume (MTV) and total lesion uptake of PHEOs in the intermediate-risk group (n = 19) were higher than those in the low-risk group (n = 5). The MTV and total lesion uptake were significantly correlated with the GAPP score. CONCLUSION: Preoperative 18 F-FDOPA PET/CT is helpful to identifying PHEOs. In addition, imaging interpretation using the standardized uptake value of the suspected tumor or the tumor-to-liver/contralateral adrenal gland ratio can be effective. The metabolic parameters of PHEOs are positively correlated with the GAPP score.

Coronary Artery Calcium Score as a Sensitive Indicator of Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus: A Long-Term Cohort Study.

BACKGRUOUND: 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.

Association of physical activity with total and cause-specific mortality in patients with diabetes: A nationwide population-based cohort study.

AIMS: Physical inactivity is a modifiable risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM); however, little is known about its association with mortality due to other causes. Herein, we investigated the association between physical activity (PA) and cause-specific mortality in patients with T2DM. METHODS: We analyzed data from the Korean National Health Insurance Service and claims database of adults with T2DM aged >20 years at baseline (n = 2,651,214). Each participant's PA volume was measured as the metabolic equivalent of tasks (METs)-min per week, and hazard ratios of all-cause and cause-specific mortality relative to PA levels were estimated. RESULTS: During the 7.8 years of follow-up, all-cause, CVD, respiratory, cancer, and other causes of mortality were lowest in patients engaged in vigorous PA. MET-min/week was inversely associated with mortality after adjusting for covariates. The reduction in total and cause-specific mortality was greater in patients aged ≥65 years than in those aged <65 years. CONCLUSIONS: Increasing PA may facilitate a reduction in mortality from various causes, especially among older patients with T2DM. Clinicians should encourage such patients to increase their daily PA levels to reduce their risk of mortality.

Whole-genome sequencing in clinically diagnosed Charcot-Marie-Tooth disease undiagnosed by whole-exome sequencing.

Whole-genome sequencing is the most comprehensive form of next-generation sequencing method. We aimed to assess the additional diagnostic yield of whole-genome sequencing in patients with clinically diagnosed Charcot-Marie-Tooth disease when compared with whole-exome sequencing, which has not been reported in the literature. Whole-genome sequencing was performed on 72 families whose genetic cause of clinically diagnosed Charcot-Marie-Tooth disease was not revealed after the whole-exome sequencing and 17p12 duplication screening. Among the included families, 14 (19.4%) acquired genetic diagnoses that were compatible with their phenotypes. The most common factor that led to the additional diagnosis in the whole-genome sequencing was genotype-driven analysis (four families, 4/14), in which a wider range of genes, not limited to peripheral neuropathy-related genes, were analysed. Another four families acquired diagnosis due to the inherent advantage of whole-genome sequencing such as better coverage than the whole-exome sequencing (two families, 2/14), structural variants (one family, 1/14) and non-coding variants (one family, 1/14). In conclusion, an evident gain in diagnostic yield was obtained from whole-genome sequencing of the whole-exome sequencing-negative cases. A wide range of genes, not limited to inherited peripheral neuropathy-related genes, should be targeted during whole-genome sequencing.

Acromegaly and the long-term fracture risk of the vertebra and hip: a national cohort study.

In this national cohort study, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up. PURPOSE: Acromegaly is characterized by the overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), both play important roles in regulating bone metabolism. We investigated the risk of vertebral and hip fractures in patients with acromegaly compared to age- and sex-matched controls. METHODS: This nationwide population-based cohort study included 1,777 patients with acromegaly aged 40 years or older in 2006-2016 and 8,885 age- and sex-matched controls. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) [95% confidence interval]. RESULTS: The mean age was 54.3 years and 58.9% were female. For approximately 8.5 years of follow-up, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls in the multivariate analyses. There were significant differences in the risks of clinical vertebral (P < 0.0001) and hip (P < 0.0001) fractures between the patients with acromegaly and the controls in the Kaplan-Meier survival analysis. The multivariable-adjusted HRs for clinical vertebral fractures comparing the patients with acromegaly with controls during and excluding the first 7 years of observation were 1.69 [1.15-2.49] and 2.70 [1.75-4.17], respectively. The HRs for hip fractures during and excluding the first 7 years of observation were 2.29 [1.25-4.18] and 3.36 [1.63-6.92], respectively. CONCLUSIONS: The patients with acromegaly had a higher risk of hip fractures as well as clinical vertebral fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up.

Increased Risk of NAFLD in Adults with Glomerular Hyperfiltration: An 8-Year Cohort Study Based on 147,162 Koreans.

This study evaluated whether glomerular hyperfiltration (GHF) could predict nonalcoholic fatty liver disease (NAFLD) and fibrosis. A longitudinal cohort study including 147,479 participants aged 20-65 years without NAFLD and kidney disease at baseline was performed. GHF cutoff values were defined as age- and sex-specific estimated glomerular filtration rate (eGFRs) above the 95th percentile, and eGFR values between the 50th and 65th percentiles were used as reference groups. NAFLD was diagnosed via abdominal ultrasonography, and the fibrosis status was evaluated using the NAFLD fibrosis score and Fibrosis-4. During 598,745 person years of follow-up (median, 4.6 years), subjects with GHF at baseline had the highest hazard ratio (HR) for the development of NAFLD (HR 1.21; 95% CI 1.14-1.29) and fibrosis progression (HR 1.42; 95% CI 1.11-1.82) after adjusting for confounding factors. A higher baseline eGFR percentile maintained a higher risk of NAFLD and fibrosis probability. The persistent GHF group during follow-up had the highest HR for NAFLD compared to the persistent non-GHF group (HR 1.31; 95% CI 1.14-1.51). These results were consistent in all subgroups and statistically more prominent in participants without diabetes. GHF was positively associated with increased risk of NAFLD and probability of liver fibrosis in healthy adults.

Effects of dabrafenib and erlotinib combination treatment on anaplastic thyroid carcinoma.

Dabrafenib is a BRAF kinase inhibitor approved for treatment of BRAF-mutated anaplastic thyroid carcinoma (ATC) in combination with trametinib. Erlotinib is a tyrosine kinase inhibitor of EGF receptor (EGFR). We evaluated effects of dabrafenib and erlotinib combination treatment on ATC cells in vitro and in vivo. Cell proliferation, colony formation, apoptosis, and migration of ATC cells harboring a BRAF mutation (BHT101, 8505C, and SW1736) were evaluated after treatment with dabrafenib in combination with erlotinib or trametinib. The changes in activation of mitogen extracellular kinase (MEK) and extracellular signal-related kinase (ERK) signaling were also evaluated by Western blot analysis. Effects of these combinations were also evaluated using an in vivo xenograft model. First, we detected EGFR activation in dabrafenib-resistant SW1736 cells using a phospho-receptor tyrosine kinase array. A dabrafenib and erlotinib combination synergistically inhibited cell proliferation, colony formation, and migration, with an induction of apoptotic cell death in all three ATC cells, compared with dabrafenib or erlotinib alone. This synergistic effect was comparable with a dabrafenib and trametinib combination. The dabrafenib and erlotinib combination effectively inhibited phosphorylated (p)-MEK, p-ERK, and p-EGFR expressions compared with dabrafenib or erlotinib alone, while the dabrafenib and trametinib combination only inhibited p-MEK and p-ERK expressions. The dabrafenib with erlotinib or trametinib combinations also significantly suppressed tumor growth and induced apoptosis in a BHT101 xenograft model. The dabrafenib and erlotinib combination could be a potential novel treatment regimen to overcome drug resistance to dabrafenib alone in patients with BRAF-mutated ATC.

Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway.

BACKGROUND: Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA). METHODS: HepG2 cells were pretreated with 400 µM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting. RESULTS: Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation. CONCLUSION: These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.

Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society.

Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

Changes in Patterns of Physical Activity and Risk of Heart Failure in Newly Diagnosed Diabetes Mellitus Patients.

BACKGROUND: Exercise is recommended for type 2 diabetes mellitus (T2DM) patients to prevent cardiovascular disease. However, the effects of physical activity (PA) for reducing the risk of heart failure (HF) has yet to be elucidated. We aimed to assess the effect of changes in patterns of PA on incident HF, especially in newly diagnosed diabetic patients. METHODS: We examined health examination data and claims records of 294,528 participants from the Korean National Health Insurance Service who underwent health examinations between 2009 and 2012 and were newly diagnosed with T2DM. Participants were classified into the four groups according to changes in PA between before and after the diagnosis of T2DM: continuously inactive, inactive to active, active to inactive, and continuously active. The development of HF was analyzed until 2017. RESULTS: As compared with those who were continuously inactive, those who became physically active after diagnosis showed a reduced risk for HF (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.66 to 0.93). Those who were continuously active had the lowest risk for HF (aHR, 0.77; 95% CI, 0.62 to 0.96). As compared with those who were inactive, those who exercised regularly, either performing vigorous or moderate PA, had a lower HF risk (aHR, 0.79; 95% CI, 0.69 to 0.91). CONCLUSION: Among individuals with newly diagnosed T2DM, the risk of HF was reduced in those with higher levels of PA after diagnosis was made. Our results suggest either increasing or maintaining the frequency of PA after the diagnosis of T2DM may lower the risk of HF.

Autonomic Imbalance Increases the Risk for Non-alcoholic Fatty Liver Disease.

Background: Although autonomic imbalance is associated with an increased risk for metabolic disease, its effects on nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to evaluate whether autonomic dysfunction predicts the risk for nonalcoholic fatty liver disease (NAFLD). Methods: A total of 33,899 participants without NAFLD who underwent health screening programs between 2011 and 2018 were enrolled. NAFLD was identified by ultrasonography. Autonomic activity was estimated using heart rate variability (HRV). Time domain [standard deviation of the normal-to-normal interval (SDNN) and root mean square difference (RMSSD)]; frequency domain [total power (TP), low frequency (LF), and high frequency (HF), and LF/HF ratio were analyzed. Findings: A total 6,466 participants developed NAFLD within a median of 5.7 years. Subjects with incident NAFLD showed decreased overall autonomic modulation and vagal activity with lowered SDNN, RMSSD, HF, normalized HF, compared to those without NAFLD. As the SDNN, RMSSD, TP, LF, and HF tertiles increased, the risk of NAFLD decreased with tertile 1 being the reference group [the hazard ratios (95% confidence intervals) of tertile 3 were 0.90 (0.85-0.96), 0.83 (0.78-0.88), 0.91 (0.86-0.97), 0.93 (0.87-0.99) and 0.89 (0.83-0.94), respectively] after adjusting for potential confounders. The risk for NAFLD was significantly higher in subjects in whom sustained elevated heart rate, normalized LF, and LF/HF ratio values than in those with sustained decrease in these parameters during follow-up. Conclusions: Overall autonomic imbalance, decreased parasympathetic activity, and recently increased sympathetic activity might increase the risk of NAFLD.

Changes in Insulin Resistance Index and the Risk of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease without Diabetes: Kangbuk Samsung Health Study.

BACKGROUND: Fibrosis is the most important prognostic factor for nonalcoholic fatty liver disease (NAFLD). Insulin resistance plays a key role of fibrosis progression. We evaluated the association between changes in homeostasis model assessment of insulin resistance (HOMA-IR) values and changes in fibrosis status in NAFLD. METHODS: We analyzed the data of 15,728 participants with NAFLD (86% men, mean age 40.5 years) who had no diabetes at baseline and visited our centers for health check-ups both in 2012 and 2016. The participants were classified into four groups according to the degree of change in HOMA-IR values from baseline to the end of follow-up: G1 (<0), G2 (0-0.50), G3 (0.51-1.00), and G4 (>1.00). NAFLD was assessed by ultrasonography, and fibrosis status was evaluated by the NAFLD fibrosis score (NFS) and the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: After the 4-year follow-up, the multivariable-adjusted odds ratio (OR) for progression of fibrosis probability increased with increasing HOMA-IR values (OR, 2.25; 95% confidence interval [CI], 1.87 to 2.71 for NFS; and OR, 2.55; 95% CI, 2.05 to 3.18 for APRI, G4). This tendency remained consistent throughout the subgroup analyses, except in those for female sex and a body mass index <25 kg/m2. The OR for regression of fibrosis probability decreased with increasing HOMA-IR values (OR, 0.33; 95% CI, 0.25 to 0.43 for NFS, G4). CONCLUSION: Changes in HOMA-IR values were associated with changes in fibrosis status in patients with NAFLD without diabetes, which underscores the role of insulin resistance in liver fibrosis.

The Effects of Glucose Lowering Agents on the Secondary Prevention of Coronary Artery Disease in Patients with Type 2 Diabetes.

BACKGROUND: Patients with diabetes have a higher risk of requiring repeated percutaneous coronary intervention (PCI) than non-diabetic patients. We aimed to evaluate and compare the effects of anti-diabetic drugs on the secondary prevention of myocardial infarction among type 2 diabetes mellitus patients. METHODS: We analyzed the general health check-up dataset and claims data of the Korean National Health Insurance Service of 199,714 participants (age ≥30 years) who underwent PCIs between 2010 and 2013. Those who underwent additional PCI within 1 year of their first PCI (n=3,325) and those who died within 1 year (n=1,312) were excluded. Patients were classified according to their prescription records for glucose-lowering agents. The primary endpoint was the incidence rate of coronary revascularization. RESULTS: A total of 35,348 patients were included in the study. Metformin significantly decreased the risk of requiring repeat PCI in all patients (adjusted hazard ratio [aHR], 0.77). In obese patients with body mass index (BMI) ≥25 kg/m2, patients treated with thiazolidinedione (TZD) exhibited a decreased risk of requiring repeat revascularization than those who were not treated with TZD (aHR, 0.77; 95% confidence interval, 0.63 to 0.95). Patients treated with metformin showed a decreased risk of requiring revascularization regardless of their BMI. Insulin, meglitinide, and alpha-glucosidase inhibitor were associated with increased risk of repeated PCI. CONCLUSION: The risk of requiring repeat revascularization was lower in diabetic patients treated with metformin and in obese patients treated with TZD. These results suggest that physicians should choose appropriate glucose-lowering agents for the secondary prevention of coronary artery disease.