The Cardiovascular Effect of Tirzepatide: A Glucagon-Like Peptide-1and Glucose-Dependent Insulinotropic Polypeptide Dual Agonist

Glucagon-like peptide-1 (GLP-1) receptor agonists have been used extensively in the clinic and have an established safety profile in cardiovascular disease settings. For the treatment of peptide-secreting enteroendocrine cells, most research has focused on developing peptide multi-agonists as most of these cells are multihormonal. Among the various peptides secreted by enteroendocrine cells, the combination of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) is an attractive strategy for treating type 2 diabetes mellitus (T2DM) because both of these hormones have glucose-lowering actions. Tirzepatide, a synthetic peptide composed of 39 amino acids, functions as a dual receptor agonist of both the GIP and GLP-1 receptors. This unique mechanism of action has earned tirzepatide the nickname “twincretin.”Tirzepatide’s dual agonist activity may be the mechanism by which tirzepatide significantly reduces glycated hemoglobin levels and body weight in patients with T2DM as observed in phase 3 clinical trials. Besides its glucose-lowering and anti-obesity effects, tirzepatide has been reported to have potential cardiovascular benefits. In this review, we discuss the cardiovascular effects of tirzepatide based on the available preclinical and clinical data.

Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells

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.

Immune-Checkpoint Inhibitors-Induced Type 1 Diabetes Mellitus: From Its Molecular Mechanisms to Clinical Practice

With the increasing use of immune-checkpoint inhibitors (ICIs), such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and anti-programmed cell death-1 (PD-1), for the treatment of malignancies, cases of ICI-induced type 1 diabetes mellitus (ICI-T1DM) have been reported globally. This review focuses on the features and pathogenesis of this disease. T1DM is an immune-related adverse event that occurs following the administration of anti-PD-1 or anti-programmed death ligand-1 (PDL1) alone or in combination with anti-CTLA-4. More than half of the reported cases presented as abrupt-onset diabetic ketoacidosis. The primary mechanism of ICI-T1DM is T-cell stimulation, which results from the loss of interaction between PD-1 and PD-L1 in pancreatic islet. The similarities and differences between ICI-T1DM and classical T1DM may provide insights into this disease entity. ICI-T1DM is a rare but often life-threatening medical emergency that healthcare professionals and patients need to be aware of. Early detection of and screening for this disease is imperative. At present, the only known treatment for ICI-T1DM is insulin injection. Further research into the mechanisms and risk factors associated with ICI-T1DM development may contribute to a better understanding of this disease entity and the identification of possible preventive strategies.

Association of Visceral Fat Obesity, Sarcopenia, and Myosteatosis with Non-Alcoholic Fatty Liver Disease without Obesity

Background/Aims@#To investigate whether non-alcoholic fatty liver disease (NAFLD) in individuals without generalized obesity is associated with visceral fat obesity (VFO), sarcopenia, and/or myosteatosis. @*Methods@#This cross-sectional analysis included 14,400 individuals (7,470 men) who underwent abdominal computed tomography scans during routine health examinations. The total abdominal muscle area (TAMA) and skeletal muscle area (SMA) at the 3rd lumbar vertebral level were measured. The SMA was divided into the normal attenuation muscle area (NAMA) and low attenuation muscle area, and the NAMA/TAMA index was calculated. VFO was defined by visceral to subcutaneous fat ratio, sarcopenia by body mass index-adjusted SMA, and myosteatosis by the NAMA/TAMA index. NAFLD was diagnosed with ultrasonography. @*Results@#Of the 14,400 individuals, 4,748 (33.0%) had NAFLD, and the prevalence of NAFLD among non-obese individuals was 21.4%. In regression analysis, both sarcopenia (men: odds ratio [OR] 1.41, 95% confidence interval [CI] 1.19–1.67, P<0.001; women: OR=1.59, 95% CI 1.40–1.90, P<0.001) and myosteatosis (men: OR=1.24, 95% CI 1.02–1.50, P=0,028; women: OR=1.23, 95% CI 1.04–1.46, P=0.017) were significantly associated with non-obese NAFLD after considering for VFO and other various risk factors, whereas VFO (men: OR=3.97, 95% CI 3.43–4.59 [adjusted for sarcopenia], OR 3.98, 95% CI 3.44–4.60 [adjusted for myosteatosis]; women: OR=5.42, 95% CI 4.53–6.42 [adjusted for sarcopenia], OR=5.33, 95% CI 4.51–6.31 [adjusted for myosteatosis]; all P<0.001) was strongly associated with non-obese NAFLD after adjustment with various known risk factors. @*Conclusions@#In addition to VFO, sarcopenia and/or myosteatosis were significantly associated with non-obese NAFLD.

Prognostic Value of Triglyceride and Glucose Index for Incident Type 2 Diabetes beyond Metabolic Health and Obesity

Background@#Metabolically healthy obese (MHO) phenotype is metabolically heterogeneous in terms of type 2 diabetes (T2D). Previously, the triglyceride and glucose (TyG) index has been considered for identifying metabolic health and future risk of T2D. This study aimed to evaluate the risk of incident T2D according to obesity status and metabolic health, categorized by four different criteria and the TyG index. @*Methods@#The study included 39,418 Koreans without T2D at baseline. The risk of T2D was evaluated based on four different definitions of metabolic health and obesity status and according to the baseline TyG index within each metabolic health and obesity group. @*Results@#During the median follow-up at 38.1 months, 726 individuals developed T2D. Compared with the metabolically healthy non-obese (MHNO) group with low TyG index, the MHO group with high TyG index showed increased risk of T2D in all four definitions of metabolic health with multivariate-adjusted hazard ratios of 2.57 (95% confidence interval [CI], 1.76 to 3.75), 3.72 (95% CI, 2.15 to 6.43), 4.13 (95% CI, 2.67 to 6.38), and 3.05 (95% CI, 2.24 to 4.15), when defined by Adult Treatment Panel III, Wildman, Karelis, and homeostasis model assessment (HOMA) criteria, respectively. @*Conclusion@#MHO subjects with high TyG index were at an increased risk of developing T2D compared with MHNO subjects, regardless of the definition of metabolic health. TyG index may serve as an additional factor for predicting the individual risk of incident T2D in MHO subjects.

Changes in prevalence and perception of complementary and alternative medicine use in Korean inflammatory bowel disease patients: results of an 8-year follow-up survey

Background/Aims@#The use of complementary and alternative medicine (CAM) is a global phenomenon, including inflammatory bowel disease (IBD) patients. We aimed to assess the change in prevalence and patterns of CAM use, and attitudes towards CAM over an 8-year time interval (2006 vs. 2014) among IBD patients in Korea. @*Methods@#A total of 221 IBD patients (CD=142, UC=79) were asked to complete a questionnaire regarding CAM at two time points: at enrollment (2006) and 8 years later (2014/2015). @*Results@#The proportion of patients ever using CAM increased significantly from 60.2% in 2006 to 79.6% in 2014 (P<0.001), while the proportion of current CAM users increased slightly (35.7% to 38.0%, P=0.635); 21.7% used CAM consistently at both time points. The proportion of patients who felt CAM was less effective (P<0.001) and more expensive (P=0.04) than conventional treatments increased over time. Also, the proportion among ever CAM users who perceived a positive effect from CAM significantly decreased in 2014 compared to 2006 (P=0.004). Higher education (adjusted odds ratio [aOR], 2.10), prior side effects to conventional therapies (aOR, 2.23), and prior use of corticosteroids (aOR, 2.51) were associated with CAM use. Interestingly, use of CAM before IBD diagnosis (aOR, 2.73) was significantly associated with consistent CAM use. @*Conclusions@#Although the attitudes toward CAM have become less favorable, the majority of IBD patients have experienced CAM with an overall increase of current CAM users over time. Moreover, more than half of current CAM users used CAM consistently over time.

Novel ABCD1 Gene Mutation in a Korean Patient with X-Linked Adrenoleukodystrophy Presenting with Addison's Disease

X-linked adrenoleukodystrophy (X-ALD) occurs due to mutations in the ABCD1 gene that encodes the peroxisomal membrane protein peroxisomal transporter ATP-binding cassette sub-family D member 1 (ABCD1). Degradation of very long-chain fatty acids in peroxisomes is impaired owing to ABCD dysfunction, subsequently leading to adrenomyeloneuropathy, cerebral adrenoleukodystrophy, and adrenal insufficiency. X-ALD frequently induces idiopathic Addison's disease in young male patients. Here, we confirmed the diagnosis of X-ALD in a young male patient with primary adrenal insufficiency, and identified a novel ABCD1 gene mutation (p.Trp664*, c.1991 G>A).

Efficacy of parenteral glutamine supplementation in adult hematopoietic stem cell transplantation patients

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) patients need parenteral nutrition because of nausea, vomiting, and mucositis caused by conditioning regimens. The demand for glutamine increases during the HSCT period. We evaluated the effects of glutamine-containing parenteral nutrition on the clinical outcomes of HSCT patients. METHODS: In this retrospective analysis, we reviewed HSCT patients from Seoul National University from August 2013 to July 2017. Depending on their glutamine supplementation status, 91 patients were divided into 2 groups: glutamine group (N=44) and non-glutamine group (N=47). We analyzed the rate of weight change, infection (clinically/microbiologically documented), complications (duration of mucositis and neutropenia, acute graft versus host disease), and 100-days mortality in each group. RESULTS: Regarding the clinical characteristics of the patients, there were no significant differences between the 2 groups except that there was a larger proportion of myeloablative conditioning regimen in the glutamine group (P=0.005). In the glutamine group, the average number of days of glutamine use, parenteral nutrition, and mucositis was 7.6±1.4, 14.6±9.9, and 13.3±9.5, respectively. Furthermore, multivariate analysis revealed odds ratios of 0.37 (95% CI, 0.14–0.96; P=0.042) and 0.08 (95% CI, 0.01–0.98; P=0.048) for clinically documented infection and 100-days mortality, respectively, in the glutamine group. CONCLUSION: Results showed that the glutamine group had less clinically documented infection and 100-days mortality than the non-glutamine group, but the other outcomes did not show significant differences. The extended duration of glutamine supplementation according to the period of total parenteral nutrition and mucositis should be considered.

Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials

BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Pulmonary artery sarcoma manifesting as a main pulmonary artery stenosis diagnosed by 18F-FDG PET/CT / 영남의대학술지

Pulmonary artery sarcoma (PAS) is a rare and fatal disease that often mimics chronic thromboembolic pulmonary hypertension (CTEPH); therefore, diagnosis of PAS is often delayed. Herein, a healthy 74-year-old man was presented with a 4-month history of dyspnea. Chest computed tomography showed wall thickening and stenosis in the main pulmonary artery as well as in both proximal pulmonary arteries. In order to differentiate between unusual CTEPH, vasculitis, and PAS, we performed right heart catheterization and pulmonary angiography. The mean pulmonary arterial pressure was 21 mmHg, and there was severe pulmonary artery stenosis. Thrombi on the pulmonary arterial wall lesions were observed in intravascular ultrasound and optical coherence tomography. Furthermore, the patient had a history of deep vein thrombosis. Therefore, we diagnosed unusual CTEPH. After 6 months of rivaroxaban anticoagulation therapy, a chest X-ray revealed a left lower lobe lung mass, and a positron emission tomography later showed hypermetabolic lesions in the main pulmonary artery wall, in both pulmonary arteries walls, in the lung parenchyma, and in the bones. A biopsy of the right proximal humerus lesion revealed undifferentiated intimal sarcoma. Pulmonary sarcoma is rare, but should be considered when differentially diagnosing main pulmonary artery wall thickening and stenosis. A positron emission tomography may aid in this diagnosis.

Pulmonary artery sarcoma manifesting as a main pulmonary artery stenosis diagnosed by 18F-FDG PET/CT / 영남의대학술지

Pulmonary artery sarcoma (PAS) is a rare and fatal disease that often mimics chronic thromboembolic pulmonary hypertension (CTEPH); therefore, diagnosis of PAS is often delayed. Herein, a healthy 74-year-old man was presented with a 4-month history of dyspnea. Chest computed tomography showed wall thickening and stenosis in the main pulmonary artery as well as in both proximal pulmonary arteries. In order to differentiate between unusual CTEPH, vasculitis, and PAS, we performed right heart catheterization and pulmonary angiography. The mean pulmonary arterial pressure was 21 mmHg, and there was severe pulmonary artery stenosis. Thrombi on the pulmonary arterial wall lesions were observed in intravascular ultrasound and optical coherence tomography. Furthermore, the patient had a history of deep vein thrombosis. Therefore, we diagnosed unusual CTEPH. After 6 months of rivaroxaban anticoagulation therapy, a chest X-ray revealed a left lower lobe lung mass, and a positron emission tomography later showed hypermetabolic lesions in the main pulmonary artery wall, in both pulmonary arteries walls, in the lung parenchyma, and in the bones. A biopsy of the right proximal humerus lesion revealed undifferentiated intimal sarcoma. Pulmonary sarcoma is rare, but should be considered when differentially diagnosing main pulmonary artery wall thickening and stenosis. A positron emission tomography may aid in this diagnosis.

Aseptic Meningitis and Acute Kidney Injury after Immunoglobulin Infusion in a Patient with Systemic Lupus Erythematosus and Immune Thrombocytopenic Purpura

A 36-yr-old woman with systemic lupus erythematosus was admitted in our center because of thrombocytopenia that was being treated with corticosteroids. She was prescribed a four-day course of intravenous immunoglobulin (IVIG) infusion. After three days of IVIG infusion, she developed aseptic meningitis with severe pleocytosis in the cerebrospinal fluid, followed by acute kidney injury. These complications resolved completely with conservative management. Here, we report these rare complications of IVIG and the outcome.

Refractory Pleural Effusion in Systemic Lupus Erythematosus Treated by Pleurectomy

Pleural effusion is a common pulmonary manifestation of systemic lupus erythematosus (SLE) and often occurs as bilateral exudative pleural effusion. The condition usually responds quickly to corticosteroid therapy. However, massive pleural effusion refractory to immunosuppressive drugs has rarely been reported; thus, the proper therapeutic modality is largely decided on a case-by-case basis. In this case, we describe successful treatment with surgical pleurectomy for massive refractory pleural effusion in a patient with SLE.

F-box only protein 9 is an E3 ubiquitin ligase of PPARγ

Peroxisome proliferator-activated receptor gamma (PPARγ) is a critical regulator of carbohydrate and lipid metabolism, adipocyte differentiation and inflammatory response. Post-translational modification of PPARγ and its degradation involve several pathways, including the ubiquitin–proteasome system. Here, we identified F-box only protein 9 (FBXO9) as an E3 ubiquitin ligase of PPARγ. We screened interacting partners of PPARγ using immunoprecipitation and mass spectrometric analysis and identified FBXO9 as an E3 ubiquitin ligase of PPARγ. FBXO9 directly interacted with PPARγ through the activation function-1 domain and ligand-binding domain. FBXO9 decreased the protein stability of PPARγ through induction of ubiquitination. We found that the F-box motif of FBXO9 was required for its ubiquitination function. The activity of PPARγ was significantly decreased by FBXO9 overexpression. Furthermore, FBXO9 overexpression in 3T3-L1 adipocytes resulted in decreased levels of endogenous PPARγ and suppression of adipogenesis. These results suggest that FBXO9 is an important enzyme that regulates the stability and activity of PPARγ through ubiquitination.

Development of Spinal Epidural Abscess during Treatment of Pneumococcal Meningitis / 대한내과학회지

There have been a few reports of pneumococcal meningitis complicated by spinal epidural abscess. A 58-year-old female with Streptococcus pneumoniae meningitis underwent a recurrent pleocytosis without apparent clinical deterioration after appropriate antibiotic treatment. Subsequently, she developed a spinal epidural abscess. Spinal epidural abscess is a rare complication of pneumococcal meningitis, and subclinical deterioration of neutrophil-dominant pleocytosis may precede development of a spinal epidural abscess in individuals with bacterial meningitis.

Differential Diagnosis of a Left Atrial Mass after Surgical Excision of Myxoma: a Remnant or a Thrombus?

Echocardiographic diagnosis of atrial myxoma may not always be straightforward, and the distinction between myxoma and thrombi is not easy, especially when we observe a mass after successful surgery. Our report describes a 72-year-old woman who presented with right upper limb hemiparesis and was subsequently diagnosed as having transient ischemic attack due to a left atrial myxoma. One month after successful surgical resection of the tumor, the patient developed left-sided weakness. Echocardiography revealed a left atrial mass attached to the interatrial septum. Intravenous heparin was administered as a therapeutic trial for postoperative thrombi, which resulted in a decrease in mass size within a week. Anticoagulation with warfarin was continued, and complete resolution was demonstrated on a 4-month follow-up transesophageal echocardiography. This case highlights the fact that thrombus formation at the surgical site should be considered an unusual but potential complication after surgical resection of left atrial myxomas.

17α-hydroxylase Deficiency Mimicking Hyperaldosteronism by Aldosterone-producing Adrenal Adenoma / 대한내과학회지

17α-hydroxylase deficiency is a rare cause of congenital adrenal hyperplasia and is characterized by primary amenorrhea, delayed puberty and hypertension. Although 17α-hydroxylase deficiency mimics mineralocorticoid-induced hypertension, impaired sexual development can aid in the differential diagnosis of this disease. A 32-year-old woman, who had a history of testicular feminization syndrome, presented with hypertension. Her aldosterone level was elevated whereas plasma renin activity was reduced, and her computed tomography scan showed a left adrenal adenoma, which was thought to be an aldosterone producing adenoma. A left adrenalectomy was performed to treat hypertension; however, the condition did not improve. The hormonal tests revealed high levels of plasma progesterone, mineralocorticoid and adrenocorticotropic hormone, and low levels of 17a hydroxyprogesterone, cortisol and sex hormones. The patient was diagnosed with 17α-hydroxylase deficiency and commenced on prednisolone, which controlled hypertension. Here, we report a case of 17α-hydroxylase deficiency mimicking hyperaldosteronism via aldosterone-producing adrenal adenoma.

Utility of a Three-Dimensional Interactive Augmented Reality Program for Balance and Mobility Rehabilitation in the Elderly: A Feasibility Study

OBJECTIVE: To improve lower extremity function and balance in elderly persons, we developed a novel, three-dimensional interactive augmented reality system (3D ARS). In this feasibility study, we assessed clinical and kinematic improvements, user participation, and the side effects of our system. METHODS: Eighteen participants (age, 56-76 years) capable of walking independently and standing on one leg were recruited. The participants received 3D ARS training during 10 sessions (30-minute duration each) for 4 weeks. Berg Balance Scale (BBS) and the Timed Up and Go (TUG) scores were obtained before and after the exercises. Outcome performance variables, including response time and success rate, and kinematic variables, such as hip and knee joint angle, were evaluated after each session. RESULTS: Participants exhibited significant clinical improvements in lower extremity balance and mobility following the intervention, as shown by improved BBS and TUG scores (p<0.001). Consistent kinematic improvements in the maximum joint angles of the hip and knee were observed across sessions. Outcome performance variables, such as success rate and response time, improved gradually across sessions, for each exercise. The level of participant interest also increased across sessions (p<0.001). All participants completed the program without experiencing any adverse effects. CONCLUSION: Substantial clinical and kinematic improvements were observed after applying a novel 3D ARS training program, suggesting that this system can enhance lower extremity function and facilitate assessments of lower extremity kinematic capacity.

Myocardial Ischemia Caused by Paroxysmal Supraventricular Tachycardia in a Patient with Anomalous Origin of Right Coronary Artery Arising from Left Sinus of Valsalva

Anomalous origin of a coronary artery is rare and does not generally lead to myocardial infarction and paroxysmal supraventricular tachycardia (PSVT). We report an uncommon case of anomalous origin of the right coronary artery (RCA) originating from the left sinus of Valsalva with PSVT and myocardial ischemia. A 58-year-old man presented with PSVT. After arrhythmia subsided, electrocardiogram showed ST and T wave abnormalities, and transient cardiac enzymes were found to be elevated. Coronary CT angiography confirmed that there was anomalous origin of the RCA originating from the left sinus of Valsalva and no intracoronary stenotic lesion. He was managed with conservative treatment, having no symptoms on clinical follow-up for 4 years.

Myocardial Ischemia Caused by Paroxysmal Supraventricular Tachycardia in a Patient with Anomalous Origin of Right Coronary Artery Arising from Left Sinus of Valsalva

Anomalous origin of a coronary artery is rare and does not generally lead to myocardial infarction and paroxysmal supraventricular tachycardia (PSVT). We report an uncommon case of anomalous origin of the right coronary artery (RCA) originating from the left sinus of Valsalva with PSVT and myocardial ischemia. A 58-year-old man presented with PSVT. After arrhythmia subsided, electrocardiogram showed ST and T wave abnormalities, and transient cardiac enzymes were found to be elevated. Coronary CT angiography confirmed that there was anomalous origin of the RCA originating from the left sinus of Valsalva and no intracoronary stenotic lesion. He was managed with conservative treatment, having no symptoms on clinical follow-up for 4 years.