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2020
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Obesity and Metabolic Syndrome
PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages
Seung Il Jo, Jung Hwan Bae, Seong Jin Kim, Jong Min Lee, Ji Hun Jeong, Jong-Seok Moon
Diabetes Metab J. 2019;43(5):683-699.   Published online October 24, 2019
DOI: https://doi.org/10.4093/dmj.2019.0112
  • 5,545 View
  • 66 Download
  • 4 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Chronic inflammation has been linked to insulin resistance and type 2 diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated with the activation of chronic inflammation in T2DM. PF-04620110, which is currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be important for the regulation of chronic inflammation in T2DM. However, the mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation remain unclear.

Methods

PF-04620110 was used in vitro and in vivo. DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured by immunoblot or cytokine analysis in vitro and in vivo.

Results

Here we show that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome activation in macrophages. In contrast, PF-04620110 did not change the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K+ efflux and the NLRP3 inflammasome complex formation, which are required for NLRP3 inflammasome activation. PF-04620110 reduced the production of interleukin 1β (IL-1β) and IL-18 and blood glucose levels in the plasma of mice fed HFD. Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 inflammasome activation.

Conclusion

Our results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation.

Citations

Citations to this article as recorded by  
  • Drug Targeting of Acyltransferases in the Triacylglyceride and 1-O-AcylCeramide Biosynthetic Pathways
    Maria Hernandez-Corbacho, Daniel Canals
    Molecular Pharmacology.2024; 105(3): 166.     CrossRef
  • Possible therapeutic targets for NLRP3 inflammasome-induced breast cancer
    Xixi Wang, Junyi Lin, Zhe Wang, Zhi Li, Minghua Wang
    Discover Oncology.2023;[Epub]     CrossRef
Pathophysiology
Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3
Kanghoon Lee, Hyunki Kim, Joonyub Lee, Chang-Myung Oh, Heein Song, Hyeongseok Kim, Seung-Hoi Koo, Junguee Lee, Ajin Lim, Hail Kim
Diabetes Metab J. 2019;43(5):649-658.   Published online April 8, 2019
DOI: https://doi.org/10.4093/dmj.2018.0232
  • 5,355 View
  • 70 Download
  • 4 Web of Science
  • 6 Crossref
AbstractAbstract PDFPubReader   
Background

Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.

Methods

Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.

Results

Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.

Conclusion

PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

Citations

Citations to this article as recorded by  
  • Role of protein arginine methyltransferase 1 in obesity‐related metabolic disorders: Research progress and implications
    Xiaolei Xuan, Yongjiao Zhang, Yufan Song, Bingyang Zhang, Junjun Liu, Dong Liu, Sumei Lu
    Diabetes, Obesity and Metabolism.2024;[Epub]     CrossRef
  • Arginine 65 methylation of Neurogenin 3 by PRMT1 is required for pancreatic endocrine development of hESCs
    Gahyang Cho, Kwangbeom Hyun, Jieun Choi, Eunji Shin, Bumsoo Kim, Hail Kim, Jaehoon Kim, Yong-Mahn Han
    Experimental & Molecular Medicine.2023; 55(7): 1506.     CrossRef
  • Protein arginine methyltransferase 1 in the generation of immune megakaryocytes: A perspective review
    Xinyang Zhao, Zechen Chong, Yabing Chen, X. Long Zheng, Qian-Fei Wang, Yueying Li
    Journal of Biological Chemistry.2022; 298(11): 102517.     CrossRef
  • Arginine 65 Methylation of Neurogenin 3 by PRMT1 Is Required for Pancreatic Endocrine Development of hESCs
    Gahyang Cho, Kwangbeom Hyun, Jieun Choi, Eun Ji Shin, Bumsoo Kim, Hail Kim, Jaehoon Kim, Yong-Mahn Han
    SSRN Electronic Journal .2022;[Epub]     CrossRef
  • Protein Arginine Methyltransferase 1 Is Essential for the Meiosis of Male Germ Cells
    Sahar Waseem, Sudeep Kumar, Kanghoon Lee, Byoung-Ha Yoon, Mirang Kim, Hail Kim, Keesook Lee
    International Journal of Molecular Sciences.2021; 22(15): 7951.     CrossRef
  • Proteome-Wide Alterations of Asymmetric Arginine Dimethylation Associated With Pancreatic Ductal Adenocarcinoma Pathogenesis
    Meijin Wei, Chaochao Tan, Zhouqin Tang, Yingying Lian, Ying Huang, Yi Chen, Congwei Chen, Wen Zhou, Tao Cai, Jiliang Hu
    Frontiers in Cell and Developmental Biology.2020;[Epub]     CrossRef
Clinical Diabetes & Therapeutics
Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials
Yu Mi Kang, Yun Kyung Cho, Jiwoo Lee, Seung Eun Lee, Woo Je Lee, Joong-Yeol Park, Ye-Jee Kim, Chang Hee Jung, Michael A. Nauck
Diabetes Metab J. 2019;43(4):410-421.   Published online December 27, 2018
DOI: https://doi.org/10.4093/dmj.2018.0070
  • 6,490 View
  • 137 Download
  • 19 Web of Science
  • 19 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
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.

Citations

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  • Sex, racial, ethnic, and geographical disparities in major adverse cardiovascular outcome of glucagon-like peptide-1 receptor agonists among patients with and without diabetes mellitus: A meta-analysis of placebo-controlled randomized controlled trials,
    Frederick Berro Rivera, Nathan Ross B. Bantayan, John Paul Aparece, Linnaeus Louisse A. Cruz, John Vincent Magallong, Polyn Luz Pine, Anne Mira Nicca Idian-Javier, Grace Nooriza O. Lumbang, Edgar V. Lerma, Kyla M. Lara-Breitinger, Martha Gulati, Krishnasw
    Journal of Clinical Lipidology.2024;[Epub]     CrossRef
  • A randomized, double‐blind trial assessing the efficacy and safety of two doses of dulaglutide in Japanese participants with type 2 diabetes (AWARD‐JPN)
    Tomoaki Morioka, Masakazu Takeuchi, Akichika Ozeki, Masanori Emoto
    Diabetes, Obesity and Metabolism.2024;[Epub]     CrossRef
  • Coronary Artery Disease in South Asian Patients: Cardiovascular Risk Factors, Pathogenesis and Treatments
    Vincenzo Sucato, Giuseppe Coppola, Girolamo Manno, Giuseppe Vadalà, Giuseppina Novo, Egle Corrado, Alfredo Ruggero Galassi
    Current Problems in Cardiology.2023; 48(8): 101228.     CrossRef
  • Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings
    Hodaka Yamada, Masashi Yoshida, Shunsuke Funazaki, Jun Morimoto, Shiori Tonezawa, Asuka Takahashi, Shuichi Nagashima, Kimura Masahiko, Otsuka Kiyoshi, Kazuo Hara
    Journal of Cardiovascular Development and Disease.2023; 10(4): 176.     CrossRef
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    L. Yu. Khamnueva, L. S. Andreeva
    Problems of Endocrinology.2023; 69(2): 38.     CrossRef
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    Sian A. Bradley, Kevin J. Spring, Roy G. Beran, Dimitrios Chatzis, Murray C. Killingsworth, Sonu M. M. Bhaskar
    Diabetes/Metabolism Research and Reviews.2022;[Epub]     CrossRef
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    Harold Edward Bays, Jennifer Ng, Jeffrey Sicat, Michelle Look
    Obesity Pillars.2022; 2: 100011.     CrossRef
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    Calvin Ke, K. M. Venkat Narayan, Juliana C. N. Chan, Prabhat Jha, Baiju R. Shah
    Nature Reviews Endocrinology.2022; 18(7): 413.     CrossRef
  • Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)
    Timothy M. E. Davis, Anna Giczewska, Yuliya Lokhnygina, Robert J. Mentz, Naveed Sattar, Rury R. Holman
    Cardiovascular Diabetology.2022;[Epub]     CrossRef
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    Xiaoling Cai, Linong Ji
    Diabetes Therapy.2021; 12(7): 1861.     CrossRef
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    Jae-Seung Yun, Seung-Hyun Ko
    Metabolism.2021; 123: 154838.     CrossRef
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    Jian L. Yeo, Emer M. Brady, Gerry P. McCann, Gaurav S. Gulsin
    Therapeutic Advances in Endocrinology and Metabolism.2021; 12: 204201882110342.     CrossRef
  • Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
    Yuan Zhu, Jiao Xu, Dong Zhang, Xingyu Mu, Yi Shi, Shangtao Chen, Zengxiang Wu, Shuangqing Li
    Frontiers in Endocrinology.2021;[Epub]     CrossRef
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    Matiullah Kamin, SajjadAli Khan, UmarYousaf Raja, Osama Ishtiaq, Asmara Malik, Tejhmal Rehman, MuhammadUmar Wahab
    Indian Journal of Endocrinology and Metabolism.2021; 25(5): 456.     CrossRef
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    Afreen I. Shariff, Nitya Kumar, William S. Yancy, Leonor Corsino
    Current Diabetes Reports.2020;[Epub]     CrossRef
  • Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors
    Christopher S. Wilcox
    Hypertension.2020; 75(4): 894.     CrossRef
  • Subpopulation Differences in the Cardiovascular Efficacy of Long-Acting Glucagon-Like Peptide 1 Receptor Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis
    Liyun He, Na Yang, Lingling Xu, Fan Ping, Wei Li, Yuxiu Li, Huabing Zhang
    Diabetes Therapy.2020; 11(9): 2121.     CrossRef
  • 2020 Consensus of Taiwan Society of Cardiology on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases
    Chern-En Chiang, Kwo-Chang Ueng, Ting-Hsing Chao, Tsung-Hsien Lin, Yih-Jer Wu, Kang-Ling Wang, Shih-Hsien Sung, Hung-I Yeh, Yi-Heng Li, Ping-Yen Liu, Kuan-Cheng Chang, Kou-Gi Shyu, Jin-Long Huang, Cheng-Dao Tsai, Huei-Fong Hung, Ming-En Liu, Tze-Fan Chao,
    Journal of the Chinese Medical Association.2020; 83(7): 587.     CrossRef
  • Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease
    Kyung-Soo Kim, Byung-Wan Lee
    Clinical and Molecular Hepatology.2020; 26(4): 430.     CrossRef
Obesity and Metabolic Syndrome
The Risk of Myocardial Infarction and Ischemic Stroke According to Waist Circumference in 21,749,261 Korean Adults: A Nationwide Population-Based Study
Jung-Hwan Cho, Eun-Jung Rhee, Se-Eun Park, Hyemi Kwon, Jin-Hyung Jung, Kyung-Do Han, Yong-Gyu Park, Hye Soon Park, Yang-Hyun Kim, Soon-Jib Yoo, Won-Young Lee
Diabetes Metab J. 2019;43(2):206-221.   Published online December 27, 2018
DOI: https://doi.org/10.4093/dmj.2018.0039
  • 5,763 View
  • 102 Download
  • 22 Web of Science
  • 24 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Waist circumference (WC) is a well-known obesity index that predicts cardiovascular disease (CVD). We studied the relationship between baseline WC and development of incident myocardial infarction (MI) and ischemic stroke (IS) using a nationwide population-based cohort, and evaluated if its predictability is better than body mass index (BMI).

Methods

Our study included 21,749,261 Koreans over 20 years of age who underwent the Korean National Health Screening between 2009 and 2012. The occurrence of MI or IS was investigated until the end of 2015 using National Health Insurance Service data.

Results

A total of 127,289 and 181,637 subjects were newly diagnosed with MI and IS. The incidence rate and hazard ratio of MI and IS increased linearly as the WC level increased, regardless of adjustment for BMI. When the analyses were performed according to 11 groups of WC, the lowest risk of MI was found in subjects with WC of 70 to 74.9 and 65 to 69.9 cm in male and female, and the lowest risk of IS in subjects with WC of 65 to 69.9 and 60 to 64.9 cm in male and female, respectively. WC showed a better ability to predict CVD than BMI with smaller Akaike information criterion. The optimal WC cutoffs were 84/78 cm for male/female for predicting MI, and 85/78 cm for male/female for predicting IS.

Conclusion

WC had a significant linear relationship with the risk of MI and IS and the risk began to increase from a WC that was lower than expected.

Citations

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  • Usefulness of New Criteria for Metabolic Syndrome Optimized for Prediction of Cardiovascular Diseases in Japanese
    Yurie Yamazaki, Kazuya Fujihara, Takaaki Sato, Mayuko Harada Yamada, Yuta Yaguchi, Yasuhiro Matsubayashi, Takaho Yamada, Satoru Kodama, Kiminori Kato, Hitoshi Shimano, Hirohito Sone
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    Ga Eun Nam, Yang-Hyun Kim, Kyungdo Han, Jin-Hyung Jung, Yong Gyu Park, Kwan-Woo Lee, Eun-Jung Rhee, Jang Won Son, Seong-Su Lee, Hyuk-Sang Kwon, Won-Young Lee, Soon Jib Yoo
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Islet Studies and Transplantation
Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5
Udayakumar Karunakaran, Suma Elumalai, Jun Sung Moon, Jae-Han Jeon, Nam Doo Kim, Keun-Gyu Park, Kyu Chang Won, Jaechan Leem, In-Kyu Lee
Diabetes Metab J. 2019;43(2):192-205.   Published online January 16, 2019
DOI: https://doi.org/10.4093/dmj.2018.0052
  • 5,049 View
  • 107 Download
  • 34 Web of Science
  • 33 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5.

Methods

To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis.

Results

Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss.

Conclusion

Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

Citations

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Epidemiology
High Proportion of Adult Cases and Prevalence of Metabolic Syndrome in Type 1 Diabetes Mellitus Population in Korea: A Nationwide Study
You-Bin Lee, Kyungdo Han, Bongsung Kim, Sang-Man Jin, Seung-Eun Lee, Ji Eun Jun, Jiyeon Ahn, Gyuri Kim, Jae Hyeon Kim
Diabetes Metab J. 2019;43(1):76-89.   Published online August 22, 2018
DOI: https://doi.org/10.4093/dmj.2018.0048
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AbstractAbstract PDFSupplementary MaterialPubReader   
Background

The prevalence and incidence of type 1 diabetes mellitus (T1DM) in all age groups and the prevalence of metabolic syndrome in patients with T1DM in Korea were estimated.

Methods

The incidence and prevalence of T1DM between 2007 and 2013 were calculated using the Korean National Health Insurance Service (NHIS) datasets of claims. Clinical characteristics and prevalence of metabolic syndrome in individuals with T1DM between 2009 and 2013 were determined using the database of NHIS preventive health checkups.

Results

The prevalence of T1DM in Korea between 2007 and 2013 was 0.041% to 0.047%. The annual incidence rate of T1DM in Korea in 2007 to 2013 was 2.73 to 5.02/100,000 people. Although the incidence rate of typical T1DM was highest in teenagers, it remained steady in adults over 30 years of age. In contrast, the incidence rate of atypical T1DM in 2013 was higher in people aged 40 years or older than in younger age groups. Age- and sex-adjusted prevalence of metabolic syndrome in patients with T1DM was 51.65% to 55.06% between 2009 and 2013.

Conclusion

T1DM may be more common in Korean adults than previously believed. Metabolic syndrome may be a frequent finding in individuals with T1DM in Korea.

Citations

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Diabetes Metab J : Diabetes & Metabolism Journal