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Nakhaei A, Marzoughi S, Ghoflchi S, Hosseini H, Afshari AR, Jalili-Nik M, Kesharwani P, Sahebkar A. An exploration of molecular signaling in drug reprocessing for Oral Squamous Cell Carcinoma. Eur J Med Chem 2025; 295:117816. [PMID: 40466285 DOI: 10.1016/j.ejmech.2025.117816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2025] [Revised: 05/14/2025] [Accepted: 05/25/2025] [Indexed: 06/11/2025]
Abstract
The unique characteristics of cancer are crucial for comprehending the processes underlying cancer initiation, development, and maintenance. These hallmarks guide the development of novel therapeutic strategies aimed at fundamental traits of cancer, resulting in more targeted therapies with the possibility for sustained effectiveness and minimized adverse effects. Drug repurposing, a novel approach that leverages the known safety and pharmacological properties of existing drugs, has surfaced as a viable alternative to traditional drug development. This method expedites the timescale for introducing novel medicines into clinical practice, often demonstrating reduced failure rates in clinical trials. Recent data substantiates the therapeutic efficacy of many repurposed medications in the management of oral squamous cell carcinomas (OSCC), a highly aggressive and treatment-resistant malignancy. Prominent instances include metformin, phenformin, propranolol, acetylsalicylic acid, celecoxib, itraconazole, statins, dihydroartemisinin, and methotrexate. These pharmaceuticals demonstrated diverse anticancer actions, rendering them valuable tools in the therapy of OSCC. This review provides a comprehensive overview of molecular signaling in the reprocessing of drugs for OSCC.
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Affiliation(s)
- Ali Nakhaei
- Student Research Committee, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran
| | - Sarah Marzoughi
- Student Research Committee, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran
| | - Sahar Ghoflchi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Basic Sciences, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran
| | - Mohammad Jalili-Nik
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh, 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India; Applied Biomedical Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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To M, Arimoto Y, Honda N, Furusho N, Kinouchi T, Takeshita Y, Haruki K, To Y. Elevated oxidative stress and steroid insensitivity in patients with asthma and high body fat percentage. Ann Allergy Asthma Immunol 2025:S1081-1206(25)00126-7. [PMID: 40097096 DOI: 10.1016/j.anai.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/12/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Obesity is a risk factor for poor asthma control. Previous research suggests that patients with asthma and obesity have reduced responsiveness to corticosteroids. Recent studies indicate that body fat percentage may be more strongly associated with obesity-related diseases compared with body mass index. However, the relationship between body fat percentage and asthma, particularly regarding steroid sensitivity, remains unclear. OBJECTIVE To investigate the association between body fat percentage and steroid sensitivity in patients with asthma and elucidate the potential mechanisms underlying this association. METHODS Adult patients with asthma were enrolled and categorized into patients with high body fat percentage (HBF) and control groups. Peripheral blood mononuclear cells were isolated from the blood samples. These cells were cultured with dexamethasone followed by stimulation with tumor necrosis factor-α to assess the half-maximal inhibitory concentration of dexamethasone (IC50-Dex). Serum adipocytokines and oxidative stress markers were also measured. The effects of metformin on steroid sensitivity and oxidative stress in peripheral blood mononuclear cells were evaluated ex vivo. RESULTS The HBF group exhibited significantly higher IC50-Dex values than the control group. In the HBF group, IC50-Dex correlated with the number of acute exacerbations per year and serum oxidative stress marker levels. Treatment with metformin significantly reduced both IC50-Dex and oxidative stress marker levels in the HBF group. CONCLUSION Oxidative stress associated with increased body fat may contribute to impaired steroid sensitivity in patients with asthma. Metformin may improve steroid sensitivity by reducing oxidative stress, suggesting a potential therapeutic approach in this patient population.
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Affiliation(s)
- Masako To
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan; Department of Respiratory Medicine, The Fraternity Memorial Hospital, Tokyo, Japan.
| | - Yoshihito Arimoto
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Natsue Honda
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Naho Furusho
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Toru Kinouchi
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Yuichiro Takeshita
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Kosuke Haruki
- Department of Laboratory Medicine, Dokkyo Medical University, Saitama Medical Center, Saitama, Japan
| | - Yasuo To
- Department of Pulmonary Medicine, International University of Health and Welfare Narita Hospital, Chiba, Japan
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Pham A, Corcoran R, Foer D. The role of type 2 diabetes in the severity of adult asthma. Curr Opin Allergy Clin Immunol 2025; 25:34-40. [PMID: 39607312 PMCID: PMC11695166 DOI: 10.1097/aci.0000000000001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
PURPOSE OF REVIEW This review summarizes recent basic, translational, and clinical research on type 2 diabetes (T2D) and its relationship with asthma severity in the context of T2D mechanisms and asthma outcomes. RECENT FINDINGS Several clinical asthma outcomes, such as lung function and exacerbations, demonstrate a strong association between T2D and asthma and support that T2D contributes to worse asthma outcomes. Multiple mechanisms underlying those observed associations, and their representative biomarkers, have been proposed. However, prospective, controlled human studies in the context of both T2D and asthma are limited. SUMMARY T2D is associated with worse asthma outcomes and more severe asthma. Yet patients with more severe or uncontrolled asthma are also at a higher risk for systemic steroid exposure, which worsens glycemic control and metabolic dysregulation. Preclinical and translational studies point to metabolic dysregulation as a driver of airway inflammation. Addressing these metabolic pathways through T2D treatment may, in turn, directly or indirectly improve clinical asthma outcomes. While additional research is needed to identify biomarkers of risk and treatment response in metabolic asthma, this review highlights the importance of considering T2D as a clinically relevant asthma comorbidity.
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Affiliation(s)
- Alisa Pham
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Rose Corcoran
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Dinah Foer
- Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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Al-Beltagi M, Bediwy AS, Saeed NK, Bediwy HA, Elbeltagi R. Diabetes-inducing effects of bronchial asthma. World J Diabetes 2025; 16:97954. [PMID: 39817208 PMCID: PMC11718464 DOI: 10.4239/wjd.v16.i1.97954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/12/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The relationship between diabetes mellitus (DM) and asthma is complex and can impact disease trajectories. AIM To explore the bidirectional influences between the two conditions on clinical outcomes and disease control. METHODS We systematically reviewed the literature on the relationship between DM and asthma, focusing on their impacts, mechanisms, and therapeutic implications. Various studies were assessed, which investigated the effect of glycemic control on asthma outcomes, lung function, and exacerbations. The study highlighted the role of specific diabetes medications in managing asthma. RESULTS The results showed that poor glycemic control in diabetes can exacerbate asthma, increase hospitalizations, and reduce lung function. Conversely, severe asthma, especially in obese individuals, can complicate diabetes management and make glycemic control more difficult. The diabetes-associated mechanisms, such as inflammation, microangiopathy, and oxidative stress, can exacerbate asthma and decrease lung function. Some diabetes medications exhibit anti-inflammatory effects that show promise in mitigating asthma exacerbations. CONCLUSION The complex interrelationship between diabetes and asthma suggests bidirectional influences that affect disease course and outcomes. Inflammation and microvascular complications associated with diabetes may worsen asthma outcomes, while asthma severity, especially in obese individuals, complicates diabetes control. However, the current research has limitations, and more diverse longitudinal studies are required to establish causal relationships and identify effective treatment strategies for individuals with both conditions.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 26671, Manama, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Busaiteen 15503, Muharraq, Bahrain
| | | | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Busiateen 15503, Muharraq, Bahrain
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Lee B, Man KKC, Wong E, Tan T, Sheikh A, Bloom CI. Antidiabetic Medication and Asthma Attacks. JAMA Intern Med 2025; 185:16-25. [PMID: 39556360 PMCID: PMC11574725 DOI: 10.1001/jamainternmed.2024.5982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 09/09/2024] [Indexed: 11/19/2024]
Abstract
Importance Elevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited. Objective To estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks. Design, Setting, and Participants The study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias. Exposure The primary exposure was metformin; secondary exposures included add-on antidiabetic medications. Main Outcomes The primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort. Results Of more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73). Conclusions and Relevance The results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.
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Affiliation(s)
- Bohee Lee
- National Heart and Lung Institute, Imperial College London, London, England
| | - Kenneth K. C. Man
- Research Department of Practice and Policy, School of Pharmacy, University College London, London, England
| | - Ernie Wong
- National Heart and Lung Institute, Imperial College London, London, England
| | - Tricia Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, England
| | - Aziz Sheikh
- Asthma UK Centre for Applied Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, England
| | - Chloe I. Bloom
- National Heart and Lung Institute, Imperial College London, London, England
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Cahill KN, Foer D. Borrowing From the Type 2 Diabetes Armamentarium for Asthma. JAMA Intern Med 2025; 185:25-27. [PMID: 39556391 DOI: 10.1001/jamainternmed.2024.5983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Affiliation(s)
- Katherine N Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dinah Foer
- Department of Medicine, Divisions of Allergy and Clinical Immunology and General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts
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Weare-Regales N, Carr T, Holguin F, Tibbitt CA, Lockey RF. Obesity and hormonal influences on asthma: Mechanisms, management challenges, and emerging therapeutic strategies. J Allergy Clin Immunol 2024; 154:1355-1368. [PMID: 39362350 DOI: 10.1016/j.jaci.2024.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/13/2024] [Accepted: 09/13/2024] [Indexed: 10/05/2024]
Abstract
Obesity and hormone dysregulation, common comorbidities of asthma, not only influence asthma risk and onset but can also complicate its management. The pathobiologic characteristics of obesity, such as insulin resistance and metabolism alterations, can impact lung function and airway inflammation while highlighting potential opportunities for therapeutic intervention. Likewise, obesity alters immune cell phenotypes and corticosteroid pharmacokinetics. Hormones such as sex hormones, incretins, and thyroid hormones can also affect asthma. This review highlights the mechanisms underlying obesity-related asthma and hormonal pathologies while exploring potential therapeutic strategies and the need for more research and innovative approaches in managing these comorbid conditions.
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Affiliation(s)
- Natalia Weare-Regales
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of South Florida, Morsani College of Medicine, and the Division of Endocrinology, Department of Internal Medicine, James A. Haley Veterans Administration, Tampa.
| | - Tara Carr
- Asthma and Airway Disease Research Center, University of Arizona, and the Section of Allergy and Immunology, Department of Medicine, University of Arizona College of Medicine, Tucson
| | - Fernando Holguin
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Medical School, Aurora
| | - Christopher Andrew Tibbitt
- Department of Medicine Huddinge, Centre for Infectious Medicine, Karolinska Institutet, and the Clinical Lung and Allergy Research Medical Unit for Lung and Allergy Diseases, Karolinska University Hospital, Stockholm
| | - Richard F Lockey
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Morsani College of Medicine, Tampa
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Bloodworth MH, Staso PJ, Huang S, Farber-Eger E, Niswender KD, Harrell FE, Wells QS, Bacharier LB, Shuey MM, Cahill KN. Impact of metabolic and weight components on incident asthma using a real-world cohort. Ann Allergy Asthma Immunol 2024; 133:660-666.e5. [PMID: 39293715 PMCID: PMC11812921 DOI: 10.1016/j.anai.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 08/30/2024] [Accepted: 09/08/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND Obesity and metabolic dysregulation (MetD) have increasing prevalence and adversely affect asthma morbidity and therapeutic response. OBJECTIVE To determine the role of weight and MetD on incident asthma in adulthood. METHODS In a retrospective, longitudinal cohort of patients, we performed a time-to-asthma diagnosis analysis after a 3-year landmark period (t0-t3) during which weight and MetD components were evaluated. We assessed incident asthma risk with MetD components and weight. RESULTS In total, 90,081 patients met the inclusion criteria, with 836 cases (0.93%) of incident asthma in our primary cohort. Diabetes present at t0, but no other MetD components, was associated with increased risk of asthma (adjusted hazard ratio = 1.85, 95% CI: 1.27-2.71, P = .0002). The effect of weight on asthma risk, independent of other MetD components, identified individuals with overweight or obesity as having a 10-year attributable risk of 15.4%. Metformin was prescribed more frequently, and hemoglobin A1c levels were lower in patients with diabetes in whom asthma did not develop (P < .0001). CONCLUSION Weight and diabetes prevention and management represent modifiable risk factors for adult asthma development.
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Affiliation(s)
- Melissa H Bloodworth
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Patrick J Staso
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Shi Huang
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Eric Farber-Eger
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kevin D Niswender
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Frank E Harrell
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Quinn S Wells
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Leonard B Bacharier
- Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, Tennessee
| | - Megan M Shuey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Katherine N Cahill
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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Rao R, Mei J, Chen H, Yang C. Association of metformin use with asthma development and adverse outcomes: A systematic review and meta-analysis. Medicine (Baltimore) 2024; 103:e39785. [PMID: 39465742 PMCID: PMC11460891 DOI: 10.1097/md.0000000000039785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND Asthma and diabetes are prevalent chronic diseases affecting a significant population globally. Research has suggested that metformin, a commonly used medication for diabetes management, may also have beneficial effects in enhancing asthma outcomes. Considering the comorbidity of asthma and diabetes, a comprehensive analysis was performed to investigate the efficacy of metformin in reducing adverse outcomes of asthma patients with diabetes. METHODS To gather relevant data, we conducted a systematic search of the PubMed, Embase, and CENTRAL databases for observational studies published prior to September 2023. We specifically looked for studies involving individuals diagnosed with both asthma and diabetes, comparing the incidence and severity of asthma exacerbations in metformin users versus nonusers. The inclusion criteria encompassed studies that recruited participants aged 18 years and older. The primary outcome of interest was the risk of newly developing asthma, while secondary outcomes included the adjusted risk of asthma-induced exacerbations, emergency room visits, and hospitalizations. All data analyses and visualizations were performed using the R programming language. RESULTS We identified and included 7 studies involving a total of 1,176,398 patients in our analysis. The pooled effect size indicated a potential reduction in the incidence of newly developed asthma among patients with type 2 diabetes who used metformin, although this finding did not reach statistical significance. Similar conclusions have also been observed in other outcomes, such as exacerbation, asthma-related emergency department visits, risk of systemic corticosteroid prescription. The only positive outcome is that the use of metformin can reduce the chance of patients being hospitalized due to asthma. CONCLUSION In most outcome indicators, it cannot be assumed that the use of metformin can reduce asthma-related adverse events. However, the conclusion is not so certain, and longer observation and more evidence are still required. Metformin still shows some potential in the intervention of respiratory diseases.
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Affiliation(s)
- Rui Rao
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Juan Mei
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Hudie Chen
- Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Chuanjing Yang
- Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
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Gao SY, Deng K, Wang J, Jin FD, Huang YL, Chen ZH, Oliver BG, Xie M, Wan HJ, Qin L, Liu D, Luo FM, Chen-Yu Hsu A, Li WM, Wang G, Wood LG. Homeostatic Measure of Insulin Resistance Is Associated With Future Asthma Exacerbations: A 1-Year Prospective Cohort Study. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:2774-2784.e3. [PMID: 38944198 DOI: 10.1016/j.jaip.2024.06.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 05/28/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND Recent evidence suggests that insulin resistance affects asthma outcomes. However, the effect of the homeostatic measure of insulin resistance (HOMA-IR) on airway inflammation and asthma exacerbations (AEs) is poorly understood. OBJECTIVE To analyze the relationship between HOMA-IR and clinical and inflammatory characteristics in patients with asthma, and the association between HOMA-IR and AEs in the following year. METHODS A prospective cohort study recruited participants with asthma, who were classified into the HOMA-IRhigh group and HOMA-IRlow group based on the cutoff value of 3.80 for HOMA-IR and were observed within 12 months. We evaluated the clinical and inflammatory features and conducted a 1-year follow-up to study the exacerbations. We used negative binomial regression models to analyze the association between HOMA-IR and AEs. RESULTS Compared with patients in the HOMA-IRlow group (n = 564), those in the HOMA-IRhigh group (n = 61) had higher levels of body mass index, a higher waist circumference and waist-hip ratio, higher triglycerides, lower cholesterol high-density lipoproteins, more neutrophils in the peripheral blood, and elevated IL-5 levels in the induced sputum. Furthermore, patients in the HOMA-IRhigh group had a significantly increased risk for moderate to severe AEs (adjusted incidence rate ratio [aIRR] = 2.26; 95% CI, 1.38-3.70), severe AEs (aIRR = 2.42; 95% CI, 1.26-4.67), hospitalization (aIRR = 2.54; 95% CI, 1.20-5.38), and emergency visits (aIRR = 3.04; 95% CI, 1.80-8.53). CONCLUSIONS The homeostatic measure of insulin resistance was associated with asthma-related clinical features and airway inflammation, and was an independent risk factor for future AEs. Therefore, insulin resistance may have important implications for managing asthma as a potential treatable trait.
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Affiliation(s)
- Si Yang Gao
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Ke Deng
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Ji Wang
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Fan Ding Jin
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Yan Li Huang
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Zhi Hong Chen
- Department of Respiratory, Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai, China
| | - Brian G Oliver
- School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales, Australia; Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Min Xie
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Jing Wan
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Ling Qin
- Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Dan Liu
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Feng Ming Luo
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China
| | - Alan Chen-Yu Hsu
- Signature Research Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
| | - Wei Min Li
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Respiratory Microbiome Laboratory, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China.
| | - Gang Wang
- Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Center of Excellence in Severe Asthma and Treatable Traits, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China.
| | - Lisa G Wood
- Hunter Medical Research Institute and School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
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11
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Chen W, Puttock EJ, Schatz M, Crawford W, Vollmer WM, Xie F, Xu S, Lustigova E, Zeiger RS. Risk Factors for Acute Asthma Exacerbations in Adults With Mild Asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:2705-2716.e6. [PMID: 38821437 PMCID: PMC11464201 DOI: 10.1016/j.jaip.2024.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 05/07/2024] [Accepted: 05/22/2024] [Indexed: 06/02/2024]
Abstract
BACKGROUND Although individuals with mild asthma account for 30% to 40% of acute asthma exacerbations (AAEs), relatively little attention has been paid to risk factors for AAEs in this population. OBJECTIVE To identify risk factors associated with AAEs in patients with mild asthma. METHODS This was a retrospective cohort study. We used administrative data from a large managed care organization to identify 199,010 adults aged 18 to 85 years who met study criteria for mild asthma between 2013 and 2018. An asthma-coded qualifying visit (index visit) was identified for each patient. We then used information at the index visit or from the year before the index visit to measure potential risk factors for AAEs in the subsequent year. An AAE was defined as either an asthma-coded hospitalization or emergency department visit, or an asthma-related systemic corticosteroid administration (intramuscular or intravenous) or oral corticosteroid dispensing. Poisson regression models with robust SEs were used to estimate the adjusted risk ratios for future AAEs. RESULTS In the study cohort, mean age was 44 years and 64% were female; 6.5% had AAEs within 1 year after the index visit. In multivariate models, age, sex, race, ethnicity, smoking status, body mass index, prior acute asthma care, and a variety of comorbidities and other clinical characteristics were significant predictors for future AAE risk. CONCLUSION Population-based disease management strategies for asthma should be expanded to include people with mild asthma in addition to those with moderate to severe disease.
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Affiliation(s)
- Wansu Chen
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif.
| | - Eric J Puttock
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif
| | - Michael Schatz
- Department of Allergy, Kaiser Permanente Southern California, San Diego, Calif; Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif
| | - William Crawford
- Department of Allergy, Kaiser Permanente Southern California, Harbor City, Calif
| | | | - Fagen Xie
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif
| | - Stanley Xu
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif
| | - Eva Lustigova
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif
| | - Robert S Zeiger
- Department of Allergy, Kaiser Permanente Southern California, San Diego, Calif; Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif
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12
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Hayashi Y, Tanabe N, Shimizu K, Maetani T, Shiraishi Y, Oguma T, Sunadome H, Sakamoto R, Sato A, Sato S, Date H, Matsumoto H, Hirai T. Lower skeletal muscle density and airway structure on computed tomography in asthma. Ann Allergy Asthma Immunol 2024:S1081-1206(24)00527-1. [PMID: 39179101 DOI: 10.1016/j.anai.2024.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUND Lower skeletal muscle density may reflect muscle adiposity and metabolic dysregulation that potentially impair disease control and lung function independent of high body mass index (BMI) in patients with asthma. OBJECTIVE To investigate whether the lower density of pectoralis muscles (PMs) and erector spinae muscles (ESMs) on chest computed tomography was associated with airway structural changes in patients with asthma. METHODS Consecutive patients with asthma and healthy controls undergoing chest computed tomography were retrospectively analyzed. The ESM and PM density, areas of subcutaneous adipose tissue near the PM and epicardial adipose tissue, wall area percent of the airways, and airway fractal dimension (AFD) were quantified on computed tomography. RESULTS The study included 179 patients with asthma (52% women) and 88 controls (47% women). All the controls were 60 years old or younger. The PM and ESM density in female patients with asthma who were 60 years old or younger were significantly lower than those in controls after adjustment for BMI. In female patients with asthma at all ages, lower PM and ESM density (but not subcutaneous or epicardial adipose tissue area) was associated with greater wall area percent of the airways and lower AFD after adjusting for age, height, BMI, smoking status, blood eosinophil count, and oral corticosteroid use. The only association between ESM density and AFD was found in male patients with asthma. CONCLUSION Lower skeletal muscle density may be associated with airway wall thickening and less complexity of the airway luminal tree in female patients with asthma.
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Affiliation(s)
- Yusuke Hayashi
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoya Tanabe
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Kaoruko Shimizu
- Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoki Maetani
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Shiraishi
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsuyoshi Oguma
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Medicine, Kyoto City Hospital, Kyoto, Japan
| | - Hironobu Sunadome
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryo Sakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsuyasu Sato
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Sato
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
| | - Hisako Matsumoto
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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13
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Olejnik AE, Kuźnar-Kamińska B. Association of Obesity and Severe Asthma in Adults. J Clin Med 2024; 13:3474. [PMID: 38930006 PMCID: PMC11204497 DOI: 10.3390/jcm13123474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
The incidence of obesity and asthma continues to enhance, significantly impacting global public health. Adipose tissue is an organ that secretes hormones and cytokines, causes meta-inflammation, and contributes to the intensification of bronchial hyperreactivity, oxidative stress, and consequently affects the different phenotypes of asthma in obese people. As body weight increases, the risk of severe asthma increases, as well as more frequent exacerbations requiring the use of glucocorticoids and hospitalization, which consequently leads to a deterioration of the quality of life. This review discusses the relationship between obesity and severe asthma, the underlying molecular mechanisms, changes in respiratory function tests in obese people, its impact on the occurrence of comorbidities, and consequently, a different response to conventional asthma treatment. The article also reviews research on possible future therapies for severe asthma. The manuscript is a narrative review of clinical trials in severe asthma and comorbid obesity. The articles were found in the PubMed database using the keywords asthma and obesity. Studies on severe asthma were then selected for inclusion in the article. The sections: 'The classification connected with asthma and obesity', 'Obesity-related changes in pulmonary functional tests', and 'Obesity and inflammation', include studies on subjects without asthma or non-severe asthma, which, according to the authors, familiarize the reader with the pathophysiology of obesity-related asthma.
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Affiliation(s)
- Aneta Elżbieta Olejnik
- Department of Pulmonology, Allergology and Pulmonary Oncology, Poznan University of Medical Sciences, Szamarzewskiego 84 Street, 60-569 Poznan, Poland;
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14
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Bartziokas K, Papaioannou AI, Drakopanagiotakis F, Gouveri E, Papanas N, Steiropoulos P. Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma. Biomedicines 2024; 12:437. [PMID: 38398039 PMCID: PMC10887139 DOI: 10.3390/biomedicines12020437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/10/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.
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Affiliation(s)
| | - Andriana I. Papaioannou
- 1st University Department of Respiratory Medicine, “Sotiria” Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Fotios Drakopanagiotakis
- Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Evanthia Gouveri
- Diabetes Centre, 2nd Department of Internal Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.G.); (N.P.)
| | - Nikolaos Papanas
- Diabetes Centre, 2nd Department of Internal Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.G.); (N.P.)
| | - Paschalis Steiropoulos
- Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
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15
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Ararat E, Landes RD, Forno E, Tas E, Perry TT. Metformin use is associated with decreased asthma exacerbations in adolescents and young adults. Pediatr Pulmonol 2024; 59:48-54. [PMID: 37772681 PMCID: PMC10872793 DOI: 10.1002/ppul.26704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023]
Abstract
RATIONALE Metformin is a commonly used antidiabetes medication with suggested anti-inflammatory and antioxidative effects. Metformin use has been associated with lower risk of asthma exacerbations and hospitalizations in adults. Here, we aimed to evaluate how asthma exacerbation rates changed after adolescents and young adults were prescribed metformin, and to learn if those changes were related to metformin prescription adherence. METHODS Using secondary data of patients between 12 and 20 years old with asthma diagnosis and a metformin prescription from the Arkansas All Payers Claim Database and Arkansas School body mass index (BMI) database, we estimated the change in annualized asthma exacerbation rates after metformin prescription. We also evaluated the association of prescription adherence to the changes in those rates using univariate and multivariate regression models. RESULTS A total of 464 patients met inclusion criteria. Outpatient exacerbation rates decreased after metformin prescription (13.4% only before vs. 7.8% only after, p = .009), and the annualized rate decreased more after metformin prescription as adherence increased (rank r = -.165, p < .001). After adjusting for potential confounders-age, sex, BMI, and inhaled corticoid steroid use-the strength of the association was attenuated. CONCLUSIONS Asthma exacerbation rates decreased after metformin prescription, but a larger sample of patients who have experienced exacerbations and including patients with asthma who have not been prescribed metformin is needed to better know whether these decreases are driven by metformin use.
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Affiliation(s)
- Erhan Ararat
- Department of Pediatrics, Division of Pulmonology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Reid D Landes
- Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Erick Forno
- Division of Pediatric Pulmonary, Allergy, and Sleep Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Emir Tas
- Pediatric Endocrinology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Tamara T Perry
- Department of Pediatrics, Allergy and Immunology, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, AR, USA
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16
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Averill SH, Forno E. Management of the pediatric patient with asthma and obesity. Ann Allergy Asthma Immunol 2024; 132:30-39. [PMID: 37827386 PMCID: PMC10760917 DOI: 10.1016/j.anai.2023.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/29/2023] [Accepted: 10/02/2023] [Indexed: 10/14/2023]
Abstract
Asthma and obesity are 2 of the most significant chronic diseases of childhood. Both are major public health problems that have been increasing in prevalence. Obesity increases the risk of developing asthma in children, and in children with asthma, obesity increases asthma severity and morbidity. The nature of this relationship is complex and not fully understood, but some pediatric patients with "obesity-related asthma" may represent a phenotype that differs from the more classical, atopic pediatric asthma. In this review, we investigate and discuss some of the currently available literature regarding treatment for asthma complicated by obesity in the pediatric population. We cover the importance of healthy lifestyle modifications, management of obesity-related comorbidities, and the potential role of nutritional supplementation or modification. We then review recent literature, mostly in adults, investigating the potential role of obesity or diabetes medications in the management of patients with asthma who have obesity. Finally, we discuss some of the necessary next steps before these potential new treatments can be considered as part of the standard clinical management of asthma.
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Affiliation(s)
- Samantha H Averill
- Division of Pulmonary, Allergy, and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Erick Forno
- Division of Pulmonary, Allergy, and Sleep Medicine, Riley Hospital for Children, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
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17
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Staggers KA, Minard C, Byers M, Helmer DA, Wu TD. Metabolic Dysfunction, Triglyceride-Glucose Index, and Risk of Severe Asthma Exacerbation. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:3700-3705.e2. [PMID: 37716524 PMCID: PMC10840907 DOI: 10.1016/j.jaip.2023.09.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/25/2023] [Accepted: 09/04/2023] [Indexed: 09/18/2023]
Abstract
BACKGROUND Metabolic conditions may worsen asthma. There is a need to define a composite biomarker of metabolic dysfunction that has relevance to asthma outcomes. OBJECTIVE To determine the association of the triglyceride-glucose index (TyG), a biomarker of metabolic syndrome and insulin resistance, with risk of severe asthma exacerbation. METHODS A 5-year retrospective cohort of patients with asthma receiving health care from the US Veterans Health Administration from January 1, 2015, to December 31, 2019, was constructed. Fasting TyG values were extracted. Patients were followed for a severe asthma exacerbation, defined as an asthma-related corticosteroid prescription fill or an emergency encounter or hospitalization for asthma. Adjusted models estimated the relative hazard of exacerbation associated with elevated TyG, accounting for known exacerbation risk factors. RESULTS A total of 108,219 patients fulfilled study criteria. Over 286,343 person-years of follow-up, 21,467 exacerbations were identified, corresponding to a crude rate of 7.5 exacerbations/100 person-years. In exploratory analysis, we found a threshold effect at a TyG of 8.3, which was defined as elevated. In a fully adjusted model, patients with an elevated TyG had a 6% (95% CI, 3%-10%) higher hazard for severe asthma exacerbation, independent of eosinophil count, smoking, obesity, and asthma treatment intensity. CONCLUSIONS Elevated TyG is a risk factor for severe asthma exacerbation independent of conventional predictors. Elevated TyG may identify patients who warrant more intensive asthma treatment and who are candidates for future clinical trials of metabolic intervention for purposes of improving asthma morbidity.
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Affiliation(s)
- Kristen A Staggers
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Charles Minard
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Michelle Byers
- Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas
| | - Drew A Helmer
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Section of Health Services Research, Baylor College of Medicine, Houston, Texas
| | - Tianshi David Wu
- Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas; Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas.
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18
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Herrera-Luis E, Rosa-Baez C, Huntsman S, Eng C, Beckman KB, LeNoir MA, Rodriguez-Santana JR, Villar J, Laprise C, Borrell LN, Ziv E, Burchard EG, Pino-Yanes M. Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth. Eur Respir J 2023; 62:2300714. [PMID: 37802634 PMCID: PMC10841414 DOI: 10.1183/13993003.00714-2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 08/20/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences. METHODS DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants. RESULTS 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 (NCOR2) and cg16412914 (AXIN1) as asthma DNAm markers. Significant DNAm markers were enriched in previous associations for asthma, fractional exhaled nitric oxide, bacterial infections, immune regulation or eosinophilia. Functional annotation highlighted epigenetically regulated gene networks involved in corticosteroid response, host defence and immune regulation. Several implicated genes are targets for approved or experimental drugs, including TNNC1 and NDUFA12. Many differentially methylated loci previously associated with asthma were validated in our study. CONCLUSIONS We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations.
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Affiliation(s)
- Esther Herrera-Luis
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Carlos Rosa-Baez
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Celeste Eng
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | | | - Michael A LeNoir
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
- Bay Area Pediatrics, Oakland, CA, USA
| | - Jose R Rodriguez-Santana
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
- Centro de Neumología Pediátrica, San Juan, Puerto Rico
| | - Jesús Villar
- Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Li Ka Shing Knowledge Institute at St Michael's Hospital, Toronto, ON, Canada
| | - Catherine Laprise
- Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Saguenay, QC, Canada
- Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, QC, Canada
| | - Luisa N Borrell
- Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA
| | - Elad Ziv
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
- Division of General Internal Medicine, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Esteban G Burchard
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Division of General Internal Medicine, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna (ULL), La Laguna, Spain
| | - Maria Pino-Yanes
- Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna (ULL), La Laguna, Spain
- These authors contributed equally as senior authors
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Shailesh H, Bhat AA, Janahi IA. Obesity-Associated Non-T2 Mechanisms in Obese Asthmatic Individuals. Biomedicines 2023; 11:2797. [PMID: 37893170 PMCID: PMC10603840 DOI: 10.3390/biomedicines11102797] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/30/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Obesity and asthma are two common health issues that have shown increased prevalence in recent years and have become a significant socioeconomic burden worldwide. Obesity increases asthma incidence and severity. Obese asthmatic individuals often experience increased exacerbation rates, enhanced airway remodeling, and reduced response to standard corticosteroid therapy. Recent studies indicate that obesity-associated non-T2 factors such as mechanical stress, hyperinsulinemia, systemic inflammation, adipose tissue mediators, metabolic dysregulation, microbiome dysbiosis, and high-fat-diet are responsible for increased asthma symptoms and reduced therapeutic response in obese asthmatic individuals. This manuscript reviews the recent findings highlighting the role of obesity-associated factors that contribute to airway hyper-reactivity, airway inflammation and remodeling, and immune cell dysfunction, consequently contributing to worsening asthma symptoms. Furthermore, the review also discusses the possible future therapies that might play a role in reducing asthma symptoms by diminishing the impact of obesity-associated non-T2 factors.
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Affiliation(s)
| | - Ajaz A. Bhat
- Precision Medicine in Diabetes, Obesity and Cancer Research Program, Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar;
| | - Ibrahim A. Janahi
- Department of Medical Education, Sidra Medicine, Doha 26999, Qatar;
- Department of Pediatric Medicine, Sidra Medicine, Doha 26999, Qatar
- Department of Pediatrics, Weill Cornell Medicine, Doha 24144, Qatar
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Khan J, Moran B, McCarthy C, Butler MW, Franciosi AN. Management of comorbidities in difficult and severe asthma. Breathe (Sheff) 2023; 19:230133. [PMID: 38020342 PMCID: PMC10644109 DOI: 10.1183/20734735.0133-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/03/2023] [Indexed: 12/01/2023] Open
Abstract
Difficult-to-treat and severe asthma are challenging clinical entities. In the face of suboptimal asthma control, the temptation for clinicians is to reflexively escalate asthma-directed therapy, including increasing exposure to corticosteroids and commencement of costly but potent biologic therapies. However, asthma control is objectively and subjectively assessed based on measurable parameters (such as exacerbations or variability in pulmonary physiology), symptoms and patient histories. Crucially, these features can be confounded by common untreated comorbidities, affecting clinicians' assessment of asthma treatment efficacy.
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Affiliation(s)
- Jehangir Khan
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared first authorship
| | - Barry Moran
- St Vincent's University Hospital, Dublin, Ireland
- Shared first authorship
| | - Cormac McCarthy
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
| | - Marcus W. Butler
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared senior authorship
| | - Alessandro N. Franciosi
- University College Dublin, Dublin, Ireland
- St Vincent's University Hospital, Dublin, Ireland
- Shared senior authorship
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Fu D, Zhao H, Huang Y, Li J, Feng H, Li A, Liu Y, He L. Metformin regulates the effects of IR and IGF-1R methylation on mast cell activation and airway reactivity in diabetic rats with asthma through miR-152-3p/DNMT1 axis. Cell Biol Toxicol 2023; 39:1851-1872. [PMID: 36547818 DOI: 10.1007/s10565-022-09787-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM Metformin is a drug for treating type 2 diabetes mellitus (T2DM). Recently, metformin has been shown to reduce the risks of asthma-associated outcomes and asthma deterioration, thereby holding promise as a superior medicine for diabetic patients with asthma. However, the mechanism by which metformin reduces diabetic asthma is yet to be clarified. This study aimed at ascertaining the downstream molecules underlying the effect of metformin on the activation of mast cells (MCs) and airway reactivity in a concomitant diabetic and asthmatic rat model. METHODS A T2DM model was induced utilizing a high-fat diet and streptozotocin. Then, 10% ovalbumin was utilized to stimulate asthma-like pathology in the T2DM rats. RBL-2H3 cells were induced by anti-dinitrophenyl-specific immunoglobulin E for constructing an in vitro model. Luciferase assay and RNA immunoprecipitation (IP) assay were conducted to identify the interaction between microRNA-152-3p (miR-152-3p) and DNA methyltransferase 1 (DNMT1), while chromatin IP to identify the binding of DNMT1 to insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) promoters. The effects of metformin on both pathological changes in vivo and biological behaviors of cells were evaluated. Using gain- and loss-of-function approaches, we assessed the role of the two interactions in the metformin-induced effect. RESULTS It was suggested that metformin could impede the MC activation and airway resistance in the concomitant diabetic and asthmatic rats. Additionally, metformin downregulated IR and IGF-1R through DNMT1-dependent methylation to repress MC activation and airway resistance. DNMT1 was testified to be a target gene of miR-152-3p. Furthermore, miR-152-3p-induced silencing of DNMT1 was blocked by metformin, hence restraining MC activation and airway resistance. CONCLUSION The findings cumulatively demonstrate that metformin downregulates IR/IGF-1R to block MC activation and airway resistance via impairing the binding affinity between miR-152-3p and DNMT1.
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Affiliation(s)
- Dan Fu
- Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, People's Republic of China
| | - Hailu Zhao
- Diabetic Systems Center, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, Guangxi, 541000, People's Republic of China
| | - Yan Huang
- Department of Anesthesiology, The Fifth Affiliated Hospital of Southern Medical University, No.566, Congcheng Ave, Guangzhou, Guangdong, 510900, People's Republic of China
| | - Jingjuan Li
- Department of Anesthesiology, The Fifth Affiliated Hospital of Southern Medical University, No.566, Congcheng Ave, Guangzhou, Guangdong, 510900, People's Republic of China
| | - Huafeng Feng
- Department of Anesthesiology, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People's Republic of China
| | - Aiguo Li
- Department of Anesthesiology, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541001, People's Republic of China
| | - Yefen Liu
- Department of Anesthesiology, The Fifth Affiliated Hospital of Southern Medical University, No.566, Congcheng Ave, Guangzhou, Guangdong, 510900, People's Republic of China
| | - Liang He
- Department of Anesthesiology, The Fifth Affiliated Hospital of Southern Medical University, No.566, Congcheng Ave, Guangzhou, Guangdong, 510900, People's Republic of China.
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Cazzola M, Rogliani P, Ora J, Calzetta L, Matera MG. Cardiovascular diseases or type 2 diabetes mellitus and chronic airway diseases: mutual pharmacological interferences. Ther Adv Chronic Dis 2023; 14:20406223231171556. [PMID: 37284143 PMCID: PMC10240559 DOI: 10.1177/20406223231171556] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/06/2023] [Indexed: 06/08/2023] Open
Abstract
Chronic airway diseases (CAD), mainly asthma and chronic obstructive pulmonary disease (COPD), are frequently associated with different comorbidities. Among them, cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) pose problems for the simultaneous treatment of CAD and comorbidity. Indeed, there is evidence that some drugs used to treat CAD negatively affect comorbidity, and, conversely, some drugs used to treat comorbidity may aggravate CAD. However, there is also growing evidence of some beneficial effects of CAD drugs on comorbidities and, conversely, of the ability of some of those used to treat comorbidity to reduce the severity of lung disease. In this narrative review, we first describe the potential cardiovascular risks and benefits for patients using drugs to treat CAD and the potential lung risks and benefits for patients using drugs to treat CVD. Then, we illustrate the possible negative and positive effects on T2DM of drugs used to treat CAD and the potential negative and positive impact on CAD of drugs used to treat T2DM. The frequency with which CAD and CVD or T2DM are associated requires not only considering the effect that drugs used for one disease condition may have on the other but also providing an opportunity to develop therapies that simultaneously favorably impact both diseases.
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Affiliation(s)
- Mario Cazzola
- Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Paola Rogliani
- Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy
| | - Josuel Ora
- Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy
| | - Luigino Calzetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maria Gabriella Matera
- Chair of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
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Lin Z, Huang J, Xie S, Zheng Z, Tang K, Li S, Chen R. The Association Between Insulin Use and Asthma: An Epidemiological Observational Analysis and Mendelian Randomization Study. Lung 2023; 201:189-199. [PMID: 36971839 DOI: 10.1007/s00408-023-00611-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/09/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Asthma is a common respiratory disease caused by genetic and environmental factors, but the contribution of insulin use to the risk of asthma remains unclear. This study aimed to investigate the association between insulin use and asthma in a large population-based cohort, and further explore their causal relationship by Mendelian randomization (MR) analysis. METHODS An epidemiological study including 85,887 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2018 was performed to evaluate the association between insulin use and asthma. Based on the inverse-variance weighted approach, MR analysis were conducted to estimate the causal effect of insulin use on asthma from the UKB and FinnGen datasets, respectively. RESULTS In the NHANES cohort, we found that insulin use was associated with an increased risk of asthma [odd ratio (OR) 1.38; 95% CI 1.16-1.64; p < 0.001]. For the MR analysis, we found a causal relationship between insulin use and a higher risk of asthma in both Finn (OR 1.10; p < 0.001) and UK Biobank cohorts (OR 1.18; p < 0.001). Meanwhile, there was no causal association between diabetes and asthma. After multivariable adjustment for diabetes in UKB cohort, the insulin use remained significantly associated with an increased risk of asthma (OR 1.17, p < 0.001). CONCLUSIONS An association between insulin use and an increased risk of asthma was found via the real-world data from the NHANES. In addition, the current study identified a causal effect and provided a genetic evidence of insulin use and asthma. More studies are needed to elucidate the mechanisms underlying the association between insulin use and asthma.
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Affiliation(s)
- Zikai Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
- Nanshan School of Medical, Guangzhou Medical University, Guangzhou, China
| | - Junfeng Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Shuojia Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
- Nanshan School of Medical, Guangzhou Medical University, Guangzhou, China
| | - Ziwen Zheng
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Kailun Tang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
- Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Clinical Medical College of Henan University, Kaifeng, China
| | - Shiyue Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Ruchong Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
- Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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Uppal P, Mohammed SA, Rajashekar S, Giri Ravindran S, Kakarla M, Ausaja Gambo M, Yousri Salama M, Haidar Ismail N, Tavalla P, Hamid P. Type 2 Diabetes Mellitus and Asthma: Pathomechanisms of Their Association and Clinical Implications. Cureus 2023; 15:e36047. [PMID: 37056543 PMCID: PMC10089620 DOI: 10.7759/cureus.36047] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/11/2023] [Indexed: 03/14/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and asthma are chronic illnesses concomitantly present in a significant percentage of the population. Their comorbidity is associated with poor disease control and lower quality of life, thus imposing a substantial medical and economic burden worldwide. This review investigates the association between asthma and T2DM, in terms of pathogenesis, clinical outcomes, and therapeutic opportunities. Our review found an increased risk of asthma among diabetics, and vice versa. Having diabetes and poor glycemic control is associated with an increased rate of asthma exacerbations and increased mortality among those hospitalized for asthma exacerbations. The mechanisms postulated for the diabetes-asthma association include chronic low-grade inflammation, obesity, hyperinsulinemia, and possibly diabetic pneumopathy. Usage of metformin, which is the first-line drug for type 2 diabetes, was found to be associated with a decreased asthma occurrence, asthma exacerbations, and asthma-related hospitalizations. Glucagon-like peptide 1 receptor agonists were also found to be associated with a lower occurrence of asthma exacerbations. Thiazolidinediones are also associated with lower rates of asthma exacerbations, but their clinical efficacy for the same was suggested to be limited. This literature review supports a partly causative association between asthma and diabetes. This comorbidity leads to poor patient compliance, worse disease outcomes, and poor quality of life. Thus, further studies are warranted to explore the prognostic implications, therapeutic opportunities, and specific clinical practice algorithms for patients with concurrent asthma and type 2 diabetes mellitus.
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Utility of Hypoglycemic Agents to Treat Asthma with Comorbid Obesity. Pulm Ther 2022; 9:71-89. [PMID: 36575356 PMCID: PMC9931991 DOI: 10.1007/s41030-022-00211-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/08/2022] [Indexed: 12/29/2022] Open
Abstract
Adults with obesity may develop asthma that is ineffectively controlled by inhaled corticosteroids and long-acting beta-adrenoceptor agonists. Mechanistic and translational studies suggest that metabolic dysregulation that occurs with obesity, particularly hyperglycemia and insulin resistance, contributes to altered immune cell function and low-grade systemic inflammation. Importantly, in these cases, the same proinflammatory cytokines believed to contribute to insulin resistance may also be responsible for airway remodeling and hyperresponsiveness. In the past decade, new research has emerged assessing whether hypoglycemic therapies impact comorbid asthma as reflected by the incidence of asthma, asthma-related emergency department visits, asthma-related hospitalizations, and asthma-related exacerbations. The purpose of this review article is to discuss the mechanism of action, preclinical data, and existing clinical studies regarding the efficacy and safety of hypoglycemic therapies for adults with obesity and comorbid asthma.
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Ke J, Hu X, Wang C, Zhang Y. Identification of the hub susceptibility genes and related common transcription factors in the skeletal muscle of Type 2 Diabetes Mellitus. BMC Endocr Disord 2022; 22:276. [PMID: 36368953 PMCID: PMC9652898 DOI: 10.1186/s12902-022-01195-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 11/01/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) and its related complications contribute to the high morbidity and mortality in worldwide. Skeletal muscle insulin resistance plays a critical role in the onset of T2DM due to the decreasing in the insulin-stimulated glucose uptake. T2DM is associated not only with the inherited factors but also with the noninherited factors. However, the susceptibility genes related with the two factors and the transcription factors (TF) regulating the susceptibility genes in skeletal muscle, which aggravate the development of T2DM were still ill-defined. METHODS In the present study, the expression profiles by the array of GSE25462 were retrieved from the GEO database. GEO2R was performed to validate the susceptibility differentially expressed genes (SDEG) in skeletal muscle of T2DM. Gene Ontology (GO) analysis and The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted via The Database for Annotation, Visualization, and Integrated Discovery (DAVID). A Protein-Protein Interaction (PPI) network was performed with the STRING. RESULTS With the performance of GEO2R, 229 SDEGs in skeletal muscle of T2DM were identified. The biological processes (BP) of SDEGs was enriched in the cellular response to UV-B most significantly. KEGG pathway analysis revealed that the SDEGs were most significantly enriched in glycosaminoglycan degradation. 5 hub susceptibility genes (GPR84, CALCB, GCG, PTGDR, GNG8) in the skeletal muscle of T2DM were identified. Eventually, the common transcription factors regulating the hub susceptibility genes were identified by means of the online tool PROMO. CONCLUSIONS Five hub susceptibility genes (GPR84, CALCB, GCG, PTGDR, GNG8) in the skeletal muscle of T2DM and the common transcription factors were identified. The outputs would provide new clues on the novel potential targets and the therapeutic strategies for treating T2DM and its related diseases.
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Affiliation(s)
- Jianjuan Ke
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 China
| | - Xiaohua Hu
- Department of Respiratory Medicine, Renmin Hospital of Lichuan, Lichuan, 445400 China
| | - Changhua Wang
- Department of Pathology & Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071 China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071 China
| | - Yemin Zhang
- Department of Pathology & Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071 China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071 China
- Demonstration Center for Experimental Basic Medicine Education of Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071 China
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Yen FS, Hsu CC, Hu KC, Hung YT, Hsu CY, Wei JCC, Hwu CM. Metformin and the Risk of Chronic Urticaria in Patients with Type 2 Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:11045. [PMID: 36078769 PMCID: PMC9517871 DOI: 10.3390/ijerph191711045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/31/2022] [Accepted: 08/31/2022] [Indexed: 06/15/2023]
Abstract
We conducted this study to determine the effect of metformin use on the risk of new-onset chronic urticaria in patients with type 2 diabetes (T2D). In total, 24,987 pairs of metformin users and nonusers were identified with propensity score-matching from Taiwan's National Health Insurance Research Database from 1 January 2000, to 31 December 2017. Multivariable Cox proportional hazards models were used to compare the risks of chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria between metformin users and nonusers. Compared with metformin nonuse, the aHRs (95% CI) for metformin use in chronic urticaria development, severe chronic urticaria, and hospitalization for chronic urticaria were 1.56 (1.39-1.74), 0.40 (0.12-1.30), and 1.45 (0.82-2.56), respectively. The cumulative incidence of chronic urticaria development was significantly higher in metformin users than in nonusers (p < 0.0001). A longer average cumulative duration of metformin use was associated with higher risks of new-onset and hospitalization for chronic urticaria than metformin nonuse. This nationwide cohort study showed that metformin use was associated with a significantly higher risk of chronic urticaria development. A longer average cumulative duration of metformin use was associated with a higher risk of outcomes. More prospective studies are needed to verify our results.
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Affiliation(s)
- Fu-Shun Yen
- Dr. Yen’s Clinic, No. 15, Shanying Road, Gueishan District, Taoyuan 33354, Taiwan
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan
- Department of Health Services Administration, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
- Department of Family Medicine, Min-Sheng General Hospital, 168 ChingKuo Road, Taoyuan 33044, Taiwan
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan
| | - Kai-Chieh Hu
- Management Office for Health Data, China Medical University Hospital, 3F, No. 373-2, Jianxing Road, Taichung 40459, Taiwan
- College of Medicine, China Medical University, No. 91, Xueshi Road, Taichung 40202, Taiwan
| | - Yu-Tung Hung
- Management Office for Health Data, China Medical University Hospital, 3F, No. 373-2, Jianxing Road, Taichung 40459, Taiwan
- College of Medicine, China Medical University, No. 91, Xueshi Road, Taichung 40202, Taiwan
| | - Chung Y. Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
| | - James Cheng-Chung Wei
- Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung 40203, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40203, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40202, Taiwan
| | - Chii-Min Hwu
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, No. 155, Sec. 2, Linong Street, Taipei 11221, Taiwan
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei 11217, Taiwan
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Yen FS, Hsu CC, Shih YH, Pan WL, Wei JCC, Hwu CM. Metformin and the Development of Asthma in Patients with Type 2 Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:8211. [PMID: 35805869 PMCID: PMC9266193 DOI: 10.3390/ijerph19138211] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/02/2022] [Accepted: 07/03/2022] [Indexed: 12/16/2022]
Abstract
We conducted this study to compare the risks of asthma development and exacerbation between metformin users and nonusers. Overall, 57,743 propensity score-matched metformin users and nonusers were identified from Taiwan’s National Health Insurance Research Database between 1 January 2000, and 31 December 2017. We used the Cox proportional hazards model with robust standard error estimates to compare the risks of asthma onset, exacerbation, and hospitalization for asthma in participants with type 2 diabetes (T2D). Compared with metformin nonuse, the aHRs (95% CI) for metformin use in asthma development, exacerbation, and hospitalization for asthma were 1.13 (1.06−1.2), 1.62 (1.35−1.95), and 1.5 (1.22−1.85), respectively. The cumulative incidences of asthma development, exacerbation, and hospitalization for asthma were significantly higher in metformin users than nonusers (p < 0.001). A longer cumulative duration of metformin use for more than 728 days was associated with significantly higher risks of outcomes than metformin nonuse. Our study demonstrated that metformin users showed significantly higher risks of asthma development, exacerbation, and hospitalization for asthma than metformin nonusers. Moreover, metformin use for more than 728 days was associated with higher risks of outcomes. A randomized control study is warranted to verify our results.
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Affiliation(s)
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County 35053, Taiwan;
- Department of Health Services Administration, China Medical University, Taichung 40402, Taiwan
- Department of Family Medicine, Min-Sheng General Hospital, Taoyuan 33044, Taiwan
| | - Ying-Hsiu Shih
- Management Office for Health Data, China Medical University Hospital, Taichung 40459, Taiwan;
- College of Medicine, China Medical University, Taichung 40201, Taiwan
| | - Wei-Lin Pan
- Department of Internal Medicine, Mackay Memorial Hospital, Taipei 10449, Taiwan;
| | - James Cheng-Chung Wei
- Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan
| | - Chii-Min Hwu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan
- Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
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Gu C, Loube J, Lee R, Bevans-Fonti S, Wu TD, Barmine JH, Jun JC, McCormack MC, Hansel NN, Mitzner W, Polotsky VY. Metformin Alleviates Airway Hyperresponsiveness in a Mouse Model of Diet-Induced Obesity. Front Physiol 2022; 13:883275. [PMID: 35574481 PMCID: PMC9098833 DOI: 10.3389/fphys.2022.883275] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/14/2022] [Indexed: 12/03/2022] Open
Abstract
Obese asthma is a unique phenotype of asthma characterized by non-allergic airway hyperresponsiveness (AHR) and inflammation which responds poorly to standard asthma therapy. Metformin is an oral hypoglycemic drug with insulin-sensitizing and anti-inflammatory properties. The objective of the current study was to test the effect of metformin on AHR in a mouse model of diet-induced obesity (DIO). We fed 12-week-old C57BL/6J DIO mice with a high fat diet for 8 weeks and treated them with either placebo (control, n = 10) or metformin (n = 10) added in drinking water (300 mg/kg/day) during the last 2 weeks of the experiment. We assessed AHR, metabolic profiles, and inflammatory markers after treatments. Metformin did not affect body weight or fasting blood glucose, but significantly reduced serum insulin (p = 0.0117). Metformin reduced AHR at 30 mg/ml of methacholine challenge (p = 0.0052) without affecting baseline airway resistance. Metformin did not affect circulating white blood cell counts or lung cytokine mRNA expression, but modestly decreased circulating platelet count. We conclude that metformin alleviated AHR in DIO mice. This finding suggests metformin has the potential to become an adjuvant pharmacological therapy in obese asthma.
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Affiliation(s)
- Chenjuan Gu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jeff Loube
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Rachel Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Shannon Bevans-Fonti
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Tianshi David Wu
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Baylor College of Medicine and the Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, United States
| | - Jessica H. Barmine
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jonathan C. Jun
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Meredith C. McCormack
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Nadia N. Hansel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Wayne Mitzner
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Vsevolod Y. Polotsky
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Vsevolod Y. Polotsky,
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Suzuki Y, Aono Y, Akiyama N, Horiike Y, Naoi H, Horiguchi R, Shibata K, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T. Involvement of autophagy in exacerbation of eosinophilic airway inflammation in a murine model of obese asthma. Autophagy 2022; 18:2216-2228. [PMID: 35098856 PMCID: PMC9397451 DOI: 10.1080/15548627.2022.2025571] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Obesity is a common comorbidity in patients with asthma, and obese asthma patients present the most refractory phenotype among patients with severe asthma. Similar to the observations in non-obese asthma patients, clinical studies have revealed heterogeneity in obese asthma patients, including the occurrences of T helper (Th)2-high and Th2-low phenotypes. However, the mechanisms underlying obesity-related asthma are not completely understood. Though macroautophagy/autophagy is involved in asthma and obesity, its role in obesity-associated asthma is unknown. We hypothesized that autophagy is involved in the pathogenesis of obese asthma. For our investigations, we used high-fat diet-induced Atg5 (autophagy related 5)-deficient mice and epithelial cell-specific atg5−/− (Scgb1a1/CCSP-atg5−/−) obesity-induced mice. House dust mite (HDM)-sensitized atg5−/− obese mice exhibited marked eosinophilic inflammation and airway hyper-reactivity (AHR), compared to wild-type (WT) obese mice. Analyses of atg5−/− obese mice showed increased levels of Th2 cells but not ILC2s together with elevated expression of Th2 cytokines in the lung. In response to the HDM challenge, activated epithelial autophagy was observed in lean but not obese WT mice. Epithelium-specific deletion of Atg5 induced eosinophilic inflammation in Scgb1a1/CCSP-atg5−/− obese mice, and genetic analyses of epithelial cells from HDM-immunized atg5−/− obesity-induced mice showed an elevated expression of thymic stromal lymphopoietin (TSLP) and IL33. Notably, HDM-sensitized atg5−/− mice developed TSLP- and IL33-dependent eosinophilic inflammation and AHR. Our results suggest that autophagy contributes to the exacerbation of eosinophilic inflammation in obese asthma. Modulations of autophagy may be a therapeutic target in obesity-associated asthma. Abbreviations: AHR: airway hyper-reactivity; BAL: bronchoalveolar lavage; Cdyn: dynamic compliance; BM: bone marrow; HDM: house dust mite; HFD: high-fat diet; ILC2s: type 2 innate lymphocyte cells; ROS: reactive oxygen species; RL: lung resistance; TSLP: thymic stromal lymphopoietin; TCC: total cell count; WT: wild type.
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Affiliation(s)
- Yuzo Suzuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuya Aono
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Norimichi Akiyama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasuoki Horiike
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hyogo Naoi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ryo Horiguchi
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kiyoshi Shibata
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hironao Hozumi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Karayama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yutaro Nakamura
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Li PF, Chung CH, Liu JS, Lu CH, Su SC, Kuo FC, Ho LJ, Chen KC, Su YT, Chu NF, Lee CH, Hsieh CH, Hung YJ, Lin FH, Chien WC, Liang YJ. Association of dipeptidyl peptidase-4 inhibitor use and the risk of asthma development among type 2 diabetes patients. Ther Adv Respir Dis 2022; 16:17534666221135320. [DOI: 10.1177/17534666221135320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: Numerous studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4i) may regulate immunological pathways implicated in asthma. The association between DPP-4i use and risk of asthma development is limited, however. Aim: We aimed to evaluate if DPP-4i treatment in individuals with type 2 diabetes mellitus (T2DM) is associated with a lower risk and severity of asthma. Methods: We performed a population-based retrospective cohort study using the Longitudinal National Health Insurance Research database between 2008 and 2015. After one-to-four propensity score matching from 1,914,201 patients with defined criteria, we enrolled 3001 patients who were on DPP-4i (DPP-4i group) for a diagnosis of T2DM but without a diagnosis of asthma for further analysis. Cox proportional hazards regression analysis was performed to estimate and compare the risk of developing and severity of asthma, including no acute exacerbations event (No-AE), acute exacerbations (AEs), status asthmaticus (Status), and required endotracheal intubation (ET-tube intubated), between the two groups. Results: The participants had a mean age of 66.05 ± 17.23 years and the mean follow-up time was 4.96 ± 4.39 years. The risk of asthma development was significantly lower in the DPP-4i group than in the non-DPP-4i group [adjusted hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.29–0.83; p < 0.001], with a class effect. This trend was observed for severity of asthma as No-AE (HR = 0.55; 95% CI = 0.24–0.70; p < 0.001), AE (HR = 0.57; 95% CI = 0.26–0.73; p < 0.001), and Status (HR = 0.78; 95% CI = 0.35–0.99; p = 0.047), but not in ET-tube intubated cases (HR = 0.96; 95% CI = 0.43–1.22; p = 0.258). Conclusion: The use of DPP-4i decreased the risk and severity of asthma with a class effect among No-AE, AE, status of asthma events, but not in ET-tube intubated events. Our report suggests that DPP-4i may play a role in attenuating the impact of asthma on incidence in the future and on more severe forms of disease exacerbation in T2DM patients.
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Affiliation(s)
- Peng-Fei Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
- Graduate Institute of Applied Science and Engineering, Fu Jen Catholic University, New Taipei
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Li-Ju Ho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Kuan-Chan Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Yu-Te Su
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Nain-Feng Chu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taipei
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center 114, Taipei
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering and Institute of Life Science, Fu Jen Catholic University, Number 510, Zhong-Zheng Road, Xin-Zhuang, New Taipei 242
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Abstract
Asthma is chronic eosinophilic bronchitis with the dominancy of T helper 2 (Th2) inflammation. However, patients with asthma and metabolic dysfunction have pathogenic and pathological differences from those with Th2 inflammation. Metabolic dysfunction, typically presented as metabolic syndrome, has several important clinical components including central obesity, insulin resistance or glucose intolerance, dyslipidemia, and vitamin D deficiency. Data from large epidemiological studies support the significance of these components in the control of asthma and their contribution to airway remodeling, suggesting the presence of an asthma phenotype with metabolic dysfunction. These components are quite interactive with each other, so it is difficult to reveal the individual role of each. It is well known that asthma is difficult to treat in patients with obesity, due in part to inadequate response to inhaled corticosteroids. Additionally, vitamin D deficiency and insulin resistance have been regarded as aggravating factors of asthma control and airway remodeling. Recent clinical and in vivo studies have revealed the specific mechanisms of these components, which may aggravate asthma control and airway remodeling. In this review article, I summarize the recent studies and unmet needs for patients with asthma and metabolic dysfunction.
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Affiliation(s)
- Jung-Won Park
- Institute for Allergy & Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
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Calco GN, Proskocil BJ, Jacoby DB, Fryer AD, Nie Z. Metformin prevents airway hyperreactivity in rats with dietary obesity. Am J Physiol Lung Cell Mol Physiol 2021; 321:L1105-L1118. [PMID: 34668415 PMCID: PMC8715020 DOI: 10.1152/ajplung.00202.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/15/2021] [Accepted: 10/15/2021] [Indexed: 11/22/2022] Open
Abstract
Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.
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Affiliation(s)
- Gina N Calco
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
| | - Becky J Proskocil
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
| | - David B Jacoby
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
| | - Allison D Fryer
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
| | - Zhenying Nie
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
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Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer. Adv Drug Deliv Rev 2021; 178:113918. [PMID: 34375681 DOI: 10.1016/j.addr.2021.113918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/23/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus (DM), is the most common metabolic disease and is characterized by sustained hyperglycemia. Accumulating evidences supports a strong association between DM and numerous lung diseases including chronic obstructive pulmonary disease (COPD), fibrosis, and lung cancer (LC). The global incidence of DM-associated lung disorders is rising and several ongoing studies, including clinical trials, aim to elucidate the molecular mechanisms linking DM with lung disorders, in particular LC. Several potential mechanisms, including hyperglycemia, hyperinsulinemia, glycation, inflammation, and hypoxia, are cited as plausible links between DM and LC. In addition, studies also propose a connection between the use of anti-diabetic medications and reduction in the incidence of LC. However, the exact cause for DM associated lung diseases especially LC is not clear and is an area under intense investigation. Herein, we review the biological links reported between DM and lung disorders with an emphasis on LC. Furthermore, we report common signaling pathways (eg: TGF-β, IL-6, HIF-1, PDGF) and miRNAs that are dysregulated in DM and LC and serve as molecular targets for therapy. Finally, we propose a nanomedicine based approach for delivering therapeutics (eg: IL-24 plasmid DNA, HuR siRNA) to disrupt signaling pathways common to DM and LC and thus potentially treat DM-associated LC. Finally, we conclude that the effective modulation of commonly regulated signaling pathways would help design novel therapeutic protocols for treating DM patients diagnosed with LC.
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Schuliga M, Read J, Knight DA. Ageing mechanisms that contribute to tissue remodeling in lung disease. Ageing Res Rev 2021; 70:101405. [PMID: 34242806 DOI: 10.1016/j.arr.2021.101405] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/13/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022]
Abstract
Age is a major risk factor for chronic respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and certain phenotypes of asthma. The recent COVID-19 pandemic also highlights the increased susceptibility of the elderly to acute respiratory distress syndrome (ARDS), a diffuse inflammatory lung injury with often long-term effects (ie parenchymal fibrosis). Collectively, these lung conditions are characterized by a pathogenic reparative process that, rather than restoring organ function, contributes to structural and functional tissue decline. In the ageing lung, the homeostatic control of wound healing following challenge or injury has an increased likelihood of being perturbed, increasing susceptibility to disease. This loss of fidelity is a consequence of a diverse range of underlying ageing mechanisms including senescence, mitochondrial dysfunction, proteostatic stress and diminished autophagy that occur within the lung, as well as in other tissues, organs and systems of the body. These ageing pathways are highly interconnected, involving localized and systemic increases in inflammatory mediators and damage associated molecular patterns (DAMPs); along with corresponding changes in immune cell function, metabolism and composition of the pulmonary and gut microbiomes. Here we comprehensively review the roles of ageing mechanisms in the tissue remodeling of lung disease.
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Affiliation(s)
- Michael Schuliga
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
| | - Jane Read
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Darryl A Knight
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; Providence Health Care Research Institute, Vancouver, British Columbia, Canada
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Abstract
PURPOSE OF REVIEW Disorders of glucose metabolism, including insulin resistance, prediabetes, and diabetes, have been identified as risk factors for worsened asthma. This review summarizes emerging evidence for their role as modifiable risk factors in asthma, including the potential benefit of diabetes medications on asthma outcomes. RECENT FINDINGS Experimental studies show that hyperinsulinemia associated with insulin resistance is associated with airway smooth muscle proliferation and promotes contractility. Epidemiologic studies have identified a higher prevalence of glycemic dysfunction among those with severe and uncontrolled asthma, and longitudinal studies have associated prediabetes and diabetes with higher risk of asthma exacerbations. The potential benefits of thiazolidinediones (TZDs), glucagon-like peptide-1 agonists, and metformin being investigated in asthma, but thus far interventional studies of TZDs have reported null results. On the contrary, observational studies have inconsistently controlled for relevant confounders which leaves conclusions vulnerable to misattribution of relationships due to corelated metabolic disorders, including dyslipidemia. SUMMARY Developing evidence suggests that disorders of glucose metabolism may be associated with worsening asthma. However, these conditions arise within a network of obesity-related metabolic diseases that may themselves worsen asthma. Few interventional trials have not identified a benefit, but data have been limited. Additional research is needed to define the potential independent impact of disorders of glucose metabolism in asthma.
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Wu TD, Fawzy A, Akenroye A, Keet C, Hansel NN, McCormack MC. Metformin Use and Risk of Asthma Exacerbation Among Asthma Patients with Glycemic Dysfunction. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:4014-4020.e4. [PMID: 34293503 DOI: 10.1016/j.jaip.2021.07.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 05/12/2021] [Accepted: 07/01/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Diabetes is associated with worse asthma morbidity. Metformin, which treats diabetes, may have a role among patients with asthma and glycemic dysfunction. OBJECTIVE To determine the association between metformin use and asthma exacerbations among patients with diabetes. METHODS We queried the Johns Hopkins electronic health record from April 1, 2013, to May 31, 2018. Adults with asthma and diabetes were followed from first hemoglobin A1c (HbA1c) test to an asthma-related systemic corticosteroid prescription, emergency department (ED) visit, or hospitalization. Multivariable Cox models estimated time to each outcome associated with metformin use, modeled as either time-invariant (status at HbA1c testing) or time-dependent (based on fill data). Mediation of results by HbA1c was assessed. Sensitivity analysis was performed by propensity score matching. RESULTS The cohort comprised 1749 adults with asthma and diabetes. Metformin use at entry was associated with a lower hazard of asthma-related ED visits (adjusted hazard ratio [aHR], 0.40; 95% CI, 0.22-0.75) but not steroid prescription (aHR, 0.89; 95% CI, 0.70-1.13) or hospitalization (aHR, 0.38; 95% CI, 0.13-1.12). HbA1c did not mediate the association with ED visits. With metformin exposure modeled as time-dependent, metformin use was additionally associated with lower hazard of asthma-related hospitalization (aHR, 0.30; 95% CI, 0.09-0.93). Results were consistent within a subcohort of 698 metformin users matched 1:1 to nonusers by propensity score. CONCLUSIONS Metformin use, independent of glycemic control and obesity, was associated with lower hazard of asthma-related ED visits and hospitalizations. Metformin may have benefit in patients with asthma and glycemic dysfunction.
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Affiliation(s)
- Tianshi David Wu
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md; Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Ashraf Fawzy
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Ayobami Akenroye
- Division of Pediatric Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Corinne Keet
- Division of Pediatric Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Nadia N Hansel
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md; Division of Pediatric Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Meredith C McCormack
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
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McCarty MF, DiNicolantonio JJ, Lerner A. Review - Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics. J Asthma Allergy 2021; 14:685-701. [PMID: 34163181 PMCID: PMC8214517 DOI: 10.2147/jaa.s307549] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/21/2021] [Indexed: 12/17/2022] Open
Abstract
Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin's precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina's versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase. Hence, spirulina or PhyCB-enriched spirulina extracts merit clinical evaluation in asthma. Promoting biosynthesis of glutathione and increasing the expression and activity of various antioxidant enzymes - as by supplementing with N-acetylcysteine, Phase 2 inducers (eg, lipoic acid), selenium, and zinc - may also blunt the contribution of oxidative stress to asthma pathogenesis. Nitric oxide (NO) and hydrogen sulfide (H2S) work in various ways to oppose pathogenic mechanisms in asthma; supplemental citrulline and high-dose folate may aid NO synthesis, high-dose biotin may mimic and possibly potentiate NO's activating impact on soluble guanylate cyclase, and NAC and taurine may boost H2S synthesis. The amino acid glycine has a hyperpolarizing effect on airway smooth muscle that is bronchodilatory. Insuring optimal intracellular levels of magnesium may modestly blunt the stimulatory impact of intracellular free calcium on bronchoconstriction. Nutraceutical regimens or functional foods incorporating at least several of these agents may have utility as nutraceutical adjuvants to standard clinical management of asthma.
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Affiliation(s)
| | - James J DiNicolantonio
- Department of Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas, MO, USA
| | - Aaron Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, 5262000, Israel
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Chetty L, Govender N, Govender GM, Reddy P. Demographic stratification of Type 2 diabetes and comorbidities in district healthcare in KwaZulu-Natal. S Afr Fam Pract (2004) 2021; 63:e1-e9. [PMID: 33881328 PMCID: PMC8377998 DOI: 10.4102/safp.v63i1.5218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/17/2020] [Accepted: 12/20/2020] [Indexed: 11/08/2022] Open
Abstract
Background Diabetes has been reported as the second leading cause of death and the top leading cause of death amongst women in South Africa; it is important to evaluate any epidemiological or demographic transition related to diabetes. This study evaluated the demographically stratified prevalence of type 2 diabetes mellitus (T2DM) and existing comorbidities amongst an outpatient population in a district healthcare facility in Kwazulu-Natal (KZN). Methods This retrospective cross-sectional study was conducted at a district hospital, and a retrospective record review of all outpatients who reported to the hospital to be treated for T2DM between the period, August 2018–January 2019, was used. Data, such as age, sex, ethnicity and any coexisting morbidity, were collected from outpatient hospital registers and electronically captured using a record review tool. Results There were significantly more female patients (3072) compared to male patients (1050) (p < 0.001) with a mean age of 59.21 years. Hypertension (77.9%) and cardiovascular problems (11.16%) were most frequent. Approximately 84% of women presented with T2DM and either one or two morbidities simultaneously. Female patients were at significantly higher risk of presenting with hypertension (odds ratio [OR] = 1.44, 95% confidence interval [CI]: 1.20;1.71), whilst their risk for cardiovascular problems was significantly lower compared to male patients (OR = 0.67, 95% CI: 0.54;0.83). Conclusion The prevalence of T2DM and comorbidities differed by demographic factors, such as sex, ethnicity and age. There is a need for flexible and adaptive approaches for the prevention and management of T2DM cases in order to allocate medical resources efficiently and according to the true burden of disease because of T2DM complications.
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Affiliation(s)
- Lauren Chetty
- Department of Community Health Studies, Faculty of Health Sciences, Durban University of Technology, Durban.
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Ma B, Athari SS, Mehrabi Nasab E, Zhao L. PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma. Inflammation 2021; 44:1895-1907. [PMID: 33860870 DOI: 10.1007/s10753-021-01466-3] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/19/2021] [Accepted: 04/05/2021] [Indexed: 11/25/2022]
Abstract
Asthma is an inflammatory airway disease wherein bronchoconstriction, airway inflammation, and airway obstruction during asthma attacks are the main problems. It is recognized that imbalance of Th1/Th2 and Th17/Treg is a critical factor in asthma pathogenesis. Manipulation of these with signaling molecules such as mTOR, PI3K, Akt, and MyD88 can control asthma. Mouse model of allergic asthma was produced and treated with ketamine, metformin, metformin and ketamine, triciribine, LY294002, and torin2. MCh challenge test, BALf's Eos Count, the IL-4, 5, INF-γ, eicosanoid, total IgE levels were determined. The MUC5a, Foxp3, RORγt, PI3K, mTOR, Akt, PU.1, and MyD88 gene expressions and histopathology study were done. Asthma groups that were treated with all six components had reduced Penh value, total IgE, IL-4 and IL-5 levels, MUC5a, RORγt, MyD88 and mTOR expression, goblet cell hyperplasia, and mucus hyper-secretion. The eosinophil percentage and Cys-LT level were decreased by metformin and ketamine, triciribine, LY294002, and torin2. The level of IFN-γ was increased in triciribine, LY294002, and torin2. Metformin, metformin and ketamine, triciribine, LY294002, and torin2 reduced Akt and PI3K expression, peribronchial and perivascular inflammation, and increased expression of Foxp3. Torin2 had an effect on PU.1 expression. Inhibition of PI3K/AKT/mTOR and TLR4/MyD88/NF-κB signaling with targeted molecules can attenuate asthma pathology and play an important role in airways protection.
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Affiliation(s)
- Baowei Ma
- Department of Thoracic Surgery, Xilingol League Hospital, Xilin Hot City, 026000, Inner Mongolia, China
| | - Seyyed Shamsadin Athari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Entezar Mehrabi Nasab
- Department of Cardiology, School of Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Limin Zhao
- Department of Respiratory and Critical Care Medicine, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
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Forno E. A Potential New Treatment Option for Asthma in the Setting of Obesity or Insulin Resistance? Am J Respir Crit Care Med 2021; 203:788-789. [PMID: 33211980 PMCID: PMC8017569 DOI: 10.1164/rccm.202010-4017ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Erick Forno
- Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania and.,Division of Pulmonary Medicine Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania
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Foer D, Beeler PE, Cui J, Karlson EW, Bates DW, Cahill KN. Asthma Exacerbations in Patients with Type 2 Diabetes and Asthma on Glucagon-like Peptide-1 Receptor Agonists. Am J Respir Crit Care Med 2021; 203:831-840. [PMID: 33052715 PMCID: PMC8017590 DOI: 10.1164/rccm.202004-0993oc] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/13/2020] [Indexed: 12/22/2022] Open
Abstract
Rationale: GLP-1R (glucagon-like peptide-1 receptor) agonists are approved to treat type 2 diabetes mellitus and obesity. GLP-1R agonists reduce airway inflammation and hyperresponsiveness in preclinical models.Objectives: To compare rates of asthma exacerbations and symptoms between adults with type 2 diabetes and asthma prescribed GLP-1R agonists and those prescribed SGLT-2 (sodium-glucose cotransporter-2) inhibitors, DPP-4 (dipeptidyl peptidase-4) inhibitors, sulfonylureas, or basal insulin for diabetes treatment intensification.Methods: This study was an electronic health records-based new-user, active-comparator, retrospective cohort study of patients with type 2 diabetes and asthma newly prescribed GLP-1R agonists or comparator drugs at an academic healthcare system from January 2000 to March 2018. The primary outcome was asthma exacerbations; the secondary outcome was encounters for asthma symptoms. Propensity scores were calculated for GLP-1R agonist and non-GLP-1R agonist use. Zero-inflated Poisson regression models included adjustment for multiple covariates.Measurements and Main Results: Patients initiating GLP-1R agonists (n = 448), SGLT-2 inhibitors (n = 112), DPP-4 inhibitors (n = 435), sulfonylureas (n = 2,253), or basal insulin (n = 2,692) were identified. At 6 months, asthma exacerbation counts were lower in persons initiating GLP-1R agonists (reference) compared with SGLT-2 inhibitors (incidence rate ratio [IRR], 2.98; 95% confidence interval [CI], 1.30-6.80), DPP-4 inhibitors (IRR, 2.45; 95% CI, 1.54-3.89), sulfonylureas (IRR, 1.83; 95% CI, 1.20-2.77), and basal insulin (IRR, 2.58; 95% CI, 1.72-3.88). Healthcare encounters for asthma symptoms were also lower among GLP-1R agonist users.Conclusions: Adult patients with asthma prescribed GLP-1R agonists for type 2 diabetes had lower counts of asthma exacerbations compared with other drugs initiated for treatment intensification. GLP-1R agonists may represent a novel treatment for asthma associated with metabolic dysfunction.
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Affiliation(s)
- Dinah Foer
- Division of Allergy and Clinical Immunology
| | - Patrick E. Beeler
- Division of General Internal Medicine and Primary Care, and
- Department of Internal Medicine, University Hospital Zurich, and Epidemiology, Biostatistics, and Prevention Institute, University of Zurich, Zurich, Switzerland; and
| | - Jing Cui
- Division of Rheumatology, Immunity, and Inflammation, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Elizabeth W. Karlson
- Division of Rheumatology, Immunity, and Inflammation, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
| | - David W. Bates
- Division of General Internal Medicine and Primary Care, and
| | - Katherine N. Cahill
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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43
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Zhang P, Lopez R, Attaway AH, Georas SN, Khatri SB, Abi-Saleh S, Zein JG. Diabetes Mellitus Is Associated with Worse Outcome in Patients Hospitalized for Asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2021; 9:1562-1569.e1. [PMID: 33181340 PMCID: PMC8043963 DOI: 10.1016/j.jaip.2020.10.054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/24/2020] [Accepted: 10/26/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Asthma is a prevalent disease with a high economic cost. More than 50% of its direct cost relates to asthma hospitalizations. Diabetes mellitus (DM) is a significant comorbidity in asthmatic patients, yet its impact on asthma-related hospitalizations is unknown. OBJECTIVE To compare the outcome of asthma-related hospitalizations in patients with and without DM. METHODS Using Healthcare Cost and Utilization Project Nationwide Readmissions Database, we analyzed data of all adults with index admission for asthma and with no other chronic pulmonary conditions, and compared outcomes between patients with and without DM. Weighted regression analysis was used to determine the impact of DM on hospitalization outcomes. All multivariate regression models were adjusted for patient demographics, socioeconomic status, and chronic medical comorbidities. RESULTS A total of 717,200 asthmatic patients were included, with 202,489 (28.3%) having DM. Diabetic patients were older and had more comorbidities. When hospitalized for asthma, diabetic patients had increased hospital length of stay, cost, and risk for 30-day all-cause and asthma-related readmission. They also had a higher risk for developing nonrespiratory complications during their hospital stay compared with nondiabetic patients. The risk of mortality was similar between the 2 groups. CONCLUSIONS Patients hospitalized for asthma with coexisting DM had increased hospital length of stay, cost, and risk for readmission. Interventions are urgently needed to reduce the risk for hospital admission and readmission in patients with coexisting DM and asthma. These interventions would have profound economic and societal impact.
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Affiliation(s)
- Peng Zhang
- Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | - Rocio Lopez
- Center for Populations Health Research, Cleveland Clinic, Cleveland, Ohio; Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - Amy H Attaway
- Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | - Steve N Georas
- Department of Medicine, University of Rochester Medical Center, Rochester, NY
| | | | | | - Joe G Zein
- Respiratory Institute, Cleveland Clinic, Cleveland, Ohio.
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44
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Lee SE, Baek JY, Han K, Koh EH. Insulin Resistance Increases Serum Immunoglobulin E Sensitization in Premenopausal Women. Diabetes Metab J 2021; 45:175-182. [PMID: 32431107 PMCID: PMC8024158 DOI: 10.4093/dmj.2019.0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/10/2019] [Indexed: 11/08/2022] Open
Abstract
Background Although studies have shown that obesity is associated with aeroallergen sensitization (atopy), controversy still exists. We aimed to investigate the association between metabolic status, obesity, and atopy stratified by sex and menopausal status. Methods A total of 1,700 adults from the 2010 Korean National Health and Nutrition Examination Survey were classified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) by body mass index and insulin resistance. Atopy was defined as a positive response to at least one aeroallergen. Multiple regression analysis was used to evaluate the risk of immunoglobulin E (IgE) elevation or atopy in relation to the degree of metabolic abnormality and obesity. Results In premenopausal women, total IgE was positively correlated with obesity and insulin resistance. MUNO participants had a higher risk of having elevated total IgE compared to MHNO participants (odds ratio [OR], 2.271; 95% confidence interval [CI], 1.201 to 4.294), while MHO participants did not show a significant difference (OR, 1.435; 95% CI, 0.656 to 3.137) in premenopausal women. MUNO, but not MHO was also associated with atopy (OR, 2.157; 95% CI, 1.284 to 3.625). In men and postmenopausal women, there was no significant difference between metabolic status, obesity, and atopy among groups. Conclusion Increased insulin resistance is associated with total IgE and atopy in premenopausal women but not in postmenopausal women or men.
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Affiliation(s)
- Seung Eun Lee
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Ji Yeon Baek
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyungdo Han
- Department of Biostatistics, The Catholic University of Korea, Seoul, Korea
| | - Eun Hee Koh
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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45
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Torres RM, Souza MDS, Coelho ACC, de Mello LM, Souza-Machado C. Association between Asthma and Type 2 Diabetes Mellitus: Mechanisms and Impact on Asthma Control-A Literature Review. Can Respir J 2021; 2021:8830439. [PMID: 33520042 PMCID: PMC7817304 DOI: 10.1155/2021/8830439] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/05/2020] [Accepted: 12/28/2020] [Indexed: 11/18/2022] Open
Abstract
The study aimed to analyze the scientific production on the association between asthma and type 2 diabetes mellitus (T2DM) in adults, the mechanisms that explain this association, and its impact on asthma control. A literature review of scientific articles indexed in the MEDLINE/PUBMED, BVS, CINAHL, Cochrane Library, and Web of Science databases was carried out, considering publications from January 2009 to December 2019, using the following descriptors: "asthma", "type 2 diabetes", "adult," and "association". Of 962 articles found, 18 were included because they met the eligibility criteria. It is suggested that the association between asthma and T2DM is caused by low-grade systemic inflammation (7 articles) or the use of corticosteroids (7 articles). It is noticed that there is a limited scientific production regarding the consequences of this association for the control of asthma (5 articles). It is concluded that asthma and T2DM are two common chronic conditions of increasing prevalence and that often coexist in the same patient. It is suggested that this coexistence worsens asthma control. Therefore, the study may support public policies and clinical health practices that value the approach of comorbidities associated with asthma such as T2DM, in order to minimize additional health risks and reduce the quality of life.
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Affiliation(s)
- Raimeyre Marques Torres
- Graduate Program of the School of Nursing at the Federal University of Bahia, Salvador (BA), Brazil
| | - Marcela Dos Santos Souza
- Graduate Program of the School of Nursing at the Federal University of Bahia, Salvador (BA), Brazil
| | | | - Luane Marques de Mello
- Department of Social Medicine, School of Medicine, University of São Paulo, Ribeirão Preto (SP), Brazil
| | - Carolina Souza-Machado
- Graduate Program of the School of Nursing at the Federal University of Bahia, Salvador (BA), Brazil
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46
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The Fatty Acid Lipid Metabolism Nexus in COVID-19. Viruses 2021; 13:v13010090. [PMID: 33440724 PMCID: PMC7826519 DOI: 10.3390/v13010090] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Enteric symptomology seen in early-stage severe acute respiratory syndrome (SARS)-2003 and COVID-19 is evidence of virus replication occurring in the intestine, liver and pancreas. Aberrant lipid metabolism in morbidly obese individuals adversely affects the COVID-19 immune response and increases disease severity. Such observations are in line with the importance of lipid metabolism in COVID-19, and point to the gut as a site for intervention as well as a therapeutic target in treating the disease. Formation of complex lipid membranes and palmitoylation of coronavirus proteins are essential during viral replication and assembly. Inhibition of fatty acid synthase (FASN) and restoration of lipid catabolism by activation of AMP-activated protein kinase (AMPK) impede replication of coronaviruses closely related to SARS-coronavirus-2 (CoV-2). In vitro findings and clinical data reveal that the FASN inhibitor, orlistat, and the AMPK activator, metformin, may inhibit coronavirus replication and reduce systemic inflammation to restore immune homeostasis. Such observations, along with the known mechanisms of action for these types of drugs, suggest that targeting fatty acid lipid metabolism could directly inhibit virus replication while positively impacting the patient's response to COVID-19.
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47
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Guo Y, Shi J, Wang Q, Hong L, Chen M, Liu S, Yuan X, Jiang S. Metformin alleviates allergic airway inflammation and increases Treg cells in obese asthma. J Cell Mol Med 2021; 25:2279-2284. [PMID: 33421348 PMCID: PMC7882927 DOI: 10.1111/jcmm.16269] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 02/02/2023] Open
Abstract
Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.
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Affiliation(s)
- Yimin Guo
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
| | - Jianting Shi
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
| | - Qiujie Wang
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
| | - Luna Hong
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
| | - Ming Chen
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
| | - Shanying Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Research Center of Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoqing Yuan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shanping Jiang
- Department of Respiratory Medicine, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen University Second University Hospital, Sun Yat-sen University, Guangzhou, China.,Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China
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48
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Kopf S, Kumar V, Kender Z, Han Z, Fleming T, Herzig S, Nawroth PP. Diabetic Pneumopathy-A New Diabetes-Associated Complication: Mechanisms, Consequences and Treatment Considerations. Front Endocrinol (Lausanne) 2021; 12:765201. [PMID: 34899603 PMCID: PMC8655305 DOI: 10.3389/fendo.2021.765201] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/22/2021] [Indexed: 01/04/2023] Open
Abstract
Patients with diabetes are over-represented among the total cases reported with "idiopathic" pulmonary fibrosis (IPF). This raises the question, whether this is an association only or whether diabetes itself can cause pulmonary fibrosis. Recent studies in mouse models of type 1 and type 2 diabetes demonstrated that diabetes causes pulmonary fibrosis. Both types of diabetes trigger a cascade, starting with increased DNA damage, an impaired DNA repair, and leading to persistent DNA damage signaling. This response, in turn, induces senescence, a senescence-associated-secretory phenotype (SASP), marked by the release of pro-inflammatory cytokines and growth factors, finally resulting in fibrosis. Restoring DNA repair drives fibrosis into remission, thus proving causality. These data can be translated clinically to patients with type 2 diabetes, characterized by long-term diabetes and albuminuria. Hence there are several arguments, to substitute the term "idiopathic" pulmonary fibrosis (IPF) in patients with diabetes (and exclusion of other causes of lung diseases) by the term "diabetes-induced pulmonary fibrosis" (DiPF). However, future studies are required to establish this term and to study whether patients with diabetes respond to the established therapies similar to non-diabetic patients.
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Affiliation(s)
- Stefan Kopf
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Varun Kumar
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
- European Molecular Biology Laboratory, Advanced Light Microscopy Facility, Heidelberg, Germany
| | - Zoltan Kender
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Zhe Han
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Fleming
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Stephan Herzig
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Munich-Neuherberg, Germany
- Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Programme, Helmholtz-Zentrum, Munich, Germany
| | - Peter P. Nawroth
- Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
- Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Programme, Helmholtz-Zentrum, Munich, Germany
- *Correspondence: Peter P. Nawroth,
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Association of Metformin Initiation and Risk of Asthma Exacerbation. A Claims-based Cohort Study. Ann Am Thorac Soc 2020; 16:1527-1533. [PMID: 31415212 DOI: 10.1513/annalsats.201812-897oc] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Rationale: Diabetes and metabolic syndrome have been associated with worsened asthma control. Metformin improves insulin resistance and metabolic function. Experimental studies suggest that metformin may improve pathologic features of asthma, but evidence of clinical benefit is limited.Objectives: To determine if treatment with metformin in a cohort of individuals with asthma and diabetes is associated with lower risk of asthma exacerbation.Methods: A 6-year retrospective cohort of individuals over age 18 with asthma and diabetes was assembled from a national administrative claims database. New users of metformin were matched to nonusers by propensity score on the basis of demographic, comorbidity, and medication-use characteristics. An exacerbation was defined as an asthma-related hospitalization, emergency department visit, or filling of a systemic corticosteroid prescription within 14 days of an asthma-related ambulatory visit. Cox proportional hazards estimated the change in hazard of asthma exacerbation associated with metformin initiation.Results: In a cohort of 23,920 individuals with asthma and diabetes, metformin initiation was associated with lower hazard of asthma exacerbation (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86-0.98), driven by lower hazards of asthma-related emergency department visits (HR, 0.81; 95% CI, 0.74-0.88) and hospitalization (HR, 0.67; 95% CI, 0.50-0.91), without differences in corticosteroid use (HR, 0.96; 95% CI, 0.86-1.03).Conclusions: In an administrative cohort of individuals with asthma and diabetes, metformin initiation was associated with a lower hazard of asthma-related emergency department visits and hospitalizations. These findings suggest a possible benefit of metformin in more severe asthma exacerbations. Investigation within cohorts with more detailed participant characterization is necessary.
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50
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Virus-Induced Asthma Exacerbations: SIRT1 Targeted Approach. J Clin Med 2020; 9:jcm9082623. [PMID: 32823491 PMCID: PMC7464235 DOI: 10.3390/jcm9082623] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/06/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022] Open
Abstract
The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients’ quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of SIRT1 in the pathogenesis of bronchial asthma. It also discusses the role of SIRT1 in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that SIRT1 is one of major contributors to cellular senescence. SIRT1 levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of SIRT1 in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and SIRT1. Therefore, targeting SIRT1 is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.
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