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Pham H, Koehl R, Woo H, Wu TD, Qiu AY, Brigham EP, Hansel NN, McCormack MC. Association Between Hemoglobin A1c and Pediatric Asthma Control. J Asthma Allergy 2025; 18:649-654. [PMID: 40322736 PMCID: PMC12047264 DOI: 10.2147/jaa.s498269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/20/2025] [Indexed: 05/08/2025] Open
Abstract
Purpose To examine the relationship between Hemoglobin A1c (HbA1c) and asthma outcomes in an urban cohort of children with asthma. Methods The AIRWEIGHS Study was a randomized controlled clinical trial of an air cleaner intervention testing the hypothesis that overweight/obese children would experience greater improvement in asthma control compared to normal weight children. The study enrolled 164 children with asthma from Baltimore, MD and assessed HbA1c levels and asthma outcomes during clinic visits at baseline and three months. HbA1c levels were analyzed as a continuous measure and categorized as either normal (<5.7%) or consistent with pre-diabetes (≥5.7%). Asthma outcomes included standardized questionnaires, spirometry, and fractional exhaled nitric oxide (FeNO). Generalized Estimating Equation (GEE) regression models were used to analyze the association between the HbA1c and asthma outcomes. Results Participants included 164 children with an average age of 11 (± 2) years, predominately African American (85%), male (59%), moderate or severe asthma by NAEPP criteria (59%), households with an income below $34,999 (60%), publicly insured (83%), and overweight/obese (61%). 52 participants were excluded from the analysis due to unsuccessful blood draws or participant refusal. Twenty of 112 distinct participants (18%) had HbA1c measurements ≥5.7%, consistent with prediabetes. Increased HbA1c levels were associated with worse asthma control as indicated by an increase in the Asthma Therapy Assessment Questionnaire (β-0.74 p<0.05). In the interaction analysis, BMI percentile had a significant interaction with HbA1c such that HbA1c had a stronger association with maximum symptoms days and exacerbation risk among children with lower versus higher BMI percentile values. Conclusion Higher HbA1c levels were associated with worse asthma control among children with asthma, adding to evidence that metabolic dysfunction may influence asthma morbidity. Additionally, HbA1c could have a stronger influence among non-obese children with underlying metabolic dysfunction, suggesting the need for future studies to investigate metabolic pathways in asthma.
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Affiliation(s)
- Hewlett Pham
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Rachelle Koehl
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Han Woo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Tianshi David Wu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Anna Yue Qiu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Emily P Brigham
- Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Nadia N Hansel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Meredith C McCormack
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Kantreva K, Katsaounou P, Saltiki K, Trakada G, Ntali G, Stratigou T, Tzanela M, Psaltopoulou T, Paschou SA. The possible effect of anti-diabetic agents GLP-1RA and SGLT-2i on the respiratory system function. Endocrine 2025; 87:378-388. [PMID: 39289244 DOI: 10.1007/s12020-024-04033-6] [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: 05/14/2024] [Accepted: 09/03/2024] [Indexed: 09/19/2024]
Abstract
Type 2 Diabetes (T2D) is a chronic disease with increasing incidence and prevalence and serious chronic complications, especially from cardiovascular system. However, other organs can be affected too. Several studies have associated T2D, especially when poorly controlled, with multiple pulmonary diseases. T2D is a common comorbidity among patients with asthma, Chronic Obstructive Pulmonary Disease (COPD), and Obstructive Sleep Apnea Syndrome (OSAS), and it is related to higher respiratory infection incidence, prevalence and severity. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are novel antihyperglycaemic agents with established cardiovascular benefits. There are also limited studies indicating their potential benefit in respiratory function. The aim of this article is to review data on the impact of GLP-1RA and SGLT-2i on respiratory function and describe the possible clinical benefits. Key findings indicate that GLP-1RA significantly improve lung function in patients with COPD, evidenced by improvements in spirometry measurements. Additionally, both GLP-1RA and SGLT-2i are associated with a decreased risk of severe and moderate exacerbations in COPD patients and have shown potential in reducing the incidence of respiratory disorders, including asthma and pneumonia. The mechanisms underlying these benefits are not yet fully understood and include multiple effects, such as anti-inflammatory action and oxidative stress reduction.
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Affiliation(s)
- Kanella Kantreva
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Department of Endocrinology, Diabetes Centre, Endo ERN member, Evangelismos General Hospital, Athens, Greece
| | - Paraskevi Katsaounou
- Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Katerina Saltiki
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgia Trakada
- Respiratory Medicine Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgia Ntali
- Department of Endocrinology, Diabetes Centre, Endo ERN member, Evangelismos General Hospital, Athens, Greece
| | - Theodora Stratigou
- Department of Endocrinology, Diabetes Centre, Endo ERN member, Evangelismos General Hospital, Athens, Greece
| | - Marinella Tzanela
- Department of Endocrinology, Diabetes Centre, Endo ERN member, Evangelismos General Hospital, Athens, Greece
| | - Theodora Psaltopoulou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Liu C, Liang D, Xiang G, Zhao X, Xiao K, Xie L. Association between oxidative balance score and all-cause, CVD and respiratory-related mortality in the US older adults of asthma patients with diabetes. Front Nutr 2025; 11:1519570. [PMID: 39882043 PMCID: PMC11775759 DOI: 10.3389/fnut.2024.1519570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Background This study aims to investigate the correlation between oxidative balance score (OBS) and all-cause, cardiovascular disease (CVD) and respiratory-related mortality within a cohort that includes older asthma patients with diabetes. Methods Data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2001 to 2018, which included 611 participants, were analyzed. Mortality outcomes were determined by linking the data to National Death Index (NDI) records through December 31, 2019. Cox regression modeling was employed to examine the relationship between OBS and all-cause, CVD and respiratory-related mortality. Restricted cubic splines (RCS), subgroup analyses and interaction tests were also conducted in this study. Results Over a median follow-up of 78.96 months, there were 216 all-cause deaths and 57 CVD-related deaths. A significant negative association was found between the OBS and all-cause and CVD mortality. We did not observe OBS could reduce respiratory-related mortality in older asthma patients with diabetes. RCS analysis indicated a linear and inverse association between the OBS and all-cause and CVD mortality. Subgroup analyses and interaction tests indicated the negative association between OBS and CVD mortality was significantly influenced by alcohol consumption. Conclusion In this sample, higher OBS was associated with lower all-cause and CVD mortality risks. These findings stressed the importance of infection status in assessing oxidative balance's impact on health.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Dan Liang
- Department of Endocrine, People's Hospital of Chongqing Liang Jiang New Area, Chongqing, China
- West China Medical College of Sichuan University, Chengdu, China
| | - Guoan Xiang
- College of Pulmonary and Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xuanbo Zhao
- Clinical Medicine College of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Kun Xiao
- College of Pulmonary and Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- College of Pulmonary and Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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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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Mohammadzadeh M, Athari SZ, Ghiasi F, Keyhanmanesh R, Ghaffari-Nasab A, Roshangar L, Korjan ES, Delkhosh A, Bavil FM. Bone Marrow-Derived C-Kit + Cells Improved Inflammatory IL-33/ST-2/ILC2 Axis in the Lung Tissue of Type 2 Diabetic Rats. Appl Biochem Biotechnol 2024; 196:7074-7088. [PMID: 38478319 DOI: 10.1007/s12010-024-04870-1] [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] [Accepted: 02/12/2024] [Indexed: 11/21/2024]
Abstract
Inflammation is an essential factor in pulmonary complications of diabetes. Bone marrow (BM)-derived C-kit+ cells have immunomodulatory properties and their transplantation is suggested as a promising strategy for ameliorating diabetes complications. This study evaluated the effect of BM-derived C-kit+ cells on the inflammation signaling pathway in lung tissue of type 2 diabetic male rats. Ten rats were used to extract C-kit cells, and 48 male Wistar rats weighing 180 ± 20 g were randomly divided into four equal groups: (1) Control (Cont), (2) Diabetic (D), (3) Diabetic + C-kit+ cells (D + C-kit pos) intravenously injected 50-µl phosphate buffer saline (PBS) containing 300,000 C-kit+ cells, and (4) Diabetic + C-kit- cells (D + C-kit neg), intravenously injected C-kit- cells. Diabetes induction increased IL-33, ST-2, CD127, and IL-2 levels and decreased IL-10. C-kit+ cell therapy significantly decreased IL-33 and CD127 and increased IL-10. In addition, lung histopathological changes significantly improved in the C-kit+ group compared to the diabetic group. These findings suggest that C-kit+ cells may have a potential therapeutic role in mitigating diabetes-induced respiratory complications via ameliorating the inflammation and histopathological changes in lung tissue.
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Affiliation(s)
- Milad Mohammadzadeh
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
- Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Seyed Zanyar Athari
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Ghiasi
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
| | - Rana Keyhanmanesh
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
| | - Arshad Ghaffari-Nasab
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
| | - Leila Roshangar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elnaz Salmani Korjan
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aref Delkhosh
- Stem Cell Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, 51666-14766, Iran
| | - Fariba Mirzaei Bavil
- Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran.
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Samaha MM, El-Desoky MM, Hisham FA. AdipoRon, an adiponectin receptor agonist, modulates AMPK signaling pathway and alleviates ovalbumin-induced airway inflammation in a murine model of asthma. Int Immunopharmacol 2024; 136:112395. [PMID: 38833845 DOI: 10.1016/j.intimp.2024.112395] [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: 03/28/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/06/2024]
Abstract
Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.
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Affiliation(s)
- Mahmoud M Samaha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Manal M El-Desoky
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Fatma A Hisham
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
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Mathur V, Karvar M, Lo T, Raby BA, Tavakkoli A, Croteau-Chonka DC, Sheu EG. Sleeve Gastrectomy is Associated with Longitudinal Improvements in Lung Function and Patient-Reported Respiratory Outcomes. Obes Surg 2024; 34:2467-2474. [PMID: 38753264 PMCID: PMC11651307 DOI: 10.1007/s11695-024-07274-6] [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: 10/30/2023] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 07/03/2024]
Abstract
PURPOSE Obesity exerts negative effects on pulmonary function through proven mechanical and biochemical pathways. Multiple studies have suggested that bariatric surgery can improve lung function. However, the timing of these effects on lung function and its association with patient reported outcomes is not known. MATERIALS AND METHODS A prospective cohort study of patients undergoing laparoscopic sleeve gastrectomy (LSG) at a tertiary care hospital was undertaken. Spirometry tests, laboratory tests, and self-reported questionnaires on asthma symptoms and asthma control (ACQ and ACT) were administered. All data were recorded pre-operatively (T0) and every 3 months post-operatively for 1 year (T3, T6, T9, T12) and were compared using a mixed-models approach for repeated measures. RESULTS For the 23 participants, mean age was 44.2 ± 12.3 years, mean BMI was 45.2 ± 7.2 kg/m2, 18(78%) were female, 9(39%) self-reported as non-white and 6(26%) reported to have asthma. Following LSG, % total body weight loss was significant at all follow-up points (P < 0.0001). Rapid improvement in forced expiratory volume (FEV)% predicted and forced vital capacity (FVC)% predicted was seen at T3. Although the overall ACQ and ACT score remained within normal range throughout the study, shortness of breath declined significantly at 3 months post-op (P < 0.05) and wheezing resolved for all patients by twelve months. Patients also reported reduced frequency of sleep interruption and inability to exercise by the end of the study (P < 0.05). CONCLUSION Improvements in objective lung function assessments and patient-reported respiratory outcomes begin as early as 3 months and continue until 12 months after sleeve gastrectomy.
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Affiliation(s)
- Vasundhara Mathur
- Laboratory of Surgical and Metabolic Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Mehran Karvar
- Laboratory of Surgical and Metabolic Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tammy Lo
- Laboratory of Surgical and Metabolic Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Benjamin A Raby
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Pulmonary Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ali Tavakkoli
- Laboratory of Surgical and Metabolic Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Damien C Croteau-Chonka
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Eric G Sheu
- Laboratory of Surgical and Metabolic Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Streba L, Popovici V, Mihai A, Mititelu M, Lupu CE, Matei M, Vladu IM, Iovănescu ML, Cioboată R, Călărașu C, Busnatu ȘS, Streba CT. Integrative Approach to Risk Factors in Simple Chronic Obstructive Airway Diseases of the Lung or Associated with Metabolic Syndrome-Analysis and Prediction. Nutrients 2024; 16:1851. [PMID: 38931206 PMCID: PMC11206714 DOI: 10.3390/nu16121851] [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: 05/28/2024] [Revised: 06/01/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
We conducted an epidemiological non-interventional cross-sectional and case-control study from 1 January 2023 until 26 May 2023 in Oltenia region, southwestern Romania. Throughout the research, 160 consecutive patients were included from two different clinical departments (1-Pneumology; 2-Diabetes and Nutritional Diseases). Subjects were voluntary adult individuals of any gender who expressed their written consent. The clinical data of the patients were correlated with the exposure to behavioral risk factors (diet, lifestyle, exposure to pollutants) to identify some negative implications that could be corrected to improve the quality of life of patients with simple chronic obstructive airway diseases of the lung or associated with metabolic syndrome (MS). In the first group of patients with respiratory diseases, there was a higher degree of exposure to toxic substances (43.75%) compared to the second group of patients with diabetes (18.75%); it is also noticeable that in the first group, there were noticeably fewer individuals who have never smoked (25%) compared to the second group (50%). Respiratory function impairment was observed to be more severe in overweight individuals. In the group of patients with known lung diseases, a positive correlation was noted between the presence of MS and respiratory dysfunctions of greater severity. Additionally, potential exacerbating factors affecting lung function, such as direct exposure to toxins and smoking, were considered. Potential secondary factors exacerbating respiratory dysfunction were considered by correlating biochemical parameters with dietary habits. These included reduced consumption of vegetables, inadequate hydration, and increased intake of sweets and products high in saturated or trans fats (commonly found in junk food), primarily due to their potential contribution to excess weight. Compared to patients without MS, the severity of the pulmonary function impairment correlated with the number of criteria met for MS and, independently, with an increase in weight.
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Affiliation(s)
- Liliana Streba
- Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Violeta Popovici
- Center for Mountain Economics, “Costin C. Kiriţescu” National Institute of Economic Research (INCE-CEMONT), Romanian Academy, 725700 Vatra-Dornei, Romania;
| | - Andreea Mihai
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.); (C.C.); (C.-T.S.)
| | - Magdalena Mititelu
- Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 020956 Bucharest, Romania
| | - Carmen Elena Lupu
- Department of Mathematics and Informatics, Faculty of Pharmacy, “Ovidius” University of Constanta, 900001 Constanta, Romania;
| | - Marius Matei
- Department of Histology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ionela Mihaela Vladu
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Maria Livia Iovănescu
- Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ramona Cioboată
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.); (C.C.); (C.-T.S.)
| | - Cristina Călărașu
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.); (C.C.); (C.-T.S.)
| | - Ștefan Sebastian Busnatu
- Department of Cardio-Thoracic Pathology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Costin-Teodor Streba
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.C.); (C.C.); (C.-T.S.)
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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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Ajayi T, Thomas A, Nikolic M, Henderson L, Zaheri A, Dwyer DS. Evolutionary conservation of putative suicidality-related risk genes that produce diminished motivation corrected by clozapine, lithium and antidepressants. Front Psychiatry 2024; 15:1341735. [PMID: 38362034 PMCID: PMC10867104 DOI: 10.3389/fpsyt.2024.1341735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/17/2024] [Indexed: 02/17/2024] Open
Abstract
Background Genome wide association studies (GWAS) and candidate gene analyses have identified genetic variants and genes that may increase the risk for suicidal thoughts and behaviors (STBs). Important unresolved issues surround these tentative risk variants such as the characteristics of the associated genes and how they might elicit STBs. Methods Putative suicidality-related risk genes (PSRGs) were identified by comprehensive literature search and were characterized with respect to evolutionary conservation, participation in gene interaction networks and associated phenotypes. Evolutionary conservation was established with database searches and BLASTP queries, whereas gene-gene interactions were ascertained with GeneMANIA. We then examined whether mutations in risk-gene counterparts in C. elegans produced a diminished motivation phenotype previously connected to suicide risk factors. Results and conclusions From the analysis, 105 risk-gene candidates were identified and found to be: 1) highly conserved during evolution, 2) enriched for essential genes, 3) involved in significant gene-gene interactions, and 4) associated with psychiatric disorders, metabolic disturbances and asthma/allergy. Evaluation of 17 mutant strains with loss-of-function/deletion mutations in PSRG orthologs revealed that 11 mutants showed significant evidence of diminished motivation that manifested as immobility in a foraging assay. Immobility was corrected in some or all of the mutants with clozapine, lithium and tricyclic antidepressant drugs. In addition, 5-HT2 receptor and muscarinic receptor antagonists restored goal-directed behavior in most or all of the mutants. These studies increase confidence in the validity of the PSRGs and provide initial clues about possible mechanisms that mediate STBs.
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Affiliation(s)
- Titilade Ajayi
- Department of Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, United States
| | - Alicia Thomas
- Department of Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, United States
| | - Marko Nikolic
- Department of Psychiatry and Behavioral Medicine, LSU Health Shreveport, Shreveport, LA, United States
| | - Lauryn Henderson
- Department of Psychiatry and Behavioral Medicine, LSU Health Shreveport, Shreveport, LA, United States
| | - Alexa Zaheri
- Department of Psychiatry and Behavioral Medicine, LSU Health Shreveport, Shreveport, LA, United States
| | - Donard S. Dwyer
- Department of Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, United States
- Department of Psychiatry and Behavioral Medicine, LSU Health Shreveport, Shreveport, LA, United States
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11
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Cazzola M, Rogliani P, Ora J, Calzetta L, Lauro D, Matera MG. Hyperglycaemia and Chronic Obstructive Pulmonary Disease. Diagnostics (Basel) 2023; 13:3362. [PMID: 37958258 PMCID: PMC10650064 DOI: 10.3390/diagnostics13213362] [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: 09/25/2023] [Revised: 10/20/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) may coexist with type 2 diabetes mellitus (T2DM). Patients with COPD have an increased risk of developing T2DM compared with a control but, on the other side, hyperglycaemia and DM have been associated with reduced predicted levels of lung function. The mechanistic relationships between these two diseases are complicated, multifaceted, and little understood, yet they can impact treatment strategy. The potential risks and benefits for patients with T2DM treated with pulmonary drugs and the potential pulmonary risks and benefits for patients with COPD when taking antidiabetic drugs should always be considered. The interaction between the presence and/or treatment of COPD, risk of infection, presence and/or treatment of T2DM and risk of acute exacerbations of COPD (AECOPDs) can be represented as a vicious circle; however, several strategies may help to break this circle. The most effective approach to simultaneously treating T2DM and COPD is to interfere with the shared inflammatory substrate, thus targeting both lung inflammation (COPD) and vascular inflammation (DM). In any case, it is always crucial to establish glycaemic management since the reduction in lung function found in people with diabetes might decrease the threshold for clinical manifestations of COPD. In this article, we examine possible connections between COPD and T2DM as well as pharmacological strategies that could focus on these connections.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome ‘Tor Vergata’, 00133 Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome ‘Tor Vergata’, 00133 Rome, Italy
- Division of Respiratory Medicine, University Hospital Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Josuel Ora
- Division of Respiratory Medicine, University Hospital Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Luigino Calzetta
- Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy
| | - Davide Lauro
- Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, University of Rome ‘Tor Vergata’, 00173 Rome, Italy
- Division of Endocrinology and Diabetes, University Hospital Fondazione Policlinico Tor Vergata, 00133 Rome, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania ‘Luigi Vanvitelli’, 81138 Naples, Italy
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12
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Abera W, Wube TB, Alemayehu T. The association of aspartate transaminase-to-alanine transaminase ratio and metabolic syndrome among HIV patients in Sidama Region, South Ethiopia. SAGE Open Med 2023; 11:20503121231196701. [PMID: 37694128 PMCID: PMC10483979 DOI: 10.1177/20503121231196701] [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: 03/13/2023] [Accepted: 08/07/2023] [Indexed: 09/12/2023] Open
Abstract
Objective Studies on the association of the aspartate transaminase-to-alanine transaminase ratio with the metabolic syndrome and its components among HIV patients were scarce. This study aims to determine the association between the aspartate transaminase-to-alanine transaminase ratio and the metabolic syndrome and its components in adult HIV patients on highly active antiretroviral therapy. Methods This was a cross-sectional study conducted on 302 HIV patients from January 15 to June 30, 2021. Sociodemographic, clinical, and anthropometric data were collected using a structured questionnaire. The patient's medical records were reviewed. Biochemical analysis was performed after 5 ml of venous blood was collected from each study participant. Metabolic syndrome was defined by the third report of the national cholesterol education program-adult treatment panel. Logistic regression was done to assess the association of MetS with the independent variables, and correlation analysis was performed to see the correlation of MetS components with the aspartate aminotransferase-to-alanine aminotransferase ratio. Result 302 HIV-positive patients on highly active antiretroviral therapy were included in this study, and 54.6% were female. The median and interquartile range of the age of the study participants were 41 (35-50) years. The prevalence of metabolic syndrome was 29.5% (confidence interval = 24.5-35.1). Chronic illness (Adjusted odds ratio = 4.8, confidence interval = 2.2-10.9) and aspartate aminotransferase-to-alanine aminotransferase ratio (adjusted odds ratio = 2.5, confidence interval = 1.4-4.4) were significantly associated with Metabolic syndrome among the study participants. The aspartate aminotransferase-to-alanine aminotransferase ratio was significantly correlated with blood pressure. Conclusion This study found the existence of a significant association between the aspartate aminotransferase-to-alanine aminotransferase ratio and metabolic syndrome among HIV patients.
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Affiliation(s)
- Wondwossen Abera
- School of Medical Laboratory Science, College of Medicine and Health Science, Hawassa University, Hawassa, Ethiopia
| | - Temesgen Bizuayehu Wube
- School of Medical Laboratory Science, College of Medicine and Health Science, Hawassa University, Hawassa, Ethiopia
| | - Tsegaye Alemayehu
- School of Medical Laboratory Science, College of Medicine and Health Science, Hawassa University, Hawassa, Ethiopia
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13
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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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14
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Subramaniam A, Ramasamy S, Palanisamy S, Punniyamurthy A, Murugaiyan S. Low Vitamin B12 Levels and Its Association With Insulin Resistance: A Potent Cardiovascular Risk Indicator in Childhood Asthma. Cureus 2023; 15:e39422. [PMID: 37362491 PMCID: PMC10288390 DOI: 10.7759/cureus.39422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2023] [Indexed: 06/28/2023] Open
Abstract
Introduction As insulin resistance metabolically affects the body mass index (BMI), obese asthma children have more severe diseases than children with normal body mass index. A low level of vitamin B12 (Vit B12) is a known atherogenic factor by increasing the homocysteine level and therefore promotes cardiovascular morbidity and mortality. Limited studies have evaluated the role of serum B12 and insulin resistance among poorly controlled asthma in children. The purpose of the study was to compare the cardio-metabolic risk factor such as BMI, waist-hip ratio (WHR), insulin resistance, and vitamin B12 in well-controlled and poorly-controlled asthma patients and to determine the relationship between these parameters with the severity of asthma as assessed by Pulmonary Function Test. Methodology Based on the asthma control questionnaire and Global Initiative for Asthma (GINA) criteria, chronic asthma patients (n=60) of age 10-15 years were divided into two groups, namely well-controlled and poorly-controlled (30 each). Anthropometry was assessed by BMI and waist-hip ratio, and fasting blood samples were collected for the estimation of blood glucose, insulin, and serum vitamin B12 levels. Insulin resistance (HOMA-IR) was calculated using the formula- fasting glucose (mg/dL) x fasting insulin (µIU/mL)]/405. Forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio were measured to assess the pulmonary function test. Results There were significant differences in the values of the BMI, insulin resistance, vitamin B12, and pulmonary function tests between poorly controlled and well-controlled asthma (p<0.01). The FEV1: FVC% was negatively correlated with BMI (r=0.53), WHR (r=0.50), glucose (r=0.68), insulin (r=0.68), Insulin resistance (r=0.80), and positive correlation with Vit B12 (0.73). In addition, Vit B12 and HOMA-IR correlate negatively (r=0.76). Conclusion This study concludes that the level of Vit B12 is decreased and insulin resistance is increased in poorly controlled asthmatic children in comparison to well-controlled asthma. These factors along with the increased BMI in poorly controlled asthma can predispose to cardiometabolic risk which needs attention.
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Affiliation(s)
- Arulvijayavani Subramaniam
- Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research Karaikal, Karaikal, IND
| | - Sathiya Ramasamy
- Biochemistry, Mahatma Gandhi Medical College and Research Institute, Puducherry, IND
| | | | - Athisankaran Punniyamurthy
- Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research Karaikal, Karaikal, IND
| | - Sathishbabu Murugaiyan
- Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research Karaikal, Karaikal, IND
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15
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Peralta GP, Granell R, Bédard A, Carsin AE, Fuertes E, Howe LD, Márquez S, Jarvis DL, Garcia-Aymerich J. Mid-childhood fat mass and airflow limitation at 15 years: The mediating role of insulin resistance and C-reactive protein. Pediatr Allergy Immunol 2022; 33:e13894. [PMID: 36564882 DOI: 10.1111/pai.13894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND We previously reported an association of high fat mass levels from age 9 to 15 years with lower forced expiratory flow in 1 s (FEV1 )/forced vital capacity (FVC) ratio (i.e., increased risk of airflow limitation) at 15 years. Here, we aimed to assess whether insulin resistance and C-reactive protein (CRP) at 15 years partially mediate this association. METHODS We included 2263 children from the UK Avon Longitudinal Study of Parents and Children population-based cohort (ALSPAC). Four fat mass index (FMI) trajectories ("low," "medium-low," "medium-high," "high") from 9 to 15 years were previously identified using Group-Based Trajectory Modeling. Data on CRP, glucose, insulin, and post-bronchodilator FEV1 /FVC were available at 15 years. We defined insulin resistance by the homeostasis model assessment-estimated insulin resistance index (HOMA-IR). We used adjusted linear regression models and a causal mediation analysis to assess the mediating role of HOMA-IR and CRP. RESULTS Compared to children in the "low" FMI trajectory, children in the "medium-high" and "high" FMI trajectories had lower FEV1 /FVC at 15 years. The percentage of the total effect explained by HOMA-IR was 19.8% [-114.1 to 170.0] and 20.4% [1.6 to 69.0] for the "medium-high" and "high" trajectories, respectively. In contrast, there was little evidence for a mediating role of CRP. CONCLUSION The association between mid-childhood fat mass and FEV1 /FVC ratio at 15 years may be partially mediated by insulin resistance.
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Affiliation(s)
- Gabriela P Peralta
- ISGlobal, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.,Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland
| | - Raquel Granell
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Annabelle Bédard
- Université Paris-Saclay, UVSQ, University Paris-Sud, Inserm, Équipe d'Épidémiologie Respiratoire Intégrative, CESP, Villejuif, France
| | - Anne-Elie Carsin
- ISGlobal, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.,IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Elaine Fuertes
- National Heart and Lung Institute, Imperial College London, London, UK.,MRC Centre for Environment and Health, Imperial College London, London, UK
| | - Laura D Howe
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sandra Márquez
- ISGlobal, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Deborah L Jarvis
- National Heart and Lung Institute, Imperial College London, London, UK.,MRC Centre for Environment and Health, Imperial College London, London, UK
| | - Judith Garcia-Aymerich
- ISGlobal, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
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16
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Allinson JP, Patel PH, Donaldson GC. Obesity, Insulin Resistance, and Asthma. Am J Respir Crit Care Med 2022; 206:1057-1058. [PMID: 35819866 PMCID: PMC9704836 DOI: 10.1164/rccm.202207-1271ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- James P Allinson
- National Heart and Lung Institute Imperial College London London, United Kingdom
- Royal Brompton Hospital London, United Kingdom
| | | | - Gavin C Donaldson
- National Heart and Lung Institute Imperial College London London, United Kingdom
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17
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Backman H, Stridsman C, Hedman L, Rönnebjerg L, Nwaru BI, Sandström T, Kankaanranta H, Lindberg A, Rönmark E. Determinants of Severe Asthma - A Long-Term Cohort Study in Northern Sweden. J Asthma Allergy 2022; 15:1429-1439. [PMID: 36248343 PMCID: PMC9562796 DOI: 10.2147/jaa.s376806] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Background Risk factors for severe asthma are not well described. The aim was to identify clinical characteristics and risk factors at study entry that are associated with severe asthma at follow-up in a long-term prospective population-based cohort study of adults with asthma. Methods Between 1986 and 2001, 2055 adults with asthma were identified by clinical examinations of population-based samples in northern Sweden. During 2012-2014, n = 1006 (71% of invited) were still alive, residing in the study area and participated in a follow-up, of which 40 were identified as having severe asthma according to ERS/ATS, 131 according to GINA, while 875 had other asthma. The mean follow-up time was 18.7 years. Results Obesity at study entry and adult-onset asthma were associated with severe asthma at follow-up. While severe asthma was more common in those with adult-onset asthma in both men and women, the association with obesity was observed in women only. Sensitization to mites and moulds, but not to other allergens, as well as NSAID-related respiratory symptoms was more common in severe asthma than in other asthma. Participants with severe asthma at follow-up had lower FEV1, more pronounced FEV1 reversibility, and more wheeze, dyspnea and nighttime awakenings already at study entry than those with other asthma. Conclusion Adult-onset asthma is an important risk factor for development of severe asthma in adults, and obesity increased the risk among women. The high burden of respiratory symptoms already at study entry also indicate long-term associations with development of severe asthma.
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Affiliation(s)
- Helena Backman
- Department of Public Health and Clinical Medicine, Section of Sustainable Health/the OLIN unit, Umeå University, Umeå, Sweden,Correspondence: Helena Backman, Department of Public Health and Clinical Medicine, Section of Sustainable Health/the OLIN Unit, Umeå University, Umeå, Sweden, Email
| | - Caroline Stridsman
- Department of Public Health and Clinical Medicine, Section of Medicine/the OLIN unit, Umeå University, Umeå, Sweden
| | - Linnea Hedman
- Department of Public Health and Clinical Medicine, Section of Sustainable Health/the OLIN unit, Umeå University, Umeå, Sweden
| | - Lina Rönnebjerg
- Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Bright I Nwaru
- Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden,Wallenberg Centre for Molecular and Translational Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Thomas Sandström
- Department of Public Health and Clinical Medicine, Section of Medicine/the OLIN unit, Umeå University, Umeå, Sweden
| | - Hannu Kankaanranta
- Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden,Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anne Lindberg
- Department of Public Health and Clinical Medicine, Section of Medicine/the OLIN unit, Umeå University, Umeå, Sweden
| | - Eva Rönmark
- Department of Public Health and Clinical Medicine, Section of Sustainable Health/the OLIN unit, Umeå University, Umeå, Sweden
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18
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Abstract
A high hemoglobin glycation index (HGI) has been repeatedly associated with greater risk for hypoglycemia in people with diabetes and greater risk for chronic vascular disease in people with or without diabetes. This review explores how different sources of analytical and biological variation in HbA1c and blood glucose individually and collectively affect the clinical information value of HGI. We conclude that HGI is a complex quantitative trait that is a clinically practical biomarker of risk for both hypoglycemia and chronic vascular disease.
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Affiliation(s)
- James M Hempe
- Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
| | - Daniel S Hsia
- Pennington Biomedical Research Center, Baton Rouge, LA, USA
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19
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Zaigham S, Tanash H, Nilsson PM, Muhammad IF. Triglyceride-Glucose Index is a Risk Marker of Incident COPD Events in Women. Int J Chron Obstruct Pulmon Dis 2022; 17:1393-1401. [PMID: 35746923 PMCID: PMC9212790 DOI: 10.2147/copd.s360793] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 04/30/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose The triglyceride-glucose index (TyG index) is a marker of insulin resistance and metabolic dysfunction and has the advantage of being universally available. Although recent evidence suggests the TyG index has relevance to respiratory health, there have been no prospective studies assessing its value as a biomarker for chronic lung diseases. We aim to assess the TyG index as a potential risk marker for future incident COPD events in the general population. Patients and Methods Baseline TyG index was assessed in 28,282 middle-aged men and women without previous history of chronic obstructive pulmonary disease (COPD) from the Malmö Preventive Project (men between 1974 and 1982 and women between 1982 and 1992). All subjects were followed up prospectively, and Cox proportional hazards regression was used to assess incident COPD events according to quartiles of TyG index. Results After an average of 31 years of follow-up, TyG index was a strong predictor of future COPD events even after adjusting for potential confounders (Q4 (highest TyG index) HR (95% CI): 1.21 (1.09–1.35) vs Q1 (reference), p-trend <0.001). After stratifying by sex, the results remained statistically significant in women only (Q4 vs Q1 HR 1.72 (1.41–2.09)). Additionally, the risk remained significant in a cohort of life-long never smokers (Q4 vs Q1 HR 1.47 (1.08–2.01)). Conclusion A raised TyG index is a novel risk marker of future incident COPD events in women. Insulin resistance as reflected by the TyG index can precede the development of obstructive lung disease and as such may be an easily measurable and useful predictor of COPD in women.
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Affiliation(s)
- Suneela Zaigham
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Hanan Tanash
- Department of Respiratory Medicine, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Peter M Nilsson
- Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden
| | - Iram F Muhammad
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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20
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Xu T, Chen Y, Zeng D, Wang Y. Self-matched learning to construct treatment decision rules from electronic health records. Stat Med 2022; 41:3434-3447. [PMID: 35511090 PMCID: PMC9283315 DOI: 10.1002/sim.9426] [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: 02/08/2021] [Revised: 08/26/2021] [Accepted: 08/31/2021] [Indexed: 11/12/2022]
Abstract
Electronic health records (EHRs) collected from large-scale health systems provide rich subject-specific information on a broad patient population at a lower cost compared to randomized controlled trials. Thus, EHRs may serve as a complementary resource to provide real-world data to construct individualized treatment rules (ITRs) and achieve precision medicine. However, in the absence of randomization, inferring treatment rules from EHR data may suffer from unmeasured confounding. In this article, we propose a self-matched learning method inspired by the self-controlled case series (SCCS) design to mitigate this challenge. We alleviate unmeasured time-invariant confounding between patients by matching different periods of treatments within the same patient (self-controlled matching) to infer the optimal ITRs. The proposed method constructs a within-subject matched value function for optimizing ITRs and bears similarity to the SCCS design. We examine assumptions that ensure Fisher consistency, and show that our method requires weaker assumptions on unmeasured confounding than alternative methods. Through extensive simulation studies, we demonstrate that self-matched learning has comparable performance to other existing methods when there are no unmeasured confounders, but performs markedly better when unobserved time-invariant confounders are present, which is often the case for EHRs. Sensitivity analyses show that the proposed method is robust under different scenarios. Finally, we apply self-matched learning to estimate the optimal ITRs from type 2 diabetes patient EHRs, which shows our estimated decision rules lead to greater advantages in reducing patients' diabetes-related complications.
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Affiliation(s)
- Tianchen Xu
- Department of Biostatistics, Columbia University, New York, New York, USA
| | - Yuan Chen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Donglin Zeng
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yuanjia Wang
- Department of Biostatistics, Columbia University, New York, New York, USA.,Department of Psychiatry, Columbia University, New York, New York, USA
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21
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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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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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Ramos-Nino ME, MacLean CD, Littenberg B. Association between the prevalence of obstructive lung disease and the use of aspirin in a diabetic population. INTERVENTIONAL PULMONOLOGY (MIDDLETOWN, DEL.) 2022; 1:5-10. [PMID: 35969698 PMCID: PMC9367676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Many diabetic patients take a daily low-dose of aspirin because they are two to three times more likely to suffer from heart attacks and strokes, but its role in obstructive lung diseases is less clear. Methods A total of 1,003 subjects in community practice settings were interviewed at home. Patients self-reported their personal and clinical characteristics, including any history of obstructive lung disease (including COPD or asthma). Current medications were obtained by the direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess for a possible association between obstructive lung disease history and the use of aspirin. Results In a multivariate logistic regression model, a history of obstructive lung disease was significantly associated with the use of aspirin even after correcting for potential confounders, including gender, low income (<USD 30,000/year), number of comorbidities, number of medications, cigarette smoking, and alcohol problems (adjusted odds ratio = 0.67, P = 0.03, 95% confidence interval = 0.47, 0.97). The opposite was found with aspirin and that for diabetic individuals that use insulin. A secondary analysis discovered a significant interaction between aspirin use and insulin: aspirin was associated with lower rates of lung disease except among those taking both drugs where the prevalence is significantly higher. Conclusion These data suggest a negative correlation between the use of aspirin and obstructive lung disease prevalence in patients with diabetes but not for those that use insulin. Further studies are required to determine if this association is causal.
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Affiliation(s)
- Maria E Ramos-Nino
- St. George’s University, Department of Microbiology, Immunology, and Pharmacology, Grenada, West Indies,Department of Pathology and Laboratory Medicine, University of Vermont 05401, Burlington, Vermont, USA,Author for correspondence:
| | - Charles D MacLean
- Department of Medicine, University of Vermont, Burlington, Vermont 05401, USA
| | - Benjamin Littenberg
- Department of Medicine, University of Vermont, Burlington, Vermont 05401, USA
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Adiponectin and Asthma: Knowns, Unknowns and Controversies. Int J Mol Sci 2021; 22:ijms22168971. [PMID: 34445677 PMCID: PMC8396527 DOI: 10.3390/ijms22168971] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/14/2022] Open
Abstract
Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.
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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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Proskocil BJ, Calco GN, Nie Z. Insulin acutely increases agonist-induced airway smooth muscle contraction in humans and rats. Am J Physiol Lung Cell Mol Physiol 2021; 320:L545-L556. [PMID: 33501891 DOI: 10.1152/ajplung.00232.2020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Obesity increases incidence and severity of asthma but the molecular mechanisms are not completely understood. Hyperinsulinemia potentiates vagally induced bronchoconstriction in obese rats. Since bronchoconstriction results from airway smooth muscle contraction, we tested whether insulin changed agonist-induced airway smooth muscle contraction. Obesity-prone and resistant rats were fed a low-fat diet for 5 wk and treated with insulin (Lantus, 3 units/rat sc) 16 h before vagally induced bronchoconstriction was measured. Ex vivo, contractile responses to methacholine were measured in isolated rat tracheal rings and human airway smooth muscle strips before and after incubation (0.5-2 h) with 100 nM insulin or 13.1 nM insulin like growth factor-1 (IGF-1). M2 and M3 muscarinic receptor mRNA expression was quantified by qRT-PCR and changes in intracellular calcium were measured in response to methacholine or serotonin in isolated rat tracheal smooth muscle cells treated with 1 µM insulin. Insulin, administered to animals 16 h prior, potentiated vagally induced bronchoconstriction in both obese-prone and resistant rats. Insulin, not IGF-1, significantly increased methacholine-induced contraction of rat and human isolated airway smooth muscle. In cultured rat tracheal smooth muscle cells, insulin significantly increased M2, not M3, mRNA expression and enhanced methacholine- and serotonin-induced increase in intracellular calcium. Insulin alone did not cause an immediate increase in intracellular calcium. Thus, insulin acutely potentiated agonist-induced increase in intracellular calcium and airway smooth muscle contraction. These findings may explain why obese individuals with hyperinsulinemia are prone to airway hyperreactivity and give insights into future targets for asthma treatment.
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Affiliation(s)
- Becky J Proskocil
- Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, Oregon
| | - Gina N Calco
- 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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Bantulà M, Roca-Ferrer J, Arismendi E, Picado C. Asthma and Obesity: Two Diseases on the Rise and Bridged by Inflammation. J Clin Med 2021; 10:jcm10020169. [PMID: 33418879 PMCID: PMC7825135 DOI: 10.3390/jcm10020169] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Asthma and obesity are two epidemics affecting the developed world. The relationship between obesity and both asthma and severe asthma appears to be weight-dependent, causal, partly genetic, and probably bidirectional. There are two distinct phenotypes: 1. Allergic asthma in children with obesity, which worsens a pre-existing asthma, and 2. An often non allergic, late-onset asthma developing as a consequence of obesity. In obesity, infiltration of adipose tissue by macrophages M1, together with an increased expression of multiple mediators that amplify and propagate inflammation, is considered as the culprit of obesity-related inflammation. Adipose tissue is an important source of adipokines, such as pro-inflammatory leptin, produced in excess in obesity, and adiponectin with anti-inflammatory effects with reduced synthesis. The inflammatory process also involves the synthesis of pro-inflammatory cytokines such as IL-1β, IL-6, TNFα, and TGFβ, which also contribute to asthma pathogenesis. In contrast, asthma pro-inflammatory cytokines such as IL-4, IL-5, IL-13, and IL-33 contribute to maintain the lean state. The resulting regulatory effects of the immunomodulatory pathways underlying both diseases have been hypothesized to be one of the mechanisms by which obesity increases asthma risk and severity. Reduction of weight by diet, exercise, or bariatric surgery reduces inflammatory activity and improves asthma and lung function.
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Affiliation(s)
- Marina Bantulà
- Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.B.); (J.R.-F.); (E.A.)
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
| | - Jordi Roca-Ferrer
- Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.B.); (J.R.-F.); (E.A.)
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
| | - Ebymar Arismendi
- Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.B.); (J.R.-F.); (E.A.)
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
- Servei de Pneumologia, Hospital Clinic, 08036 Barcelona, Spain
| | - César Picado
- Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.B.); (J.R.-F.); (E.A.)
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
- Correspondence: ; Tel.: +34-93-227-5400
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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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29
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ERSOY C. Diabetes mellitus and the lungs. TURKISH JOURNAL OF INTERNAL MEDICINE 2020. [DOI: 10.46310/tjim.768962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Sourg HAA, Ahmed ABM, Elhakeem RF, Lutfi MF. Indicators of metabolic syndrome in normotensive normoglycemic asthmatic patients. J Clin Transl Res 2020; 6:27-35. [PMID: 33330745 PMCID: PMC7735662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/22/2020] [Accepted: 07/07/2020] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Pathophysiology of hypertension and bronchial asthma (BA) shares many similarities, especially those related to the metabolic syndrome (MS). AIM In this study, the indicators of the MS were evaluated in normoglycemic normotensive asthmatic patients to clarify if the components of the MS can still interact to increase the risk of BA, provided that blood pressure and glucose level are kept within the normal physiological ranges. METHODS Body mass index (BMI), waist circumference (WC), mean arterial blood pressure (MABP), fasting blood glucose (FBG) and fasting blood insulin (FBI) levels, the quantitative insulin sensitivity check index (QUICKI), serum lipid profile, and spirometric measurements were all compared between 120 asthmatic patients and 59 non-asthmatic subjects. Cigarette smoking, pregnancy, age below 20 years or above 40 years, diabetes mellitus and hypertension, and other chronic diseases were excluded from all studied groups. RESULTS Asthmatic patients demonstrated higher WC (median [25th-75th interquartile]=88.50 [78.00-101.75], FBI [19.98 (11.12-40.14)], and triglyceride (TG) level [109.5 (76.50-134.0)]) compared with non-asthmatic subjects (81.00 [72.00-92.00], 13.78 [8.84-30.24], and 89.00 [64.25-104], P<0.05). QUICKI and MABP were lower in asthmatic patients (0.310 [0.283-0.338] and 86.66 [83.33-93.33]) compared with non-asthmatic subjects (0.320 [0.297-0.353] and 93.33 [83.33-93.33]), (P<0.05). BMI, FBG, low-density lipoprotein, high-density lipoprotein, and total cholesterol levels were comparable in the studied groups. CONCLUSIONS The present finding gives further evidence for higher WC, FBI, TG level, and insulin resistance in normotensive, normoglycemic asthmatic patients compared to healthy controls. RELEVANCE FOR PATIENTS The findings of this study suggested that abdominal obesity, hypertriglyceridemia, hyperinsulinemia, and insulin resistance may still be interacting and hence increase the risk of BA in normotensive, normoglycemic subjects.
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Affiliation(s)
- Hanadi Abdelgadir Ahmed Sourg
- Faculty of Medicine, University of Khartoum, Khartoum, Sudan
- Faculty of Medicine, Al Neelain University, Khartoum, Sudan
| | | | | | - Mohamed Faisal Lutfi
- College of Medicine, Qassim University, Qassim, KSA
- Nile College of Medicine Khartoum, Sudan
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Preserving Airway Smooth Muscle Contraction in Precision-Cut Lung Slices. Sci Rep 2020; 10:6480. [PMID: 32296115 PMCID: PMC7160136 DOI: 10.1038/s41598-020-63225-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/21/2020] [Indexed: 12/13/2022] Open
Abstract
Precision-cut lung slices (PCLS) are ideal for measuring small airway contraction. However, these measurements are currently limited to acute exposure scenarios that typically last a few minutes to a few hours. Using an insulin-supplemented culture medium, we prolong the small airway contractility in mouse PCLS for up to two weeks. Compared to conventional culture medium, insulin-supplemented culture medium provides no additional benefit in preserving cellular viability or airway structure. However, it protects the airway smooth muscle (ASM) against a loss of smooth muscle myosin heavy chain (SMMHC) expression. We elucidate the significance of this new culture medium for chronic disease modeling of IL-13-induced airway hyper-responsiveness.
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Eaves LA, Smeester L, Hartwell HJ, Lin YH, Arashiro M, Zhang Z, Gold A, Surratt JD, Fry RC. Isoprene-Derived Secondary Organic Aerosol Induces the Expression of MicroRNAs Associated with Inflammatory/Oxidative Stress Response in Lung Cells. Chem Res Toxicol 2020; 33:381-387. [PMID: 31765140 PMCID: PMC7243464 DOI: 10.1021/acs.chemrestox.9b00322] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Exposure to fine particulate matter (PM2.5), of which secondary organic aerosol (SOA) is a major constituent, is linked to adverse health outcomes, including cardiovascular disease, lung cancer, and preterm birth. Atmospheric oxidation of isoprene, the most abundant nonmethane hydrocarbon emitted into Earth's atmosphere primarily from vegetation, contributes to SOA formation. Isoprene-derived SOA has previously been found to alter inflammatory/oxidative stress genes. MicroRNAs (miRNAs) are epigenetic regulators that serve as post-transcriptional modifiers and key mediators of gene expression. To assess whether isoprene-derived SOA alters miRNA expression, BEAS-2B lung cells were exposed to laboratory-generated isoprene-derived SOA constituents derived from the acid-driven multiphase chemistry of authentic methacrylic acid epoxide (MAE) or isomeric isoprene epoxydiols (IEPOX) with acidic sulfate aerosol particles. These IEPOX- and MAE-derived SOA constituents have been shown to be measured in large quantities within PM2.5 collected from isoprene-rich areas affected by acidic sulfate aerosol particles derived from human activities. A total of 29 miRNAs were identified as differentially expressed when exposed to IEPOX-derived SOA and 2 when exposed to MAE-derived SOA, a number of which are inflammatory/oxidative stress associated. These results suggest that miRNAs may modulate the inflammatory/oxidative stress response to SOA exposure, thereby advancing the understanding of airway cell epigenetic response to SOA.
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Affiliation(s)
- Lauren A. Eaves
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Lisa Smeester
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Hadley J. Hartwell
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Ying-Hsuan Lin
- Department of Environmental Sciences, University of California, Riverside, California 92521, United States
| | - Maiko Arashiro
- Department of Environmental Studies, Dickinson College, Carlisle, Pennsylvania 17013, United States
| | - Zhenfa Zhang
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Avram Gold
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Jason D. Surratt
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Rebecca C. Fry
- Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Sowers ML, Tang H, Tian B, Goldblum R, Midoro-Horiuti T, Zhang K. Bisphenol A Activates an Innate Viral Immune Response Pathway. J Proteome Res 2020; 19:644-654. [PMID: 31816243 PMCID: PMC8311900 DOI: 10.1021/acs.jproteome.9b00548] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bisphenol A (BPA) is a ubiquitous component in the manufacturing of plastic. It is commonly found in food and beverage containers. Because of its broad exposure and evidence that it may act as an estrogen-like molecule, many have studied its potential effects. For example, epidemiological studies have found an association between in utero BPA exposure and onset of childhood asthma. Our previous work suggested BPA treated mice induced asthma-like symptoms in both mothers and their pups. In order to better understand theconsequences of BPA exposure and potential mechanisms, we used a proteomics approach. Using both CD4+ T cells from an in vivo model of BPA exposure and an in vitro epithelial cell model, we identified activation of both innate and adaptive immune signaling following BPA exposure. Furthermore, our proteomic results from our multigenerational mouse model study implicates aberrant immune activation across several generations. We propose the following; BPA can active an innate viral immune response by upregulating a probable palmitoyltransferase ZDHHC1, and its binding partner stimulator of interferon-gamma (STING). It also has additional histone epigenetic perturbations, suggesting a role for epigenetic inheritance of these immune perturbations.
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Affiliation(s)
- Mark L. Sowers
- MD-PhD Combined Degree Program, University of Texas Medical Branch Galveston, Texas, 77555
- Department of Pharmacology and Toxicology, University of Texas Medical Branch Galveston, Texas, 77555
| | - Hui Tang
- Department of Pharmacology and Toxicology, University of Texas Medical Branch Galveston, Texas, 77555
| | - Bing Tian
- Department of Internal Medicine-Endocrinology, University of Texas Medical Branch Galveston, Texas, 77555
| | - Randall Goldblum
- Department of Pediatrics Child Health Research Center, University of Texas Medical Branch Galveston, Texas, 77555
| | - Terumi Midoro-Horiuti
- Department of Pediatrics Child Health Research Center, University of Texas Medical Branch Galveston, Texas, 77555
| | - Kangling Zhang
- MD-PhD Combined Degree Program, University of Texas Medical Branch Galveston, Texas, 77555
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Abstract
Diabetes mellitus is a chronic, progressive, incompletely understood metabolic disorder whose prevalence has been increasing steadily worldwide. Even though little attention has been paid to lung disorders in the context of diabetes, its prevalence has recently been challenged by newer studies of disease development. In this review, we summarize and discuss the role of diabetes mellitus involved in the progression of pulmonary diseases, with the main focus on pulmonary fibrosis, which represents a chronic and progressive disease with high mortality and limited therapeutic options.
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Affiliation(s)
- Saeed Kolahian
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
- Department of Pharmacogenomics, University of Tübingen, Wilhelmstrasse. 56, D-72074, Tübingen, Germany.
| | - Veronika Leiss
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
| | - Bernd Nürnberg
- Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, and Interfaculty Center of Pharmacogenomics and Drug Research (ICePhA), Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
- Department of Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
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Rayner L, McGovern A, Creagh-Brown B, Woodmansey C, de Lusignan S. Type 2 Diabetes and Asthma: Systematic Review of the Bidirectional Relationship. Curr Diabetes Rev 2019; 15:118-126. [PMID: 29992891 DOI: 10.2174/1573399814666180711114859] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 04/10/2018] [Accepted: 07/04/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND OBJECTIVE Obesity is an important contributor to the risk of both asthma and Type 2 Diabetes (T2DM). However, it has been suggested that T2DM and asthma are also independently associated. The aim of this systematic review was to synthesize the evidence for an independent relationship between T2DM and asthma. METHODS MEDLINE and EMBASE were searched for studies reporting the relationship between asthma and T2DM in adults. Given a potential bidirectional relationship, articles relating to T2DM as a risk factor for asthma, and asthma as a risk factor for T2DM were examined separately. RESULTS Eight studies were identified for inclusion in the review (n=2,934,399 participants). Four studies examined incident diabetes in those with asthma. The pooled (random effects model) adjusted hazard ratio for incident T2DM in asthma was 1.37 (95%CI 1.12-1.69; p <0.001) after controlling for BMI. Four studies reported prevalence or incidence rates of asthma in people with T2DM; higher rates of asthma in those with T2DM were reported in all four studies. Meta-analysis of results was not possible due to methodological heterogeneity. The quality of included studies was good, but due to small numbers, publication bias cannot be excluded. CONCLUSION The published literature suggests a bidirectional independent relationship between T2DM and asthma, although we cannot exclude publication bias.
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Affiliation(s)
- Louise Rayner
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
- Royal Surrey County Hospital NHS Foundation Trust, Guildford, United Kingdom
| | - Andrew McGovern
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
| | - Ben Creagh-Brown
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
- Royal Surrey County Hospital NHS Foundation Trust, Guildford, United Kingdom
| | - Chris Woodmansey
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
- Royal Surrey County Hospital NHS Foundation Trust, Guildford, United Kingdom
| | - Simon de Lusignan
- Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, United Kingdom
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Odessa National Medical University 2, Valikhovsky Lane, Odessa 65028, Ukraine, Bazhora YI, Romanchuk OP. Variability and Respiration Pattern of Patients with Persistent Asthma and Obesity. UKRAÏNSʹKIJ ŽURNAL MEDICINI, BÌOLOGÌÏ TA SPORTU 2018; 3:74-83. [DOI: 10.26693/jmbs03.07.074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
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The Relationship Between Insulin Resistance and Pulmonary Functions in Morbidly Obese Patients. Bariatr Surg Pract Patient Care 2018. [DOI: 10.1089/bari.2017.0053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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Park S, Choi NK, Kim S, Lee CH. The relationship between metabolic syndrome and asthma in the elderly. Sci Rep 2018; 8:9378. [PMID: 29925841 PMCID: PMC6010438 DOI: 10.1038/s41598-018-26621-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 05/10/2018] [Indexed: 01/28/2023] Open
Abstract
The burden of asthma in the elderly is increasing, but the etiology of asthma in the elderly is not clearly understood. Recent studies have reported the epidemiological link between metabolic syndrome (MS) and asthma, but it has rarely been studied in the elderly. This study investigated the association between MS and asthma and the contribution of insulin resistance (IR) and systemic inflammation to this MS-asthma association in the elderly. Our study analyzed 4,060 elderly participants (≥65 years old) from a cross-sectional survey, the Korean National Health and Nutritional Examination Survey 2007–2012. Mediation analyses were performed to examine whether IR and systemic inflammation mediates the MS-asthma association. Participants with MS had significantly higher prevalence of asthma (adjusted odds ratio = 1.34; 95% confidence interval = 1.09–1.64), and those who had greater waist circumference and lower HDL-C were especially likely to have asthma. Participants with IR and systemic inflammation were associated with higher prevalence of asthma. Prevalence of IR and systemic inflammation were higher in participants with MS or with each MS component. The MS-asthma association was substantially mediated by IR and systemic inflammation. Our study showed a significant association between MS and asthma in the elderly. MS might affect asthma through both IR and systemic inflammation.
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Affiliation(s)
- Sangshin Park
- Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States.,Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States
| | - Nam-Kyong Choi
- Department of Health Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Seungsoo Kim
- Division of Allergy and Pulmonology, Department of Internal Medicine, Catholic University of Korea Daejeon St. Mary's Hospital, Daejeon, Republic of Korea
| | - Chang-Hoon Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
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Ferreira SS, Nunes FPB, Casagrande FB, Martins JO. Insulin Modulates Cytokine Release, Collagen and Mucus Secretion in Lung Remodeling of Allergic Diabetic Mice. Front Immunol 2017; 8:633. [PMID: 28649241 PMCID: PMC5465276 DOI: 10.3389/fimmu.2017.00633] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/12/2017] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION The role of insulin in lung remodeling in a model of asthma in healthy and diabetic mice was evaluated. MATERIAL AND METHODS Diabetic male BALB/c mice (alloxan, 50 mg/kg, intravenous) and controls were sensitized by subcutaneous (s.c.) injection of ovalbumin (OA, 20 µg) in aluminum hydroxide (Al(OH)3, 2 mg) 10 days after the alloxan injection and received the same dose 12 days later. Six days after the last sensitization, animals were nebulized with OA solution for 7 days. The first set of diabetic and control mice received 2 and 1 IU, respectively, of s.c. neutral protamine Hagedorn (NPH) insulin and were analyzed 8 h later. The second set of diabetic and control mice received 2 and 1 IU, respectively, of insulin 12 h before the OA challenge and half doses of insulin 2 h before each the seven OA challenges. Twenty-four hours after the last challenge, the following analyses were performed: (a) quantification of the cells in the bronchoalveolar lavage fluid (BALF), the white cell count, and blood glucose; (b) morphological analysis of lung tissues by hematoxylin and eosin staining; (c) quantification of collagen deposition in lung tissues and mucus by morphometric analysis of histological sections stained with Masson's trichrome and periodic acid-Schiff (PAS), respectively; and (d) quantification of the cytokine concentrations (IL-4, IL-5, and IL-13) in the BALF supernatant. RESULTS Compared to controls, diabetic mice had significantly reduced inflammatory cells (81%) in the BALF, no eosinophils in the BALF and peripheral blood and reduced collagen deposition and mucus in the lungs. BALF concentrations of IL-4 (48%) and IL-5 (31%) decreased and IL-13 was absent. A single dose of insulin restored peripheral blood eosinophils and BALF mononuclear cells but not BALF eosinophils, collagen deposition, and mucus levels. However, multiple doses of insulin restored both total cells and eosinophils in the BALF and peripheral blood, BALF cytokines, and collagen deposition and mucus secretion into the lungs. CONCLUSION The results suggest that insulin modulates the production/release of cytokines, cell migration, deposition of collagen, and mucus secretion in lung remodeling of a mouse model of asthma.
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Affiliation(s)
- Sabrina S. Ferreira
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences of University São Paulo (FCF/USP), São Paulo, Brazil
| | - Fernanda P. B. Nunes
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences of University São Paulo (FCF/USP), São Paulo, Brazil
| | - Felipe B. Casagrande
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences of University São Paulo (FCF/USP), São Paulo, Brazil
| | - Joilson O. Martins
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences of University São Paulo (FCF/USP), São Paulo, Brazil
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El-Aarag SA, Mahmoud A, Hashem MH, Abd Elkader H, Hemeida AE, ElHefnawi M. In silico identification of potential key regulatory factors in smoking-induced lung cancer. BMC Med Genomics 2017; 10:40. [PMID: 28592245 PMCID: PMC5463402 DOI: 10.1186/s12920-017-0284-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 05/28/2017] [Indexed: 12/18/2022] Open
Abstract
Background Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. Methods We used a systems biology approach to identify potential key regulatory factors in smoking-induced lung cancer. We first identified genes that were differentially expressed between smokers with normal lungs and those with cancerous lungs, then integrated these differentially expressed genes (DEGs) with data from a protein-protein interaction database to build a network model with functional modules for pathway analysis. We also carried out a gene set enrichment analysis of DEG lists using the Kinase Enrichment Analysis (KEA), Protein-Protein Interaction (PPI) hubs, and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. Results Twelve transcription factors were identified as having potential significance in lung cancer (CREB1, NUCKS1, HOXB4, MYCN, MYC, PHF8, TRIM28, WT1, CUX1, CRX, GABP, and TCF3); three of these (CRX, GABP, and TCF) have not been previously implicated in lung carcinogenesis. In addition, 11 kinases were found to be potentially related to lung cancer (MAPK1, IGF1R, RPS6KA1, ATR, MAPK14, MAPK3, MAPK4, MAPK8, PRKCZ, and INSR, and PRKAA1). However, PRKAA1 is reported here for the first time. MEPCE, CDK1, PRKCA, COPS5, GSK3B, BRCA1, EP300, and PIN1 were identified as potential hubs in lung cancer-associated signaling. In addition, we found 18 pathways that were potentially related to lung carcinogenesis, of which 12 (mitogen-activated protein kinase, gonadotropin-releasing hormone, Toll-like receptor, ErbB, and insulin signaling; purine and ether lipid metabolism; adherens junctions; regulation of autophagy; snare interactions in vesicular transport; and cell cycle) have been previously identified. Conclusion Our systems-based approach identified potential key molecules in lung carcinogenesis and provides a basis for investigations of tumor development as well as novel drug targets for lung cancer treatment.
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Affiliation(s)
- Salem A El-Aarag
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Amal Mahmoud
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Medhat H Hashem
- Animal biotechnology Department, Genetic Engineering and Biotechnology Research Institute, (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Hatem Abd Elkader
- Information Systems Department, Faculty of Computer and Information, Menoufia University, Al Minufiyah, Egypt
| | - Alaa E Hemeida
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Mahmoud ElHefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Center, Cairo, Egypt. .,Center of Informatics, Nile university, Sheikh Zayed City, Giza, Egypt.
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Molina SA, Moriarty HK, Infield DT, Imhoff BR, Vance RJ, Kim AH, Hansen JM, Hunt WR, Koval M, McCarty NA. Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner. Am J Physiol Lung Cell Mol Physiol 2017; 312:L688-L702. [PMID: 28213469 PMCID: PMC5451595 DOI: 10.1152/ajplung.00364.2016] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 02/07/2017] [Accepted: 02/08/2017] [Indexed: 12/13/2022] Open
Abstract
Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose uptake assays. Phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling and cystic fibrosis transmembrane conductance regulator (CFTR) activity were analyzed by pharmacological and immunoblot assays. We found that normal human primary airway epithelial cells expressed glucose transporter 4 and that application of insulin stimulated cytochalasin B-inhibitable glucose uptake, consistent with a requirement for glucose transporter translocation. Application of insulin to normal primary human airway epithelial cells promoted airway barrier function as demonstrated by increased transepithelial electrical resistance and decreased paracellular flux of small molecules. This provides the first demonstration that airway cells express insulin-regulated glucose transporters that act in concert with tight junctions to form an airway glucose barrier. However, insulin failed to increase glucose uptake or decrease paracellular flux of small molecules in human airway epithelia expressing F508del-CFTR. Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR. These results indicate that the airway glucose barrier is regulated by insulin and is dysfunctional in CF.
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Affiliation(s)
- Samuel A Molina
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia;
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Hannah K Moriarty
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Daniel T Infield
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonology, Allergy & Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; and
| | - Barry R Imhoff
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonology, Allergy & Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; and
| | - Rachel J Vance
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Agnes H Kim
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Jason M Hansen
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
| | - William R Hunt
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Michael Koval
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
- Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia
| | - Nael A McCarty
- Emory+Children's Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia
- Division of Pulmonology, Allergy & Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; and
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Chen CZ, Hsu CH, Li CY, Hsiue TR. Insulin use increases risk of asthma but metformin use reduces the risk in patients with diabetes in a Taiwanese population cohort. J Asthma 2017; 54:1019-1025. [PMID: 28135899 DOI: 10.1080/02770903.2017.1283698] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Recent reports have suggested that insulin promotes airway smooth muscle contraction and enhances airway hyperresponsiveness, which are cardinal features of asthma. In contrast, metformin can reduce both airway inflammatory and remodeling properties. However, these results are all from in vitro and animal studies. This study investigated whether diabetes and various antidiabetic agents associate with the risk of asthma. METHODS We used a retrospective population-based cohort study using Taiwan's National Health Insurance claim database from 2000 to 2010 and a Cox proportional hazards regression model to compare the incidence of asthma between patients with diabetes (n = 19,428) and a matched non-diabetic group (n = 38,856). We also used a case-control study nested from the above cohort including 1,982 incident cases of asthma and 1,982 age- and sex-matched controls. A time density sampling technique was used to assess the effects of various antidiabetic agents on the risk of asthma. RESULTS The incidence of asthma was significantly higher in the diabetic cohort than that in the non-diabetic cohort after adjustment for age, sex, and obesity, with a hazard ratio of 1.30 (95% confidence interval [CI]: 1.24-1.38). Insulin was found to increase the risk of asthma among diabetic patients (odds ratio [OR] 2.23; 95% CI: 1.52-3.58). In contrast, the use of metformin correlated with a decreased risk of asthma (OR 0.75; 95% CI: 0.60-0.95). CONCLUSIONS Individuals with diabetes are at an increased risk of asthma. Insulin may further increase the risk of asthma, but the risk could possibly be reduced by using metformin.
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Affiliation(s)
- Chiung-Zuei Chen
- a Division of Chest Medicine, Department of Internal Medicine , National Cheng Kung University Medical College and Hospital , Tainan , Taiwan
| | - Chih-Hui Hsu
- a Division of Chest Medicine, Department of Internal Medicine , National Cheng Kung University Medical College and Hospital , Tainan , Taiwan
| | - Chung-Yi Li
- b Institute of Public Health, National Cheng Kung University Medical College , Tainan , Taiwan
| | - Tzuen-Ren Hsiue
- a Division of Chest Medicine, Department of Internal Medicine , National Cheng Kung University Medical College and Hospital , Tainan , Taiwan
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López IP, Piñeiro-Hermida S, Pais RS, Torrens R, Hoeflich A, Pichel JG. Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation. PLoS One 2016; 11:e0166388. [PMID: 27861515 PMCID: PMC5115747 DOI: 10.1371/journal.pone.0166388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.
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Affiliation(s)
- Icíar P López
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Sergio Piñeiro-Hermida
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Rosete S Pais
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Raquel Torrens
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Andreas Hoeflich
- Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - José G Pichel
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
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Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. THE LANCET. RESPIRATORY MEDICINE 2016; 4:574-584. [PMID: 27283230 PMCID: PMC5007068 DOI: 10.1016/s2213-2600(16)30048-0] [Citation(s) in RCA: 386] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/25/2016] [Accepted: 04/08/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity. METHODS In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts. FINDINGS Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% [SD 19·5] vs 78·3% [19·7]; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL-6 high than in IL-6 low patients (66% [73/111] vs 48% [85/178]; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1-2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% [SD 23·1] vs 83·2% [20·4] predicted; p<0·0001; 59% [16/27] vs 34% [108/320]; p=0·01). INTERPRETATION Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials. FUNDING NIH and the Parker B Francis Foundation.
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Affiliation(s)
- Michael C Peters
- Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Kelly Wong McGrath
- Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Gregory A Hawkins
- Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA
| | - Annette T Hastie
- Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA
| | - Bruce D Levy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Elliot Israel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Brenda R Phillips
- Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA, USA
| | - David T Mauger
- Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA, USA
| | - Suzy A Comhair
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA
| | - Serpil C Erzurum
- Department of Pathobiology, Cleveland Clinic, Cleveland, OH, USA
| | - Mats W Johansson
- Department of Biomolecular Chemistry, University of Wisconsin School of Medicine, Madison, WI, USA
| | - Nizar N Jarjour
- Section of Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, WI, USA
| | - Andrea M Coverstone
- Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
| | - Mario Castro
- Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, Washington University, St Louis, MO, USA
| | - Fernando Holguin
- Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sally E Wenzel
- Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Prescott G Woodruff
- Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Eugene R Bleecker
- Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University Winston-Salem, NC, USA
| | - John V Fahy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
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45
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White MJ, Risse-Adams O, Goddard P, Contreras MG, Adams J, Hu D, Eng C, Oh SS, Davis A, Meade K, Brigino-Buenaventura E, LeNoir MA, Bibbins-Domingo K, Pino-Yanes M, Burchard EG. Novel genetic risk factors for asthma in African American children: Precision Medicine and the SAGE II Study. Immunogenetics 2016; 68:391-400. [PMID: 27142222 DOI: 10.1007/s00251-016-0914-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 04/25/2016] [Indexed: 01/06/2023]
Abstract
Asthma, an inflammatory disorder of the airways, is the most common chronic disease of children worldwide. There are significant racial/ethnic disparities in asthma prevalence, morbidity, and mortality among US children. This trend is mirrored in obesity, which may share genetic and environmental risk factors with asthma. The majority of asthma biomedical research has been performed in populations of European decent. We sought to identify genetic risk factors for asthma in African American children. We also assessed the generalizability of genetic variants associated with asthma in European and Asian populations to African American children. Our study population consisted of 1227 (812 asthma cases, 415 controls) African American children with genome-wide single nucleotide polymorphism (SNP) data. Logistic regression was used to identify associations between SNP genotype and asthma status. We identified a novel variant in the PTCHD3 gene that is significantly associated with asthma (rs660498, p = 2.2 × 10(-7)) independent of obesity status. Approximately 5 % of previously reported asthma genetic associations identified in European populations replicated in African Americans. Our identification of novel variants associated with asthma in African American children, coupled with our inability to replicate the majority of findings reported in European Americans, underscores the necessity for including diverse populations in biomedical studies of asthma.
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Affiliation(s)
- Marquitta J White
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA.
| | - O Risse-Adams
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
- Lowell Science Research Program, Lowell High School, San Francisco, CA, USA
| | - P Goddard
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - M G Contreras
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
- SF BUILD, San Francisco State University, San Francisco, CA, USA
| | - J Adams
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - D Hu
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - C Eng
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - S S Oh
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - A Davis
- Children's Hospital and Research Center Oakland, Oakland, CA, USA
| | - K Meade
- Children's Hospital and Research Center Oakland, Oakland, CA, USA
| | - E Brigino-Buenaventura
- Department of Allergy and Immunology, Kaiser Permanente Vallejo Medical Center, Vallejo, CA, USA
| | | | - K Bibbins-Domingo
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
| | - M Pino-Yanes
- Research Unit, Hospital Universitario N.S. de Candelaria, Tenerife, Spain
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - E G Burchard
- Department of Medicine, University of California, San Francisco, UCSF Box 2911, San Francisco, CA, 94143-2911, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
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46
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Kankaanranta H, Kauppi P, Tuomisto LE, Ilmarinen P. Emerging Comorbidities in Adult Asthma: Risks, Clinical Associations, and Mechanisms. Mediators Inflamm 2016; 2016:3690628. [PMID: 27212806 PMCID: PMC4861800 DOI: 10.1155/2016/3690628] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 01/07/2023] Open
Abstract
Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Most studies with asthma have been performed in patients being otherwise healthy. However, in real life, comorbid diseases are very common in adult patients. We review here the emerging comorbid conditions to asthma such as obesity, metabolic syndrome, diabetes mellitus type 2 (DM2), and cardiac and psychiatric diseases. Their role as risk factors for incident asthma and whether they affect clinical asthma are evaluated. Obesity, independently or as a part of metabolic syndrome, DM2, and depression are risk factors for incident asthma. In contrast, the effects of comorbidities on clinical asthma are less well-known and mostly studies are lacking. Cross-sectional studies in obese asthmatics suggest that they may have less well controlled asthma and worse lung function. However, no long-term clinical follow-up studies with these comorbidities and asthma were identified. These emerging comorbidities often occur in the same multimorbid adult patient and may have in common metabolic pathways and inflammatory or other alterations such as early life exposures, systemic inflammation, inflammasome, adipokines, hyperglycemia, hyperinsulinemia, lung mechanics, mitochondrial dysfunction, disturbed nitric oxide metabolism, and leukotrienes.
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Affiliation(s)
- Hannu Kankaanranta
- Department of Respiratory Medicine, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland
- Department of Respiratory Medicine, University of Tampere, 33521 Tampere, Finland
| | - Paula Kauppi
- Department of Respiratory Medicine and Allergology, Skin and Allergy Hospital, Helsinki University Hospital and Helsinki University, 00029 Helsinki, Finland
| | - Leena E. Tuomisto
- Department of Respiratory Medicine, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland
| | - Pinja Ilmarinen
- Department of Respiratory Medicine, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland
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47
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Singh S, Bodas M, Bhatraju NK, Pattnaik B, Gheware A, Parameswaran PK, Thompson M, Freeman M, Mabalirajan U, Gosens R, Ghosh B, Pabelick C, Linneberg A, Prakash YS, Agrawal A. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol 2016; 310:L837-45. [PMID: 26919895 DOI: 10.1152/ajplung.00091.2015] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 02/12/2016] [Indexed: 12/13/2022] Open
Abstract
There is limited knowledge regarding the consequences of hyperinsulinemia on the lung. Given the increasing prevalence of obesity, insulin resistance, and epidemiological associations with asthma, this is a critical lacuna, more so with inhaled insulin on the horizon. Here, we demonstrate that insulin can adversely affect respiratory health. Insulin treatment (1 μg/ml) significantly (P < 0.05) increased the proliferation of primary human airway smooth muscle (ASM) cells and induced collagen release. Additionally, ASM cells showed a significant increase in calcium response and mitochondrial respiration upon insulin exposure. Mice administered intranasal insulin showed increased collagen deposition in the lungs as well as a significant increase in airway hyperresponsiveness. PI3K/Akt mediated activation of β-catenin, a positive regulator of epithelial-mesenchymal transition and fibrosis, was observed in the lungs of insulin-treated mice and lung cells. Our data suggests that hyperinsulinemia may have adverse effects on airway structure and function. Insulin-induced activation of β-catenin in lung tissue and the contractile effects on ASM cells may be causally related to the development of asthma-like phenotype.
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Affiliation(s)
- Suchita Singh
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Manish Bodas
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Naveen K Bhatraju
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Bijay Pattnaik
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Atish Gheware
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | | | - Michael Thompson
- Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Michelle Freeman
- Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Ulaganathan Mabalirajan
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Reinoud Gosens
- Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, Netherlands
| | - Balaram Ghosh
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Christina Pabelick
- Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Allan Linneberg
- Research Centre for Prevention and Health, the Capital Region of Denmark, Copenhagen, Denmark; Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Y S Prakash
- Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; and
| | - Anurag Agrawal
- Center of Excellence for Translational Research in Asthma and Lung Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India;
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48
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Baffi CW, Wood L, Winnica D, Strollo PJ, Gladwin MT, Que LG, Holguin F. Metabolic Syndrome and the Lung. Chest 2016; 149:1525-34. [PMID: 26836925 DOI: 10.1016/j.chest.2015.12.034] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 12/04/2015] [Accepted: 12/24/2015] [Indexed: 01/01/2023] Open
Abstract
A link between metabolic syndrome (MetS) and lung diseases has been observed in several cross-sectional and longitudinal studies. This syndrome has been identified as an independent risk factor for worsening respiratory symptoms, greater lung function impairment, pulmonary hypertension, and asthma. This review will discuss several potential mechanisms to explain these associations, including dietary factors and the effect of adiposity and fat-induced inflammation on the lungs, and the role of other comorbidities that frequently coexist with MetS, such as OSA and obesity. In contrast to the well-known association between asthma and obesity, the recognition that MetS affects the lung is relatively new. Although some controversy remains as to whether MetS is a unique disease entity, its individual components have independently been associated with changes in pulmonary function or lung disease. There is, however, uncertainty as to the relative contribution that each metabolic factor has in adversely affecting the respiratory system; also, it is unclear how much of the MetS-related lung effects occur independently of obesity. In spite of these epidemiological limitations, the proposed mechanistic pathways strongly suggest that this association is likely to be causal. Given the wide prevalence of MetS in the general population, it is imperative that we continue to further understand how this metabolic disorder impacts the lung and how to prevent its complications.
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Affiliation(s)
- Cynthia W Baffi
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Lisa Wood
- Hunter Medical Research Institute and University of Newcastle, NSW, Australia
| | - Daniel Winnica
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | | | - Mark T Gladwin
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | | | - Fernando Holguin
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
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49
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Abstract
PURPOSE OF REVIEW Obesity has significant impact on asthma incidence and manifestations. The purpose of the review is to discuss recent observations regarding the association between obesity and asthma focusing on underlying mechanisms, clinical presentation, response to therapy and effect of weight reduction. RECENT FINDINGS Clinical and epidemiological studies indicate that obese patients with asthma may represent a unique phenotype, which is more difficult to control, less responsive to asthma medications and by that may have higher healthcare utilization. A number of common comorbidities have been linked to both obesity and asthma, and may, therefore, contribute to the obese-asthma phenotype. Furthermore, recently published studies indicate that even a modest weight reduction can improve clinical manifestations and outcome of asthma. SUMMARY Compared with normal-weight patients, obese and overweight patients with asthma have poorer asthma control and respond less to corticosteroid therapy. Future studies focusing on the mechanism underlying both obesity and asthma including the obese-asthma phenotype are required to better characterize the link between the conditions and target the management of this patient group.
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50
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Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, Agrawal A. Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs. PLoS One 2015; 10:e0129850. [PMID: 26098111 PMCID: PMC4476757 DOI: 10.1371/journal.pone.0129850] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 05/13/2015] [Indexed: 12/16/2022] Open
Abstract
Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.
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Affiliation(s)
- Vijay Pal Singh
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
- * E-mail:
| | - Rangoli Aggarwal
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Suchita Singh
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Arpita Banik
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Tanveer Ahmad
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Bijay Ranjan Patnaik
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Giridharan Nappanveettil
- National Centre for Laboratory Animal Sciences, National Institute of Nutrition, Tarnaka, Hyderabad, AP, India
| | - Kunal Pratap Singh
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | | | - Balaram Ghosh
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
| | - Anurag Agrawal
- Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India
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