Causal effects of insulin resistance on chronic airway inflammatory diseases: a two-sample Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

ZHAO Chongyang ¹ , WANG Qin ¹ , DENG Cong ² , LI Li ¹ , SONG Jia ¹ ,  KANG Deying ^1,3

1. Department of Evidence-based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, China;
2. Department of Respiratory and Critical Care Medicine, General Hospital of the Western Theater Command of the People's Liberation Army of China;
3. Center of Biostatistics, Design, Measurement and Evaluation (CBDME), Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, China;

Corresponding author：

KANG Deying, Email: deyingkang@126.com

Keywords：

Insulin resistance; Chronic airway inflammatory diseases; COPD; Asthma; Mendelian randomization

DOI：

10.7507/1672-2531.202501012

Video：

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Objective Exploring the potential causal effects and directions of insulin resistance (IR) and chronic airway inflammatory diseases, including asthma and chronic obstructive pulmonary disease (COPD), through two sample Mendelian randomization (MR). Methods A total of 53 validated single nucleotide polymorphisms (SNPs) associated with IR were selected as instrumental variables. The inverse variance-weighted (IVW) method was used to model the causal association, and sensitivity analyses through leave-one-out analysis and pleiotropy testing were conducted to assess the relationship between IR and asthma and COPD. Results MR analysis revealed no significant causal effect of IR on asthma (IVW: OR=1.067, 95%CI 0.871 to 1.306, P=0.531) or COPD (IVW: OR=0.906, 95%CI 0.686 to –1.196, P=0.557). The results were consistent across sensitivity analyses and multiple pleiotropy tests, with no evidence of horizontal pleiotropy detected. Conclusion No causal association was found between IR and the development of asthma or COPD. The relationship between these conditions may be influenced indirectly through complex interactions between metabolic and inflammatory pathways affecting disease progression.

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5.	Yang G, Han YY, FORNO E, et al. Glycated hemoglobin A1c, lung function, and hospitalizations among adults with asthma. J Allergy Clin Immunol Pract, 2020, 8(10): 3409-3415.
6.	Staggers KA, Minard C, Byers M, et al. Metabolic dysfunction, triglyceride-glucose index, and risk of severe asthma exacerbation. J Allergy Clin Immunol Pract, 2023, 11(12): 3700-3705.
7.	Sadeghimakki R, McCarthy HD. Interactive effects of adiposity and insulin resistance on the impaired lung function in asthmatic adults: cross-sectional analysis of NHANES data. Ann Hum Biol, 2019, 46(1): 56-62.
8.	Kuschnir FC, Felix MMR, Caetano Kuschnir MC, et al. Severe asthma is associated with metabolic syndrome in Brazilian adolescents. J Allergy Clin Immunol, 2018, 141(5): 1947-1949.
9.	Machado FVC, Pitta F, Hernandes NA, et al. Physiopathological relationship between chronic obstructive pulmonary disease and insulin resistance. Endocrine, 2018, 61(1): 17-22.
10.	Peters MC, Schiebler ML, Cardet JC, et al. The impact of insulin resistance on loss of lung function and response to treatment in asthma. Am J Respir Crit Care Med, 2022, 206(9): 1096-1106.
11.	Park SS, Perez Perez JL, Perez Gandara B, et al. Mechanisms linking COPD to type 1 and 2 diabetes mellitus: is there a relationship between diabetes and COPD. Medicina (Kaunas), 2022, 58(8): 1030.
12.	Wu TD. Diabetes, insulin resistance, and asthma: a review of potential links. Curr Opin Pulm Med, 2021, 27(1): 29.
13.	Bhammar DM, Babb TG, Xu M, et al. Impact of insulin resistance on asthma: is there truly no role of "obesity". Am J Respir Crit Care Med, 2023, 207(1): 110-111.
14.	Piazzolla G, Castrovilli A, Liotino V, et al. Metabolic syndrome and chronic obstructive pulmonary disease (COPD): the interplay among smoking, insulin resistance and vitamin D. PLoS One, 2017, 12(10): e0186708.
15.	Carr TF, Granell R, Stern DA, et al. High insulin in early childhood is associated with subsequent asthma risk independent of body mass index. J Allergy Clin Immunol Pract, 2022, 10(3): 785-792.
16.	Cardet JC, Ash S, Kusa T, et al. Insulin resistance modifies the association between obesity and current asthma in adults. Eur Respir J, 2016, 48(2): 403-410.
17.	Sánchez Jiménez J, Herrero Espinet FJ, Mengibar Garrido JM, et al. Asthma and insulin resistance in obese children and adolescents. Pediatr Allergy Immunol, 2014, 25(7): 699-705.
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19.	Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
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21.	Lotta LA, Gulati P, Day FR, et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet, 2017, 49(1): 17-26.
22.	Wang Q, Holmes MV, Davey Smith G, et al. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care, 2017, 40(12): 1779-1786.
23.	Zhang F, Yu Z. Mendelian randomization study on insulin resistance and risk of hypertension and cardiovascular disease. Sci Rep, 2024, 14: 6191.
24.	Chen W, Wang S, Lv W, et al. Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis. BMJ Open Diabetes Res Care, 2020, 8(1): e001217.
25.	Perry BI, Burgess S, Jones HJ, et al. The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study. PLoS Med, 2021, 18(3): e1003455.
26.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiol, 2016, 40(4): 304-314.
27.	Nazarzadeh M, Pinho-Gomes AC, Bidel Z, et al. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J, 2020, 41(40): 3913-3920.
28.	Kelsey MM, Zeitler PS. Insulin resistance of puberty. Curr Diab Rep, 2016, 16(7): 64.
29.	Peters MC, Schiebler ML, Cardet JC, et al. The impact of insulin resistance on loss of lung function and response to treatment in asthma. Am J Respir Crit Care Med, 206(9): 1096-1106.
30.	Gao SY, Deng K, Wang J, et al. Homeostatic measure of insulin resistance is associated with future asthma exacerbations: a 1-year prospective cohort study. J Allergy Clin Immunol Pract, 2024, 12(10): 2774-2784.
31.	Park K H, Zaichenko L, Brinkoetter M, et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab, 2013, 98(12): 4899-4907.
32.	Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 2001, 414(6865): 799-806.
33.	Beijers RJHCG, van de Bool C, van den Borst B, et al. Normal weight but low muscle mass and abdominally obese: implications for the cardiometabolic risk profile in chronic obstructive pulmonary disease. J Am Med Dir Assoc, 2017, 18(6): 533-538.
34.	Bartziokas K, Papaioannou AI, Drakopanagiotakis F, et al. Unraveling the link between ιnsulin resistance and bronchial asthma. Biomedicines, 2024, 12(2): 437.
35.	Škrgat S, Harlander M, Janić M. Obesity and insulin resistance in asthma pathogenesis and clinical outcomes. Biomedicines, 2024, 12(1): 173.
36.	Singh S, Bodas M, Bhatraju NK, et al. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol, 2016, 310(9): L837-L845.
37.	Kim SH, Kim HS, Min HK, et al. Association between insulin resistance and lung function trajectory over 4 years in South Korea: community-based prospective cohort. BMC Pulm Med, 2021, 21(1): 110.

1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med, 2017, 5(9): 691-706.
2. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: 2024 Report. 2024.
3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for prevention, diagnosis and management of COPD: 2024 Report. 2024.
4. GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet, 2024, 403(10440): 2133-2161.
5. Yang G, Han YY, FORNO E, et al. Glycated hemoglobin A1c, lung function, and hospitalizations among adults with asthma. J Allergy Clin Immunol Pract, 2020, 8(10): 3409-3415.
6. Staggers KA, Minard C, Byers M, et al. Metabolic dysfunction, triglyceride-glucose index, and risk of severe asthma exacerbation. J Allergy Clin Immunol Pract, 2023, 11(12): 3700-3705.
7. Sadeghimakki R, McCarthy HD. Interactive effects of adiposity and insulin resistance on the impaired lung function in asthmatic adults: cross-sectional analysis of NHANES data. Ann Hum Biol, 2019, 46(1): 56-62.
8. Kuschnir FC, Felix MMR, Caetano Kuschnir MC, et al. Severe asthma is associated with metabolic syndrome in Brazilian adolescents. J Allergy Clin Immunol, 2018, 141(5): 1947-1949.
9. Machado FVC, Pitta F, Hernandes NA, et al. Physiopathological relationship between chronic obstructive pulmonary disease and insulin resistance. Endocrine, 2018, 61(1): 17-22.
10. Peters MC, Schiebler ML, Cardet JC, et al. The impact of insulin resistance on loss of lung function and response to treatment in asthma. Am J Respir Crit Care Med, 2022, 206(9): 1096-1106.
11. Park SS, Perez Perez JL, Perez Gandara B, et al. Mechanisms linking COPD to type 1 and 2 diabetes mellitus: is there a relationship between diabetes and COPD. Medicina (Kaunas), 2022, 58(8): 1030.
12. Wu TD. Diabetes, insulin resistance, and asthma: a review of potential links. Curr Opin Pulm Med, 2021, 27(1): 29.
13. Bhammar DM, Babb TG, Xu M, et al. Impact of insulin resistance on asthma: is there truly no role of "obesity". Am J Respir Crit Care Med, 2023, 207(1): 110-111.
14. Piazzolla G, Castrovilli A, Liotino V, et al. Metabolic syndrome and chronic obstructive pulmonary disease (COPD): the interplay among smoking, insulin resistance and vitamin D. PLoS One, 2017, 12(10): e0186708.
15. Carr TF, Granell R, Stern DA, et al. High insulin in early childhood is associated with subsequent asthma risk independent of body mass index. J Allergy Clin Immunol Pract, 2022, 10(3): 785-792.
16. Cardet JC, Ash S, Kusa T, et al. Insulin resistance modifies the association between obesity and current asthma in adults. Eur Respir J, 2016, 48(2): 403-410.
17. Sánchez Jiménez J, Herrero Espinet FJ, Mengibar Garrido JM, et al. Asthma and insulin resistance in obese children and adolescents. Pediatr Allergy Immunol, 2014, 25(7): 699-705.
18. 吕国悦, 郁金泰. 孟德尔随机化: 基于遗传变异的因果推断方法(第2版). 北京: 人民卫生出版社, 2024.
19. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA, 2021, 326(16): 1614-1621.
20. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
21. Lotta LA, Gulati P, Day FR, et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet, 2017, 49(1): 17-26.
22. Wang Q, Holmes MV, Davey Smith G, et al. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care, 2017, 40(12): 1779-1786.
23. Zhang F, Yu Z. Mendelian randomization study on insulin resistance and risk of hypertension and cardiovascular disease. Sci Rep, 2024, 14: 6191.
24. Chen W, Wang S, Lv W, et al. Causal associations of insulin resistance with coronary artery disease and ischemic stroke: a Mendelian randomization analysis. BMJ Open Diabetes Res Care, 2020, 8(1): e001217.
25. Perry BI, Burgess S, Jones HJ, et al. The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study. PLoS Med, 2021, 18(3): e1003455.
26. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiol, 2016, 40(4): 304-314.
27. Nazarzadeh M, Pinho-Gomes AC, Bidel Z, et al. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J, 2020, 41(40): 3913-3920.
28. Kelsey MM, Zeitler PS. Insulin resistance of puberty. Curr Diab Rep, 2016, 16(7): 64.
29. Peters MC, Schiebler ML, Cardet JC, et al. The impact of insulin resistance on loss of lung function and response to treatment in asthma. Am J Respir Crit Care Med, 206(9): 1096-1106.
30. Gao SY, Deng K, Wang J, et al. Homeostatic measure of insulin resistance is associated with future asthma exacerbations: a 1-year prospective cohort study. J Allergy Clin Immunol Pract, 2024, 12(10): 2774-2784.
31. Park K H, Zaichenko L, Brinkoetter M, et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab, 2013, 98(12): 4899-4907.
32. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 2001, 414(6865): 799-806.
33. Beijers RJHCG, van de Bool C, van den Borst B, et al. Normal weight but low muscle mass and abdominally obese: implications for the cardiometabolic risk profile in chronic obstructive pulmonary disease. J Am Med Dir Assoc, 2017, 18(6): 533-538.
34. Bartziokas K, Papaioannou AI, Drakopanagiotakis F, et al. Unraveling the link between ιnsulin resistance and bronchial asthma. Biomedicines, 2024, 12(2): 437.
35. Škrgat S, Harlander M, Janić M. Obesity and insulin resistance in asthma pathogenesis and clinical outcomes. Biomedicines, 2024, 12(1): 173.
36. Singh S, Bodas M, Bhatraju NK, et al. Hyperinsulinemia adversely affects lung structure and function. Am J Physiol Lung Cell Mol Physiol, 2016, 310(9): L837-L845.
37. Kim SH, Kim HS, Min HK, et al. Association between insulin resistance and lung function trajectory over 4 years in South Korea: community-based prospective cohort. BMC Pulm Med, 2021, 21(1): 110.

Chinese Journal of Evidence-Based Medicine

Latest ArticlesCausal effects of insulin resistance on chronic airway inflammatory diseases: a two-sample Mendelian randomization study

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