Visceral adiposity is related to insulin sensitivity and inflammation in adolescents with obesity and mild sleep disordered breathing

Mary Ellen Vajravelu; Joseph M. Kindler; Babette S. Zemel; Abbas Jawad; Dorit Koren; Preneet Brar; Lee J. Brooks; Jessica Reiner; Lorraine E. Levitt Katz

doi:10.1515/jpem-2021-0745

Article

Visceral adiposity is related to insulin sensitivity and inflammation in adolescents with obesity and mild sleep disordered breathing

Mary Ellen Vajravelu , Joseph M. Kindler , Babette S. Zemel , Abbas Jawad , Dorit Koren , Preneet Brar , Lee J. Brooks , Jessica Reiner and Lorraine E. Levitt Katz

Published/Copyright: July 11, 2022

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 35 Issue 8

Abstract

Objectives

To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents.

Methods

Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO₂; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO₂; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP).

Results

Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3–0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=−0.4, p=0.005) and SpO₂ nadir (r=−0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance.

Conclusions

Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO₂ nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

Keywords: adolescent; obesity; sleep; inflammation; adiposity; insulin resistance

Corresponding author: Mary Ellen Vajravelu, MD MSHP, Division of Pediatric Endocrinology, Diabetes, and Metabolism, UPMC Children’s Hospital of Pittsburgh Faculty Pavilion, University of Pittsburgh School of Medicine, 6th Floor 4401 Penn Ave, Pittsburgh, 15224, PA, USA; and Center for Pediatric Research in Obesity and Metabolism, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, E-mail: MaryEllen.Vajravelu@pitt.edu.

Funding source: National Institute of Diabetes and Digestive and Kidney Diseases

Award Identifier / Grant number: 5T32DK063688

Award Identifier / Grant number: 7K23DK125719-03

Funding source: PA State Tobacco Settlement Fund

Funding source: National Center for Advancing Translational Sciences

Award Identifier / Grant number: UL1-TR000003

Research funding: Dr. Vajravelu is supported by grant NIH 7K23DK125719-03. Dr. Katz is supported by UL1-TR000003. The study was supported by the PA State Tobacco Settlement Fund (LLK) and 5T32DK063688 (DK).
Author contributions: All authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. MEV, LLK, and LJB were responsible for conception and design of the study. MEV and LLK carried out analysis, interpretation of data, and drafting and critical revision of the article. JK, BZ, and AJ assisted with study conception and design, analysis and interpretation, and critical revision of the article for important intellectual content. JR assisted with data analysis and critical revision of the article. LLK, DK and PB carried out the study visits. DK, PB and LJB critically revised the article for important intellectual content. study, and takes responsibility for the integrity of the data and accuracy of the data analysis.
Competing interests: The funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The Children’s Hospital of Philadelphia Institutional Review Board approved this study.

References

1. Styne, DM, Arslanian, SA, Connor, EL, Farooqi, IS, Murad, MH, Silverstein, JH, et al.. Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2017;102:709–57. https://doi.org/10.1210/jc.2016-2573.Search in Google Scholar PubMed PubMed Central

2. Tershakovec, AM, Kuppler, KM, Zemel, BS, Katz, L, Weinzimer, S, Harty, MP, et al.. Body composition and metabolic factors in obese children and adolescents. Int J Obes Relat Metab Disord 2003;27:19–24. https://doi.org/10.1038/sj.ijo.0802185.Search in Google Scholar PubMed

3. Ryan, S. Adipose tissue inflammation by intermittent hypoxia: mechanistic link between obstructive sleep apnoea and metabolic dysfunction. J Physiol 2017;595:2423–30. https://doi.org/10.1113/jp273312.Search in Google Scholar PubMed PubMed Central

4. Ryan, S, Taylor, CT, McNicholas, WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Postgrad Med 2010;85:693–8. https://doi.org/10.1136/thx.2008.105577.Search in Google Scholar PubMed

5. Larkin, EK, Rosen, CL, Kirchner, HL, Storfer-Isser, A, Emancipator, JL, Johnson, NL, et al.. Variation of C-reactive protein levels in adolescents: association with sleep-disordered breathing and sleep duration. Circulation 2005;111:1978–84. https://doi.org/10.1161/01.cir.0000161819.76138.5e.Search in Google Scholar

6. Deboer, MD, Mendoza, JP, Liu, L, Ford, G, Yu, PL, Gaston, BM. Increased systemic inflammation overnight correlates with insulin resistance among children evaluated for obstructive sleep apnea. Sleep Breath 2012;16:349–54. https://doi.org/10.1007/s11325-011-0499-8.Search in Google Scholar PubMed PubMed Central

7. Gaines, J, Vgontzas, AN, Fernandez-Mendoza, J, Calhoun, SL, He, F, Liao, D, et al.. Inflammation mediates the association between visceral adiposity and obstructive sleep apnea in adolescents. Am J Physiol Endocrinol Metab 2016;311:E851–8. https://doi.org/10.1152/ajpendo.00249.2016.Search in Google Scholar PubMed PubMed Central

8. Redline, S, Storfer-Isser, A, Rosen, CL, Johnson, NL, Kirchner, HL, Emancipator, J, et al.. Association between metabolic syndrome and sleep-disordered breathing in adolescents. Am J Respir Crit Care Med 2007;176:401–8. https://doi.org/10.1164/rccm.200703-375oc.Search in Google Scholar PubMed PubMed Central

9. Hannon, TS, Lee, S, Chakravorty, S, Lin, Y, Arslanian, SA. Sleep-disordered breathing in obese adolescents is associated with visceral adiposity and markers of insulin resistance. Int J Pediatr Obes 2011;6:157–60. https://doi.org/10.3109/17477166.2010.482156.Search in Google Scholar PubMed PubMed Central

10. Canapari, CA, Hoppin, AG, Kinane, TB, Thomas, BJ, Torriani, M, Katz, ES. Relationship between sleep apnea, fat distribution, and insulin resistance in obese children. J Clin Sleep Med 2011;7:268–73. https://doi.org/10.5664/JCSM.1068.Search in Google Scholar PubMed PubMed Central

11. Weber, DR, Levitt Katz, LE, Zemel, BS, Gallagher, PR, Murphy, KM, Dumser, SM, et al.. Anthropometric measures of abdominal adiposity for the identification of cardiometabolic risk factors in adolescents. Diabetes Res Clin Pract 2014;103:e14–7. https://doi.org/10.1016/j.diabres.2013.12.050.Search in Google Scholar PubMed PubMed Central

12. Koren, D, Levitt Katz, LE, Brar, PC, Gallagher, PR, Berkowitz, RI, Brooks, LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care 2011;34:2442–7. https://doi.org/10.2337/dc11-1093.Search in Google Scholar PubMed PubMed Central

13. Kuczmarski, RJ, Ogden, CL, Guo, SS, Grummer-Strawn, LM, Flegal, KM, Mei, Z, et al.. 2000 CDC growth charts for the United States: methods and development. Vital Health Stat 2002;11:1–190.Search in Google Scholar

14. American Diabetes A. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care 2021;44:S15–33. https://doi.org/10.2337/dc21-S002.Search in Google Scholar PubMed

15. Yeckel, CW, Weiss, R, Dziura, J, Taksali, SE, Dufour, S, Burgert, TS, et al.. Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents. J Clin Endocrinol Metab 2004;89:1096–101. https://doi.org/10.1210/jc.2003-031503.Search in Google Scholar PubMed

16. Boston, RC, Stefanovski, D, Moate, PJ, Sumner, AE, Watanabe, RM, Bergman, RN. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Therapeut 2003;5:1003–15. https://doi.org/10.1089/152091503322641060.Search in Google Scholar PubMed

17. Iber CAASM. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, IL: American Academy of Sleep Medicine; 2007.Search in Google Scholar

18. Bosch, TA, Dengel, DR, Kelly, AS, Sinaiko, AR, Moran, A, Steinberger, J. Visceral adipose tissue measured by DXA correlates with measurement by CT and is associated with cardiometabolic risk factors in children. Pediatr Obes 2015;10:172–9. https://doi.org/10.1111/ijpo.249.Search in Google Scholar PubMed PubMed Central

19. Kaess, BM, Pedley, A, Massaro, JM, Murabito, J, Hoffmann, U, Fox, CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia 2012;55:2622–30. https://doi.org/10.1007/s00125-012-2639-5.Search in Google Scholar PubMed PubMed Central

20. American Diabetes A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care 2018;41(Suppl 1):S13–27.10.2337/dc18-S002Search in Google Scholar PubMed

21. Pareek, M, Bhatt, DL, Nielsen, ML, Jagannathan, R, Eriksson, KF, Nilsson, PM, et al.. Enhanced predictive capability of a 1-hour oral glucose tolerance test: a prospective population-based cohort study. Diabetes Care 2018;41:171–7. https://doi.org/10.2337/dc17-1351.Search in Google Scholar PubMed

22. Trico, D, Galderisi, A, Mari, A, Santoro, N, Caprio, S. One-hour post-load plasma glucose predicts progression to prediabetes in a multi-ethnic cohort of obese youths. Diabetes Obes Metabol 2019;21:1191–8. https://doi.org/10.1111/dom.13640.Search in Google Scholar PubMed PubMed Central

23. Serbis, A, Giapros, V, Challa, A, Chaliasos, N, Siomou, E. Elevated 1-hour post-load plasma glucose identifies obese youth with abnormal glucose metabolism and an unfavourable inflammatory profile. Clin Endocrinol (Oxf). 2018;89:757–64. https://doi.org/10.1111/cen.13859.Search in Google Scholar PubMed

24. Abdul-Ghani, MA, Lyssenko, V, Tuomi, T, DeFronzo, RA, Groop, L. Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes: results from the Botnia Study. Diabetes Care 2009;32:281–6. https://doi.org/10.2337/dc08-1264.Search in Google Scholar PubMed PubMed Central

25. Weigensberg, MJ, Cruz, ML, Goran, MI. Association between insulin sensitivity and post-glucose challenge plasma insulin values in overweight latino youth. Diabetes Care 2003;26:2094–9. https://doi.org/10.2337/diacare.26.7.2094.Search in Google Scholar PubMed

26. Muniyappa, RMR, Varghese, RT. Assessing insulin sensitivity and resistance in humans. South Dartmouth, MA: MDText.com, Inc; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278954/.Search in Google Scholar

27. Petrangeli, E, Coroniti, G, Brini, AT, de Girolamo, L, Stanco, D, Niada, S, et al.. Hypoxia promotes the inflammatory response and stemness features in visceral fat stem cells from obese subjects. J Cell Physiol 2016;231:668–79. https://doi.org/10.1002/jcp.25113.Search in Google Scholar PubMed

28. Gileles-Hillel, A, Almendros, I, Khalyfa, A, Nigdelioglu, R, Qiao, Z, Hamanaka, RB, et al.. Prolonged exposures to intermittent hypoxia promote visceral white adipose tissue inflammation in a murine model of severe sleep apnea: effect of normoxic recovery. Sleep 2017;40:1–10. https://doi.org/10.1093/sleep/zsw074.Search in Google Scholar PubMed

29. Poulain, L, Thomas, A, Rieusset, J, Casteilla, L, Levy, P, Arnaud, C, et al.. Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis. Eur Respir J 2014;43:513–22. https://doi.org/10.1183/09031936.00019913.Search in Google Scholar PubMed

30. Borel, AL, Monneret, D, Tamisier, R, Baguet, JP, Faure, P, Levy, P, et al.. The severity of nocturnal hypoxia but not abdominal adiposity is associated with insulin resistance in non-obese men with sleep apnea. PLoS One 2013;8:e71000. https://doi.org/10.1371/journal.pone.0071000.Search in Google Scholar PubMed PubMed Central

31. Koren, D, Gozal, D, Philby, MF, Bhattacharjee, R, Kheirandish-Gozal, L. Impact of obstructive sleep apnoea on insulin resistance in nonobese and obese children. Eur Respir J 2016;47:1152–61. https://doi.org/10.1183/13993003.01430-2015.Search in Google Scholar PubMed

32. Suliga, E. Visceral adipose tissue in children and adolescents: a review. Nutr Res Rev 2009;22:137–47. https://doi.org/10.1017/s0954422409990096.Search in Google Scholar

33. Benfield, LL, Fox, KR, Peters, DM, Blake, H, Rogers, I, Grant, C, et al.. Magnetic resonance imaging of abdominal adiposity in a large cohort of British children. Int J Obes 2008;32:91–9. https://doi.org/10.1038/sj.ijo.0803780.Search in Google Scholar PubMed

34. Staiano, AE, Katzmarzyk, PT. Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents. Int J Obes 2012;36:1261–9. https://doi.org/10.1038/ijo.2012.95.Search in Google Scholar PubMed PubMed Central

Received: 2021-12-10

Accepted: 2022-06-17

Published Online: 2022-07-11

Published in Print: 2022-08-26

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Articles in the same Issue

https://doi.org/10.1515/jpem-2021-0745

Keywords for this article

adolescent; obesity; sleep; inflammation; adiposity; insulin resistance