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Adipocyte and Cell Biology

Usefulness of surrogate markers to determine insulin action in fat cells

International Journal of Obesity volume 44, pages 2436–2443 (2020)Cite this article

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Abstract

Background

Obesity is a major factor behind insulin resistance. The validity of simple biochemical surrogate measures to estimate insulin resistance at the fat cell level is unclear.

Objective

To investigate if the surrogate measures HOMA-IR (glucose/insulin product) and Adipo-IR (fatty acids/insulin product) reflect insulin action on glucose/lipid metabolism in fat cells.

Design

Insulin-induced lipogenesis and lipolysis inhibition (antilipolysis) in subcutaneous fat cells were investigated for sensitivity (reflecting receptor-near events) and responsiveness (i.e., maximum action reflecting distal post-receptor events) in 363 subjects. Results were compared with log10 transformed values for HOMA-IR and Adipo-IR.

Results

Individually, the four measures of in vitro insulin action on fat cells correlated significantly (p < 0.0001) but weakly with each other (adjusted r2 0.05–0.23). HOMA-IR and Adipo-IR correlated strongly with each other (adjusted r2 = 0.81). Using Spearman or simple linear regression all in vitro measures except antilipolytic responsiveness expressed per lipid weight, correlated significantly with Adipo-IR or HOMA-IR (p values <0.0001). Similar relationships remained after combined correction for age, body mass index and sex. Together, the four in vitro measures explained 50% of the variability in HOMA-IR and ADIPO-IR (p < 0.0001). Receiver-operating characteristic analysis showed good sensitivity and specificity for Adipo-IR and HOMA-IR to detect combined insulin resistance of antilipolysis and lipogenesis in fat cells (area under the curve = 0.8).

Conclusions

Insulin action at the receptor and post-receptor levels on lipolysis and lipogenesis in fat cells correlates significantly with Adipo-IR and HOMA-IR. Both surrogate measures give similar information about insulin resistance of glucose and lipid metabolism in fat cells.

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Fig. 1: Relationship between in vitro or in vivo insulin action parameters.
Fig. 2: Sensitivity and specificity of Adipo-IR and HOMA-IR to detect fat cell insulin resistance.

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References

  1. Singh B, Saxena A. Surrogate markers of insulin resistance: a review. World J Diabetes. 2010;1:36–47.

    Article  Google Scholar 

  2. Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab. 2003;17:305–22.

    Article  CAS  Google Scholar 

  3. Smith U, Kahn BB. Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids. J Intern Med. 2016;280:465–75.

    Article  CAS  Google Scholar 

  4. Arner P. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends Endocrinol Metab. 2003;14:137–45.

    Article  CAS  Google Scholar 

  5. Sondergaard E, Jensen MD. Quantification of adipose tissue insulin sensitivity. J Investig Med. 2016;64:989–91.

    Article  Google Scholar 

  6. Ryden M, Petrus P, Andersson DP, Medina-Gomez G, Escasany E, Corrales Cordon P, et al. Insulin action is severely impaired in adipocytes of apparently healthy overweight and obese subjects. J Intern Med. 2019;285:578–88.

    Article  CAS  Google Scholar 

  7. Hershkop K, Besor O, Santoro N, Pierpont B, Caprio S, Weiss R. Adipose insulin resistance in obese adolescents across the spectrum of glucose tolerance. J Clin Endocrinol Metab. 2016;101:2423–31.

    Article  CAS  Google Scholar 

  8. Gastaldelli A, Gaggini M, DeFronzo RA. Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the san antonio metabolism study. Diabetes. 2017;66:815–22.

    Article  Google Scholar 

  9. Gastaldelli A, Gaggini M, Daniele G, Ciociaro D, Cersosimo E, Tripathy D, et al. Exenatide improves both hepatic and adipose tissue insulin resistance: a dynamic positron emission tomography study. Hepatology. 2016;64:2028–37.

    Article  CAS  Google Scholar 

  10. Ter Horst KW, van Galen KA, Gilijamse PW, Hartstra AV, de Groot PF, van der Valk FM, et al. Methods for quantifying adipose tissue insulin resistance in overweight/obese humans. Int J Obes. 2017;41:1288–94.

    Article  Google Scholar 

  11. Sondergaard E, Espinosa De Ycaza AE, Morgan-Bathke M, Jensen MD. How to measure adipose tissue insulin sensitivity. J Clin Endocrinol Metab. 2017;102:1193–9.

    Article  Google Scholar 

  12. Ryden M, Arner P. Cardiovascular risk score is linked to subcutaneous adipocyte size and lipid metabolism. J Intern Med. 2017;282:220–8.

    Article  CAS  Google Scholar 

  13. Ryden M, Arner P. Subcutaneous adipocyte lipolysis contributes to circulating lipid levels. Arterioscler Thromb Vasc Biol. 2017;37:1782–7.

    Article  CAS  Google Scholar 

  14. Arner P, Ryden M. Fatty acids, obesity and insulin resistance. Obes Facts. 2015;8:147–55.

    Article  CAS  Google Scholar 

  15. Hoffstedt J, Andersson DP, Eriksson Hogling D, Theorell J, Naslund E, Thorell A, et al. Long-term protective changes in adipose tissue after gastric bypass. Diabetes Care. 2017;40:77–84.

    Article  CAS  Google Scholar 

  16. Arner P, Bolinder J, Hellmér J, Engfeldt P. Studies on human fat cell metabolism in small adipose tissue samples. In: Clarke. WL, Larner J, Pohl SL, Eds. Methods in Diabetes Research. Volume II: Clinical Methods. First Edition. New York, Chichester, Brisbane, Toronto, Singapore: Johh Wiley Sons; 1986. p. 233–58.

    Google Scholar 

  17. Arner P, Engfeldt P. Fasting-mediated alteration studies in insulin action on lipolysis and lipogenesis in obese women. Am J Physiol. 1987;253:E193–201.

    Article  CAS  Google Scholar 

  18. Ryden M, Andersson DP, Bergstrom IB, Arner P. Adipose tissue and metabolic alterations: regional differences in fat cell size and number matter, but differently: a cross-sectional study. J Clin Endocrinol Metab. 2014;99:E1870–6.

    Article  CAS  Google Scholar 

  19. Rizza RA, Mandarino LJ, Gerich JE. Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding. Am J Med. 1981;70:169–76.

    Article  CAS  Google Scholar 

  20. Kenakin T. Principles: receptor theory in pharmacology. Trends Pharmacol Sci. 2004;25:186–92.

    Article  CAS  Google Scholar 

  21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  CAS  Google Scholar 

  22. Ferrannini E, Iozzo P, Virtanen KA, Honka MJ, Bucci M, Nuutila P. Adipose tissue and skeletal muscle insulin-mediated glucose uptake in insulin resistance: role of blood flow and diabetes. Am J Clin Nutr. 2018;108:749–58.

    Article  Google Scholar 

  23. Virtanen KA, Lonnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, et al. Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab. 2002;87:3902–10.

    Article  CAS  Google Scholar 

  24. Brown RJ, Yanovski JA. Estimation of insulin sensitivity in children: methods, measures and controversies. Pediatr Diabetes. 2014;15:151–61.

    Article  CAS  Google Scholar 

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Acknowledgements

The excellent technical assistance of Britt-Marie Leijonhufvud, Katarina Hertel, Yvonne Widlund, Eva Sjölin, Kerstin Wåhlén, Ana Maria Suzuki, Thais de Castro-Barbosa, and Gaby Åström is greatly appreciated. The study was supported by grants from Swedish Research Council, Knut and Alice Wallenberg’s foundation, Novo Nordisk Foundation (including the Tripartite Immuno-metabolism Consortium Grant Number NNF15CC0018486 and the MSAM consortium NNF15SA0018346), Stockholm County Council, CIMED, the Strategic Research Program in Diabetes at Karolinska Institutet and the Swedish Society of Medicine.

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  1. Department of Medicine (H7) and Karolinska University Hospital, Karolinska Institutet, 141 86, Stockholm, Sweden

    Mikael Rydén, Daniel P. Andersson & Peter Arner

Authors
  1. Mikael Rydén
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  2. Daniel P. Andersson
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  3. Peter Arner
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Contributions

PA and MR designed the study, wrote the first version of the MS and are the guarantors of the work. All authors analyzed data, contributed to further writing, and accepted the final version of the paper.

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Correspondence to Mikael Rydén or Peter Arner.

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Rydén, M., Andersson, D.P. & Arner, P. Usefulness of surrogate markers to determine insulin action in fat cells. Int J Obes 44, 2436–2443 (2020). https://doi.org/10.1038/s41366-020-0592-9

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