Endocrinol Metab.  2023 Jun;38(3):315-327. 10.3803/EnM.2023.1621.

Association between Serum Amyloid A Levels and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

• Liu T
• Li M
• Cui C
• Zhou J

• KMID: 2543318
• DOI: http://doi.org/10.3803/EnM.2023.1621

Abstract

Background
To date, consistent data have not been reported on the association between serum amyloid A (SAA) levels and type 2 diabetes mellitus (T2DM). The purpose of this study was to systematically summarize their relationship.
Methods
Databases including PubMed, Cochrane Library, Embase, Web of Science, and MEDLINE were searched until August 2021. Cross-sectional and case-control studies were included.
Results
Twenty-one studies with 1,780 cases and 2,070 controls were identified. SAA levels were significantly higher in T2DM patients than in healthy groups (standardized mean difference [SMD], 0.68; 95% confidence interval [CI], 0.39 to 0.98). A subgroup analysis showed that the mean age of participants and the continent that participants were from were related to differences in SAA levels between cases and controls. Furthermore, in T2DM patients, SAA levels were positively associated with body mass index (r=0.34; 95% CI, 0.03 to 0.66), triglycerides (r=0.12; 95% CI, 0.01 to 0.24), fasting plasma glucose (r=0.26; 95% CI, 0.07 to 0.45), hemoglobin A1c (r=0.24; 95% CI, 0.16 to 0.33), homeostasis model assessment for insulin resistance (r=0.22; 95% CI, 0.10 to 0.34), C-reactive protein (r=0.77; 95% CI, 0.62 to 0.91), and interleukin-6 (r=0.42; 95% CI, 0.31 to 0.54), but negatively linked with highdensity lipoprotein cholesterol (r=–0.23; 95% CI, –0.44 to –0.03).
Conclusion
The meta-analysis suggests that high SAA levels may be associated with the presence of T2DM, as well as lipid metabolism homeostasis and the inflammatory response.

Keyword

Serum amyloid A protein; Diabetes mellitus, type 2; Metabolism; Inflammation; Meta-analysis

Figure

• 

  Fig. 1. Flow chart for screening articles. SAA, serum amyloid A; SD, standard deviation.

• 

  Fig. 2. Forest plot of differences in serum amyloid A levels between patients with type 2 diabetes mellitus (T2DM) and healthy controls. SMD, standardized mean difference; CI, confidence interval.

• 

  Fig. 3. The sensitivity analysis of differences in serum amyloid A levels between patients with type 2 diabetes mellitus and healthy controls. CI, confidence interval.

• 

  Fig. 4. Correlations of serum amyloid A levels with cardiometabolic risk factors in patients with type 2 diabetes mellitus. CI, confidence interval; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment for insulin resistance; CRP, C-reactive protein; IL-6, interleukin-6.

• 

Reference

1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010; 87:4–14.

2. Tseng KH. Standards of medical care in diabetes 2006: response to the American Diabetes Association. Diabetes Care. 2006; 29:2563–4.

3. Tomkin GH. Atherosclerosis, diabetes and lipoproteins. Expert Rev Cardiovasc Ther. 2010; 8:1015–29.

4. Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol. 2016; 94:146–50.

5. Halim M, Halim A. The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes). Diabetes Metab Syndr. 2019; 13:1165–72.

6. Zhang Y, Zhang J, Sheng H, Li H, Wang R. Acute phase reactant serum amyloid A in inflammation and other diseases. Adv Clin Chem. 2019; 90:25–80.

7. Zhou J, Sheng J, Fan Y, Zhu X, Tao Q, He Y, et al. Association between serum amyloid A levels and cancers: a systematic review and meta-analysis. Postgrad Med J. 2018; 94:499–507.

8. Malle E, Sodin-Semrl S, Kovacevic A. Serum amyloid A: an acute-phase protein involved in tumour pathogenesis. Cell Mol Life Sci. 2009; 66:9–26.

9. Chen C, Chai H, Wang X, Jiang J, Jamaluddin MS, Liao D, et al. Soluble CD40 ligand induces endothelial dysfunction in human and porcine coronary artery endothelial cells. Blood. 2008; 112:3205–16.

10. Ronsein GE, Vaisar T. Inflammation, remodeling, and other factors affecting HDL cholesterol efflux. Curr Opin Lipidol. 2017; 28:52–9.

11. Vallon R, Freuler F, Desta-Tsedu N, Robeva A, Dawson J, Wenner P, et al. Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases. J Immunol. 2001; 166:2801–7.

12. Song C, Hsu K, Yamen E, Yan W, Fock J, Witting PK, et al. Serum amyloid A induction of cytokines in monocytes/macrophages and lymphocytes. Atherosclerosis. 2009; 207:374–83.

13. Zhao Y, He X, Shi X, Huang C, Liu J, Zhou S, et al. Association between serum amyloid A and obesity: a meta-analysis and systematic review. Inflamm Res. 2010; 59:323–34.

14. Zhou J, Dai Y, Lin Y, Chen K. Association between serum amyloid A and rheumatoid arthritis: a systematic review and meta-analysis. Semin Arthritis Rheum. 2022; 52:151943.

15. Zhou J, Lu Y, Wang S, Chen K. Association between serum amyloid A levels and coronary heart disease: a systematic review and meta-analysis of 26 studies. Inflamm Res. 2020; 69:331–45.

16. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25:603–5.

17. Johnson BD, Kip KE, Marroquin OC, Ridker PM, Kelsey SF, Shaw LJ, et al. Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004; 109:726–32.

18. Liu T, Li G, Li L, Korantzopoulos P. Association between C-reactive protein and recurrence of atrial fibrillation after successful electrical cardioversion: a meta-analysis. J Am Coll Cardiol. 2007; 49:1642–8.

19. Liu T, Li L, Korantzopoulos P, Goudevenos JA, Li G. Meta-analysis of association between C-reactive protein and immediate success of electrical cardioversion in persistent atrial fibrillation. Am J Cardiol. 2008; 101:1749–52.

20. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5:13.

21. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005; 28:123–37.

22. Ebtehaj S, Gruppen EG, Parvizi M, Tietge UJ, Dullaart RP. The anti-inflammatory function of HDL is impaired in type 2 diabetes: role of hyperglycemia, paraoxonase-1 and low grade inflammation. Cardiovasc Diabetol. 2017; 16:132.

23. Yang LY, Yu CG, Wang XH, Yuan SS, Zhang LJ, Lang JN, et al. Angiopoietin-like protein 4 is a high-density lipoprotein (HDL) component for HDL metabolism and function in nondiabetic participants and type-2 diabetic patients. J Am Heart Assoc. 2017; 6:e005973.

24. Griffiths K, Pazderska A, Ahmed M, McGowan A, Maxwell AP, McEneny J, et al. Type 2 diabetes in young females results in increased serum amyloid A and changes to features of high density lipoproteins in both HDL2 and HDL3. J Diabetes Res. 2017; 2017:1314864.

25. Zhao D, Yang LY, Wang XH, Yuan SS, Yu CG, Wang ZW, et al. Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients. Cardiovasc Diabetol. 2016; 15:132.

26. Moura Neto A, Parisi MC, Tambascia MA, Pavin EJ, Alegre SM, Zantut-Wittmann DE. Relationship of thyroid hormone levels and cardiovascular events in patients with type 2 diabetes. Endocrine. 2014; 45:84–91.

27. Hatanaka E, Monteagudo PT, Marrocos MS, Campa A. Interaction between serum amyloid A and leukocytes: a possible role in the progression of vascular complications in diabetes. Immunol Lett. 2007; 108:160–6.

28. Karlsson HK, Tsuchida H, Lake S, Koistinen HA, Krook A. Relationship between serum amyloid A level and Tanis/SelS mRNA expression in skeletal muscle and adipose tissue from healthy and type 2 diabetic subjects. Diabetes. 2004; 53:1424–8.

29. Muller S, Martin S, Koenig W, Hanifi-Moghaddam P, Rathmann W, Haastert B, et al. Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia. 2002; 45:805–12.

30. Catalan V, Gomez-Ambrosi J, Ramirez B, Rotellar F, Pastor C, Silva C, et al. Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obes Surg. 2007; 17:1464–74.

31. Leinonen ES, Hiukka A, Hurt-Camejo E, Wiklund O, Sarna SS, Mattson Hulten L, et al. Low-grade inflammation, endothelial activation and carotid intima-media thickness in type 2 diabetes. J Intern Med. 2004; 256:119–27.

32. Morgantini C, Natali A, Boldrini B, Imaizumi S, Navab M, Fogelman AM, et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes. 2011; 60:2617–23.

33. Murakami H, Tanabe J, Tamasawa N, Matsumura K, Yamashita M, Matsuki K, et al. Reduction of paraoxonase-1 activity may contribute the qualitative impairment of HDL particles in patients with type 2 diabetes. Diabetes Res Clin Pract. 2013; 99:30–8.

34. Yassine HN, Trenchevska O, He H, Borges CR, Nedelkov D, Mack W, et al. Serum amyloid A truncations in type 2 diabetes mellitus. PLoS One. 2015; 10:e0115320.

35. Tsun JG, Shiu SW, Wong Y, Yung S, Chan TM, Tan KC. Impact of serum amyloid A on cellular cholesterol efflux to serum in type 2 diabetes mellitus. Atherosclerosis. 2013; 231:405–10.

36. Du JL, Sun CK, Lu B, Men LL, Yao JJ, An LJ, et al. Association of SelS mRNA expression in omental adipose tissue with Homa-IR and serum amyloid A in patients with type 2 diabetes mellitus. Chin Med J (Engl). 2008; 121:1165–8.

37. Stettler C, Witt N, Tapp RJ, Thom S, Allemann S, Tillin T, et al. Serum amyloid A, C-reactive protein, and retinal microvascular changes in hypertensive diabetic and nondiabetic individuals: an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy. Diabetes Care. 2009; 32:1098–100.

38. Turgutalp K, Ozhan O, Helvaci I, Ata A, Arican A, Boztepe B, et al. Serum levels of cancer biomarkers in diabetic and non-diabetic proteinuric patients: a preliminary study. Clin Chem Lab Med. 2013; 51:889–95.

39. Kumon Y, Suehiro T, Itahara T, Ikeda Y, Hashimoto K. Serum amyloid A protein in patients with non-insulin-dependent diabetes mellitus. Clin Biochem. 1994; 27:469–73.

40. Wu TL, Tsai IC, Chang PY, Tsao KC, Sun CF, Wu LL, et al. Establishment of an in-house ELISA and the reference range for serum amyloid A (SAA): complementarity between SAA and C-reactive protein as markers of inflammation. Clin Chim Acta. 2007; 376:72–6.

41. Chen FQ, Wang J, Liu XB, Ma XY, Zhang XB, Huang T, et al. Levels of inflammatory cytokines in type 2 diabetes patients with different urinary albumin excretion rates and their correlation with clinical variables. J Diabetes Res. 2013; 2013:138969.

42. Leinonen E, Hurt-Camejo E, Wiklund O, Hulten LM, Hiukka A, Taskinen MR. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis. 2003; 166:387–94.

43. Poitou C, Viguerie N, Cancello R, De Matteis R, Cinti S, Stich V, et al. Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition. Diabetologia. 2005; 48:519–28.

44. Engin A. The pathogenesis of obesity-associated adipose tissue inflammation. Adv Exp Med Biol. 2017; 960:221–45.

45. Permana PA, Menge C, Reaven PD. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun. 2006; 341:507–14.

46. Scheja L, Heese B, Zitzer H, Michael MD, Siesky AM, Pospisil H, et al. Acute-phase serum amyloid A as a marker of insulin resistance in mice. Exp Diabetes Res. 2008; 2008:230837.

47. Fletcher B, Gulanick M, Lamendola C. Risk factors for type 2 diabetes mellitus. J Cardiovasc Nurs. 2002; 16:17–23.

48. Wright SM, Aronne LJ. Causes of obesity. Abdom Imaging. 2012; 37:730–2.

49. Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat Rev Clin Oncol. 2017; 14:85–99.

50. Niswender K. Diabetes and obesity: therapeutic targeting and risk reduction: a complex interplay. Diabetes Obes Metab. 2010; 12:267–87.

51. Du JL, Liu JF, Men LL, Yao JJ, Sun LP, Sun GH, et al. Effects of five-year intensive multifactorial intervention on the serum amyloid A and macroangiopathy in patients with shortduration type 2 diabetes mellitus. Chin Med J (Engl). 2009; 122:2560–6.

52. Hu Y, Tong G, Xu W, Pan J, Ryan K, Yang R, et al. Anti-inflammatory effects of simvastatin on adipokines in type 2 diabetic patients with carotid atherosclerosis. Diab Vasc Dis Res. 2009; 6:262–8.

53. Kluppelholz B, Thorand B, Koenig W, de Las Heras Gala T, Meisinger C, Huth C, et al. Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study. Diabetologia. 2015; 58:2269–77.

54. Urieli-Shoval S, Linke RP, Matzner Y. Expression and function of serum amyloid A, a major acute-phase protein, in normal and disease states. Curr Opin Hematol. 2000; 7:64–9.