Abstract
Patients with type 2 diabetes (T2DM) are known at risk for developing cardiovascular disease (CVD), nephropathy, and cancer. We were interested to find out whether multiple markers associated with chronic inflammation are detectable in patients with T2DM and are increased in patients with T2DM who developed additional clinical complications. A sequence of multiple risk markers for atherogenesis, associated with chronic inflammation, was measured in patients with T2DM before and after the development of clinical complications. We found that multiple clinical complications frequently developed simultaneously in patients with T2DM. At the early stage of T2DM, only low levels and low percent elevations of multiple risk markers were detected. However, both the level and the percent elevation of these markers were found to increase with disease progression and the development of clinical complications. We believe that chronic inflammation not only contributes to the pathogenesis of T2DM but also continues to increase in T2DM patients who are developing additional clinical complications. It appears that these multiple markers are potentially useful not only for monitoring the progression of T2DM but also predicting the risk of developing macro‐ and microvascular disease, nephropathy, and cancer. J. Clin. Lab. Anal. 22:6–13, 2008. © 2008 Wiley‐Liss, Inc.
Keywords: type 2 diabetes, chronic inflammation, inflammation markers, nephropathy, cancer, macrovascular disease, microvascular disease
| Abbreviations | |
|---|---|
| CVD | cardiovascular disease |
| CRP | C‐reactive protein |
| ELISA | enzyme linked immunoassay |
| Hcy | homocysteine |
| PVD | peripheral vascular disease |
| uMA | urinary microalbumin |
| VCAM‐1 | vascular cell adhesion molecule |
| IL‐6 | interleukin 6 |
| ICAM‐1 | intracellular adhesion molecule |
| T2DM | type 2 diabetes mellitus |
| UA | uric acid |
| uMA | urinary microalbumin |
REFERENCES
- 1. Caballero AE. Endothelial dysfunction, inflammation, and insulin resistance: a focus on subjects at risk for type 2 diabetes. Curr Diab Rep 2004;4:237–246. [DOI] [PubMed] [Google Scholar]
- 2. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes [Review]. Diabetes Care 2004;27:813–823. [DOI] [PubMed] [Google Scholar]
- 3. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–126. [DOI] [PubMed] [Google Scholar]
- 4. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109 (Suppl 1):II2–II10. [DOI] [PubMed] [Google Scholar]
- 5. Yao Q, Axelsson J, Stenvinkel P, Lindholm B. Chronic systemic inflammation in dialysis patients: an update on causes and consequences. ASAIO J 2004;50:lii–lvii. [DOI] [PubMed] [Google Scholar]
- 6. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006;12:5910–5918. [DOI] [PubMed] [Google Scholar]
- 7. Gabay C, Kushner I. Acute‐phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–454. [DOI] [PubMed] [Google Scholar]
- 8. Konig P, Goldstein D, Poehlmann M, Rife D, Ge B, Hewett J. Effect of nebulized albuterol on blood glucose in patients with diabetes mellitus with and without cystic fibrosis. Pediatr Pulmonol 2005;40:105–108. [DOI] [PubMed] [Google Scholar]
- 9. Altman P. Risk factors in coronary atherosclerosis athero‐inflammation: the meeting point. Thromb J 2003;1:4–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Gonzalez‐Gay MA, Gonzalez‐Juanatey C, Pineiro A, Garcia‐Porrua C, Testa A, Llorca J. High‐grade C‐reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005;32:1219–1223. [PubMed] [Google Scholar]
- 11. Beck JD, Pankow J, Tyroler HA, Offenbacher S. Dental infections and atherosclerosis. Am Heart J 1999;138:S528–S533. [DOI] [PubMed] [Google Scholar]
- 12. Lane JT. Microalbuminuria as a marker of cardiovascular and renal risk in type 2 diabetes mellitus: a temporal perspective. Am J Physiol Renal Physiol 2004;286:F442–F450. [DOI] [PubMed] [Google Scholar]
- 13. Caballero AE. Endothelial dysfunction, inflammation, and insulin resistance: a focus on subjects at risk for type 2 diabetes. Curr Diab Rep 2004;4:237–246. [DOI] [PubMed] [Google Scholar]
- 14. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111–1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Rossing P. Prediction, progression and prevention of diabetic nephropathy. The Minkowski Lecture 2005. Diabetologia 2006;49:11–19. [DOI] [PubMed] [Google Scholar]
- 16. Ziegler D. Type 2 diabetes as an inflammatory cardiovascular disorder. Curr Mol Med 2005;5:309–322. [DOI] [PubMed] [Google Scholar]
- 17. Leinonen ES, Hiukka A, Hurt‐Camejo E, et al. Low‐grade inflammation, endothelial activation and carotid intima‐media thickness in type 2 diabetes. J Intern Med 2004;256:119–127. [DOI] [PubMed] [Google Scholar]
- 18. Wu JT, Wu LL. Linking inflammation and atherogenesis: soluble markers identified for the detection of risk factors and for early risk assessment. Clin Chim Acta 2006;366:74–80. [DOI] [PubMed] [Google Scholar]
- 19. Wu JT, Wu LL. Association of soluble markers with various stages and major events of atherosclerosis [Review]. Ann Clin Lab Sci 2005;35:240–250. [PubMed] [Google Scholar]
- 20. Wu T‐L, Chang P‐Y, Li C‐N, Tsao K‐C, Sun C‐F, Wu JT. Development of ELISA on microplate for C‐reactive protein and establishment of age‐dependent normal reference range. Clin Chim Acta 2002;322:163–166. [DOI] [PubMed] [Google Scholar]
- 21. Chang P‐Y, Wu T‐L, Tsao K‐C, Li CC, Sun CF, Wu JT. Establishment of ELISAs on microplate for soluble VCAM‐1 and ICAM. Ann Clin Lab Sci 2005;35:312–317. [PubMed] [Google Scholar]
- 22. Tsao K‐C, Chang P‐Y, Li CC, Wu T‐L, Sun C‐F, Wu JT. Development of an ELISA on microplate for circulating E‐selectin: assay characterization, comparison with commercial kit and establishment of normal reference values. J Clin Lab Anal 2003;17:97–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Wu T‐L, Sun YC, Hung CC, Chang PY, Wu JT. Development of an ELISA for serum IL‐6 and determination of its serum level in healthy person and patients with type 2 diabetes. Clin Chem 2005;51:A7. [Google Scholar]
- 24. Wu TL, Chang PY, Li CC, Tsao KC, Sun CF, Wu JT. Microplate ELISA for urine microalbumin: reference values and results in patients with type 2 diabetes and cardiovascular disease. Ann Clin Lab Sci 2005:35:149–154. [PubMed] [Google Scholar]
- 25. Chan EC, Chang PY, Wu TL, Wu JT. Enzymatic assay of homocysteine on microtiter plates or a TECAN analyzer using crude lysate containing recombinant methionine µ‐lyase. Ann Clin Lab Sci 2005;35:155–160. [PubMed] [Google Scholar]
- 26. Short RA, Johnson RJ, Tuttle KR. Uric acid, microalbuminuria and cardiovascular events in high‐risk patients. Am J Nephrol 2005;25:36–44. [DOI] [PubMed] [Google Scholar]
- 27. Gori AM, Corsi AM, Fedi S, et al. A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am J Clin Nutr 2005;82:335–341. [DOI] [PubMed] [Google Scholar]
- 28. Leyva F, Anker SD, Godsland IF, et al. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 1998;19:1814–1822. [DOI] [PubMed] [Google Scholar]
- 29. Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy. Circulation 2003;108:250–252. [DOI] [PubMed] [Google Scholar]
- 30. Hayden M, Tyagi S. Uric acid: a new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: the urate redox shuttle. Nutr Metab (Lond) 2004;1:10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Semin Nephrol 2005;25:39–42. [DOI] [PubMed] [Google Scholar]
- 32. Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C‐reactive protein for the treatment of cardiovascular disease. Nature 2006;440:1217–1221. [DOI] [PubMed] [Google Scholar]
- 33. Kitsis RN, Jialal I. Limiting myocardial damage during acute myocardial infarction by inhibiting C‐reactive protein. N Engl J Med 2006;355:513–515. [DOI] [PubMed] [Google Scholar]
- 34. Sironi L, Gianazza E, Gelosa P, et al. Rosuvastatin, but not simvastatin, provides end‐organ protection in stroke‐prone rats by antiinflammatory effects. Arterioscler Thromb Vasc Biol 2005;25:598–603. [DOI] [PubMed] [Google Scholar]