The role of inflammation in diabetes and its complications.

The contribution of inflammation to morbidity in the closely related conditions of cardiovascular disease, obesity, the metabolic syndrome, and type 2 diabetes has been the focus of extensive research and intense speculation over the past decade. (1,2) Many inflammatory markers such as C-reactive protein (CRP), fibrinogen, the interleukins, tumor necrosis factor-[alpha], tissue-type plasminogen activator, and serum amyloid A have been included in the ever-expanding list of emerging or "nontraditional" risk factors for the atherosclerotic process, (3) and they may represent underlying oxidative stress and generation of free radicals that promote damage to the vascular wall. Endothelial injury, plaque rupture, and atherothrombosis are believed to be related by a series of mutually-related cascades that lead to adverse macrovascular (coronary, cerebrovascular, and peripheral vascular) outcomes. (4) Histologic and pathophysiologic studies have established a significant inflammatory component against the back-drop of a complex interplay of clinically recognizable risk factors (for example, hypertension, hyperglycemia, dyslipidemia, obesity, and smoking). (5)

Some of the inflammatory proteins, especially CRP, have been shown to predict, and correlate independently with, major cardiovascular endpoints such as myocardial infarction and death. (6,7) Nonetheless, their use is controversial, and the situation has been further confused and complicated by divergent recommendations. (8,9) Advocates argue that testing individuals at moderate risk for cardiovascular disease would help to stratify risk status. Skeptics, on the other hand, contend that the role of these acute-phase reactants in disease causation is murky, that screening would not add any meaningful information or lead to a change in management strategy for the majority of patients tested, and that a specific and proven therapeutic intervention targeting these markers alone is lacking. In short, the question is whether the new substances are merely measurable markers of a generalized, chronic vasculotoxic pattern, or actual etiologic targets for therapy; this distinction is critical for determining the validity of any screening, assessment, and treatment methodology. By linking cardiovascular disease to obesity and type 2 diabetes, the "common-soil" hypothesis makes inflammation pertinent. (10) Insulin resistance and beta cell dysfunction are prominent in the evolution of glucose intolerance. The concepts of "glucotoxicity" and "lipotoxicity" implicate hyperglycemia and elevated free fatty acids, respectively, in the inexorable progression of type 2 diabetes.

Prospective studies show that low-grade systemic inflammation is associated with not only the development of diabetes but also with its large-vessel and microvascular complications. (11,12) Retinopathy and nephropathy are linked to increased levels of inflammatory markers in both type 1 and type 2 diabetes. (13-15) There continue to be conflicting opinions regarding the significance of this relationship, however. From a therapeutic standpoint, does CRP measurement in diabetics provide information beyond what is obtained through the established risk factors? Increased body mass index (BMI) alone, regardless of the presence of the metabolic syndrome or diabetes, accounted for the bulk of the proinflammatory picture in some analyses. (16) The need for better identification of genetic, biochemical, and imaging risk indicators has been emphasized before screening can be advocated. (17) Similarly, hypercoagulability states and hemostatic factors like fibrinogen have been postulated to play a pathologic role in the development of diabetic complications, ostensibly through abnormal rheology and elevated blood viscosity. (18,19) Nevertheless, controversy about a true correlation and its clinical significance seems to rage on.

In this issue of the Southern Medical Journal, Takebayashi (20) report their findings in 73 Japanese patients with sub-optimally controlled type 2 diabetes in which correlations were made between circulating inflammatory markers (CRP and fibrinogen) and the presence of microvascular complications (microalbuminuria, retinopathy, and autonomic neuropathy) as well as large-vessel atherosclerosis (using carotid intimal-medial thickness measurements). The latter did not show an association with either marker, while among the traditional cardiovascular risk factors only dyslipidemia showed a relation with fibrinogen. With respect to small-vessel disease, an interesting dichotomy was seen. CRP failed to show an association with microangiopathy: on the contrary, fibrinogen levels were positively associated with the presence of microvascular complications. These observations reinforce similar results shown by Streja et al (21) where fibrinogen, but not CRP, was significantly associated with microvascular disease. The current study provides evidence that these findings may also be true in other genetic and ethnic populations. The effect of race on variation in inflammatory markers has been noted previously in Caucasians and African-Americans. (17) The lack of a strong correlation between metabolic factors and inflammation is a finding in the present report that is in dispute with some other studies. (18,21)

Limitations of this study include its nonprospective nature and the possible confounding effect of differences in age, weight, and glycemic control. Although some patients were overweight, the average BMI was within the normal range, probably reflecting the typical Japanese patient with type 2 diabetes. Therefore the effect of obesity, as measured in Western societies, cannot be ascertained. (To be sure, it is not clear if uniform standards of BMI apply globally in relation to cardiovascular and diabetic morbidity.) It is tempting to conclude from the study of Takebayashi that CRP appears not to be a discriminatory factor for diabetic complications, although it probably has a pathogenetic role at the level of the vascular endothelium. Elevated fibrinogen, on the other hand, may offer a clue to the propensity to microvascular complications in patients with diabetes. It would be premature to speculate about firm recommendations for its utility, since means of screening and follow up for microvascular complications are widely known and easily available.

How does the additional knowledge gained through this and other similar studies translate into clinically useful information for practitioners? Besides providing a window into the complicated world of inflammation and the diabetic vasculature, they remind us to stay cautious, rather than being over zealous, in our quest for meaningful answers. Additional studies, ideally performed in a prospective, randomized, and interventional manner, are necessary before the big secrets of the inflammatory markers are unraveled for the benefits of our patients. (22) In the meantime, the proven and tested recommendations of employing a multifactorial approach in the treatment of diabetes (23) and related disorders through optimal management of the well-known, "traditional" risk factors remains good advice.

References

1. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other markers of inflammation in the prediction of coronary artery disease. N Engl J Med 2004;350:1387-1397.

2. Wannamethee SG, Lowe GD, Shaper AG, et al. Insulin resistance, haemostatic and inflammatory markers and coronary heart disease risk factors in type 2 diabetic men with and without coronary heart disease. Diabetalogia 2004;47(9):1557-1565.

3. Muntner P, He J, Chen J, Fonseca V, Whelton PK. Prevalence of non-traditional cardiovascular risk factors among persons with impaired fasting glucose, impaired glucose tolerance, diabetes, and the metabolic syndrome: analysis of the Third National Health and Nutrition Examination Survey (NHANES III). Ann Epidemiol 2004;14:686-695.

4. Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance. Am J Cardiol. 2003;92:10J-17J.

5. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.

6. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979. (Erratum, N Engl J Med 1997;337:356).

7. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565.

8. Mosca L. C-reactive protein--to screen or not to screen? N Engl J Med 2002;347:1615-1617.

9. Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA 2003;290:932-940.

10. Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vase Biol 2004;24:816-823.

11. Freeman DJ, Norrie J, Caslake MJ, et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002;51:1596-1600.

12. Pradhan A, Manson J, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327-334.

13. Asakawa H, Tokunaga K, Kawakami F. Elevation of fibrinogen and thrombin-antithrombin III complex levels of type 2 diabetes patients with retinopathy and nephropathy. J Diabetes Complications 2000;14(3):121-126.

14. Saraheimo M, Teppo AM, Forsblom C, et al. Diabetic nephropathy is associated with low-grade inflammation in type 1 diabetic patients. Diabetalogia 2003;46:1402-1407.

15. Stehouwer CDA, Gall M, Twisk JWR, et al. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes. Progressive, interrelated, and independently associated with risk of death. Diabetes 2002;51:1157-1165.

16. Duncan BB, Schmidt MI, Pankow JI, et al. Low-grade systemic inflammation and the development of type 2 diabetes. The Atherosclerosis Risk in Communities study. Diabetes 2003;52:1799-1805.

17. Tall AR. C-reactive protein reassessed. N Engl J Med 2004;350:1450-1452.

18. Bruno G, Cavallo-Perin P, Bargero G, et al. Hyperfibrinogenemia and metabolic syndrome in type 2 diabetes: a population-based study. Diabetes Metab Res Rev 2001;17(2):124-130.

19. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001;15(1):44-54.

20. Takebayashi, K, et al. High-sensitivity C-reactive protein & plasma fibrinogen show different specificities as markers of individual complications in patients with type 2 diabetes. South Med J 2006;99:23-27.

21. Streja D, Cressey P, Rabkin SW. Associations between inflammatory markers, traditional risk factors, and complications in patients with type 2 diabetes mellitus. J Diabetes Complications 2003;17:120-127.

22. Bhatt DL, Topol EJ. Need to test the inflammation hypothesis. Circulation 2002;106:136-140.

23. Gaede P, Vedel P, Larsen N, et al. Multufactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393.

Ali A. Rizvi, MD

From the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of South Carolina School of Medicine, Columbia, SC.

Reprint requests to Ali A. Rizvi, MD, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of South Carolina School of Medicine, Two Medical Park, Suite 502, Columbia, SC 29203. Email: [e-mail]

Accepted April 20, 2005.