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EPM Tools - Progression to Diabetes - Inflammatory Markers
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Inflammatory Markers and Risk of Developing Type Diabetes Mellitus in Women

Diabetes 53:693-700, 2004

  1. Baseline levels of:

    • Tumor necrosis factor (TNF)-alpha receptor 2
    • Interleukin (IL)-6
    • C-Reactive Protein (CRP)
    • were significantly higher among women who progressed on to Diabetes than those who did not.

  2. After adjusting for BMI and other lifestyle factors, all three biomarkers significantly predicted diabetes risk.

  3. The data support the role of inflammation in the pathogenesis of type 2 Diabetes.

  4. Elevated CRP levels are a strong independent predictor of type 2 diabetes and may mediate association to TNF-alpha R2 and IL-6.

  5. Elevated adiposity is the most important risk factor for the development of insulin resistance and type 2 diabetes.

    • Obesity may be an inflammatory condition.
    • Inflammatory cytokines secreted by adipose tissue exert an endocrine effect conferring insulin resistance in liver, skeletal muscle and vascular endothelial tissue.
    • Elevated adipocyte cytokines, such as TNF-alpha and IF-6 leads to an acute-phase response with increased hepatic production of CRP.
    • CRP, TNF-alpha and IL-6, not only promote insulin resistance, but stimulate endothelial production of adhesion molecule such as:

      1. E-selectin
      2. intercellular adhesion molecute-1 (CAM-1)
      3. vascular adhesion molecure-1 (VCAM-1)
      4. critical mediators of endothelial dysfunction in capillary and arteriolar endothelium.

  6. Women who developed diabetes had higher

    • BMI
    • Wasit circumference
    • Wasit-to-hip ratio
    • Lower levels of physical activity
    • Lower intake of cereal fiber
    • More likely to have family history of diabetes
    • Slightly more likely to use aspirin
    • Higher levels of:

      1. TNR-alpha R2
      2. CRP
      3. IL-6
      4. ICAM-1
      5. E-selectin
      6. Fasting insulin

    • Markers of endothelium dysfunction, especially E-selectin, significantly predicted risk of type 2 diabetes.

    • TNR-alphaR2 significantly predicted diabetes risk among women with:

      1. Non-obese
      2. lower physical activity levels
      3. a lower diet score
      4. no family history of diabetes.

Concept of atherosclerosis as an inflammatory disease is well established.

  1. Elevated CRP are associated with

    • Obesity
    • Insulin resistance
    • Glucose intolerance

  2. CRP was an independent predictor of metabolic syndrome and type 2 diabetes in women but not in men.

  3. These data support the hypothesis that low-grade systemic inflammation is a common antecedent for both type 2 diabetes and CVD.

  4. The inflammatory role of CRP may be mitigated by aspirin use.

Biological mechanisms through which CRP increases risk of type 2 diabetes not well understood.

  1. Elevated CRP is a marker of low-grade inflammation

  2. CRP may have indirect influence on insulin resistance and insulin secretion through altered innate immune response.

  3. Elevated CRP stimulates endothelial production of E-Selectin, ICAM-1 and VCAM-1 important mediators of:

    • impaired vascular reactivity,
    • reduced insulin delivery and
    • increased peripheral insulin resistance.

  4. The association between CRP and type 2 diabetes may simply reflect underlying endothelial dysfunction and subclinical atherosclerosis

  5. However, this study shows that CRP acts independent of E-selectin.

  6. Combination of higher CRP and E-selectin confers the greatest risk of diabetes.

Production of CRP is regulated by inflammatory cytokines such as TNR-alpha and IL-6.

  1. Association between CRP and diabetes may partly reflect the detrimental affects of cytokines.

  2. Adipose tissue is a major source of endogenous TNR-alpha production.

  3. TNF-alpha may be a critical mechanism by which fat cells induce peripheral insulin resistance.

  4. TNF-alpha may mediate insulin resistance through indirect effects including increasing free fatty acid oxidation, stimulation of insulin counter regulatory hormones or cytokines, impairment of endothelia function or direct inhibitory effects on glucose transporter protein (GLUT4).

Conclusion

  1. Elevated CRP levels in apparently healthy subjects may help to identiy high-risk populations for obt type 2 diabetes and CVD

  2. Elevated CRP can serve as a common target for lifstyl and therapeutic interventions for these two conditions.

  3. Lower CRP with

    • Exercise
    • Weight loss
    • Statins
    • ACE inhibitors

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