Clustering of Insulin Resistance With Vascular Dysfunction and Low-Grade Inflammation in Type 2 Diabetes

  1. Andrea Natali1,
  2. Elena Toschi1,
  3. Stephanie Baldeweg2,
  4. Demetrio Ciociaro1,
  5. Stefania Favilla1,
  6. Luigi Saccà3 and
  7. Ele Ferrannini1
  1. 1Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa, Pisa, Italy
  2. 2Department of Medicine, University College London, London, U.K
  3. 3Department of Internal Medicine and Cardiovascular Sciences, “Federico II” University, Naples, Italy
  1. Address correspondence and reprint requests to Dr. Andrea Natali, Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. E-mail: anatali{at}


Vascular dysfunction, low-grade inflammation, insulin resistance, and impaired fibrinolysis have each been reported to be present in type 2 diabetes, but their relationships, and the role of obesity, have not been investigated. We measured insulin sensitivity (euglycemic clamp), forearm blood flow responses to graded local acetylcholine (Ach) and sodium nitroprusside (SNP) infusions, plasma concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), and high-sensitivity C-reactive protein (hs-CRP) in 81 diabetic patients. When patients were stratified by insulin resistance, more severe insulin resistance was associated (P < 0.05) with overweight, central fat distribution, hypertension, and dyslipidemia (with similar sex distribution, age, fasting plasma glucose, and HbA1c). With regard to vascular function, both endothelium-dependent (Ach) (−22, −40, and −52%; P < 0.0001) and -independent (SNP) (−3, −7, and −27%; P < 0.02) vasodilatation were progressively reduced across insulin resistance tertiles. In multivariate analysis, inflammatory markers (IL-6, hs-CRP, and TNF-α) were independently associated with insulin resistance and fasting glycemia, fibrinolytic markers PAI-1 and tPA with insulin resistance and central fat distribution, and vascular indexes (vWF, Ach, and SNP vasodilation) with insulin resistance and obesity or cytokines (TNF-α or IL-6). In type 2 diabetes, insulin resistance is associated with vascular dysfunction/damage, impaired fibrinolysis, and low-grade inflammation independently of obesity and poor glycemic control.


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    • Accepted January 17, 2006.
    • Received August 19, 2005.
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