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Articles in PresS, published online ahead of print November 13, 2001
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00444.2001
Submitted on October 3, 2001
Accepted on November 7, 2001
1 Endocrinology, Hospital Dr Josep Trueta, Girona, Spain
2 Endocrinology, Hospital Dr Josep Trueta, Girona, Spain; Immunology, University of Barcelona, Barcelona, Spain
3 Endocrinology, Hospital Joan XXIII de Tarragona, Tarragona, Spain
4 Endocrinology, Hospital de Sant Pau, Barcelona, Spain
5 Internal Medicine, Hospital Dr Josep Trueta, Girona, Spain
6 Immunology, University of Barcelona, Barcelona, Spain
* To whom correspondence should be addressed. E-mail: endocrino{at}htrueta.scs.es.
Abnormalities in immune system function and inflammatory mediators have been described in both hypertension and type 2 diabetes mellitus. Tumor necrosis factor-alpha (TNF-alpha) is increasingly recognized as a key component in the development of insulin resistance and increased blood pressure. In a sample of 368 individuals, the ratio of soluble TNF-alpha receptors (sTNFR2/sTNFR1) correlated positively with systolic (SBP) and diastolic (DBP) blood pressure (p<0.01). This ratio was significantly greater in type 2 diabetic subjects (DM-2) than in type 1 diabetic patients, and in both greater than in control nondiabetic subjects (p<0.00001). We studied shedding (flow cytometry) of TNF-alpha receptors 1 and 2 (TNF-R1 and TNF-R2) in association with insulin resistance and vascular dysfunction (high-resolution ultrasound) in DM-2 patients. The differences in sTNFR2/sTNFR1 ratio were mainly due to decreased circulating sTNFR1 levels in DM-2 in comparison with age and BMI-matched control subjects (p=0.001). The TNF-R1 density in peripheral blood monocytes were similar in DM-2 patients than in nondiabetic subjects. After phorbol 12 myristate 13-acetate (PMA), TNF-R1 shedding was significantly decreased in DM-2 compared with control subjects and it was directly associated with insulin sensitivity (r=0.54, p=0.03). Serum sTNFR1 concentration was also linked to the vasodilatory response to glyceryl-trinitrate (p=0.01). Conversely, TNF-R2 shedding was negatively associated with insulin sensitivity (r=-0.54, p=0.03) while shedding of L-selectin showed no significant associations. After exercise-induced lowering of blood pressure (objectived during a twenty-four-hour ambulatory blood pressure recording) we observed a parallel decrease of the sTNFR2/sTNFR1 ratio in DM-2 patients. Our findings suggest that insulin resistance and blood pressure are linked to altered shedding of TNF-alpha receptors in DM-2. The latter seems reversible and not genetically determined.
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