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Am J Physiol Endocrinol Metab 282: E952-E959, 2002. First published November 13, 2001; doi:10.1152/ajpendo.00444.2001
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Vol. 282, Issue 4, E952-E959, April 2002

Shedding of TNF-alpha receptors, blood pressure, and insulin sensitivity in type 2 diabetes mellitus

José-Manuel Fernandez-Real1,2, Begoña Lainez1,3, Joan Vendrell2, Mercedes Rigla4, Antoni Castro5, Georgina Peñarroja5, Montserrat Broch2, Antonio Pérez4, Cristobal Richart2, Pablo Engel3, and Wifredo Ricart1,2

1 Unitat de Diabetologia, Endocrinologia i Nutricio, 5 Servei de Medicina Interna, University Hospital of Girona, 17001 Girona; 2 Unitat de Endocrinologia i Nutricio, University Hospital of Tarragona; Institut d'Estudis Avançats, Tarragona; 3 Immunology Unit, Department of Cellular Biology and Pathology, Institut de Investigació Biomèdica August Pi Sunyer, Medical School, University of Barcelona, Barcelona; and 4 Servei d'Endocrinologia, Hospital de Sant Pau, Barcelona, Spain

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 and diastolic blood pressure (P < 0.01). This ratio was significantly greater in type 2 diabetic subjects (DM-2) than in type 1 diabetic patients and was greater than in control nondiabetic subjects (P < 0.00001). The TNF-alpha receptor 1 (TNFR1) density in peripheral blood monocytes was similar in DM-2 patients and in nondiabetic subjects. After phorbol 12-myristate 13-acetate, TNFR1 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 glyceryltrinitrate (P = 0.01). Conversely, TNF-alpha receptor 2 shedding was negatively associated with insulin sensitivity (r = -0.54, P = 0.03), whereas shedding of L-selectin showed no significant association. After exercise-induced lowering of blood pressure, a parallel decrease in sTNFR2/sTNFR1 was observed 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 is not genetically determined.

vascular dysfunction; exercise; flow cytometry; nitric oxide


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