This Article Full Text Full Text (PDF) All Versions of this Article: 108/15/1815    most recent 01.CIR.0000091406.72832.11v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rask-Madsen, C. Articles by Torp-Pedersen, C. Search for Related Content PubMed PubMed Citation Articles by Rask-Madsen, C. Articles by Torp-Pedersen, C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Hazardous Substances DB GLUCOSE NITRIC OXIDE Related Collections Growth factors/cytokines Type 2 diabetes Endothelium/vascular type/nitric oxide

(Circulation. 2003;108:1815.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Tumor Necrosis Factor- Inhibits Insulin’s Stimulating Effect on Glucose Uptake and Endothelium-Dependent Vasodilation in Humans

Christian Rask-Madsen, MD, PhD; Helena Domínguez, MD; Nikolaj Ihlemann, MD; Thomas Hermann, MD; Lars Køber, MD, DSc; Christian Torp-Pedersen, MD, DSc

From Joslin Diabetes Center (C.R.-M.), Boston, Mass; Department of Cardiology Y (H.D., N.I., T.H. C.T.-P.), Bispebjerg University Hospital, Copenhagen, Denmark; and The Heart Center (L.K.), Rigshospitalet University Hospital, Copenhagen, Denmark.

Correspondence to Christian Rask-Madsen, MD, PhD, Joslin Diabetes Center, Section on Vascular Cell Biology and Complications, One Joslin Place, Room 4504, Boston, MA 02215. E-mail christian.rask-madsen{at}joslin.harvard.edu

Received October 14, 2002; de novo received May 28, 2003; accepted July 17, 2003.

Background— Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)- inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans.

Methods and Results— Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF- were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220±44%. This increase was completely inhibited during coinfusion of TNF- (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF- inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by N^G-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF- was smaller (P<0.001); TNF- had no effect on the SNP response without insulin infusion. Thus, TNF- inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production.

Conclusion— These results support the concept that TNF- could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Key Words: tumor necrosis factor • insulin • acetylcholine • blood flow • endothelium-derived factors

This article has been cited by other articles:

				M. A. ALZadjali, V. Godfrey, F. Khan, A. Choy, A. S. Doney, A. K. Wong, J. R. Petrie, A. D. Struthers, and C. C. Lang Insulin resistance is highly prevalent and is associated with reduced exercise tolerance in nondiabetic patients with heart failure. J. Am. Coll. Cardiol., March 3, 2009; 53(9): 747 - 753. [Abstract] [Full Text] [PDF]

				R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]

				F. M.A.C. Martens, T. J. Rabelink, J. op 't Roodt, E. J.P. de Koning, and F. L.J. Visseren TNF-{alpha} induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-{gamma} agonist pioglitazone Eur. Heart J., July 1, 2006; 27(13): 1605 - 1609. [Abstract] [Full Text] [PDF]

				R. Krogh-Madsen, P. Plomgaard, K. Moller, B. Mittendorfer, and B. K. Pedersen Influence of TNF-{alpha} and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E108 - E114. [Abstract] [Full Text] [PDF]

				R. Kelly, T. Ruane-O'Hora, M. I. M. Noble, A. J. Drake-Holland, and H. M. Snow Differential inhibition by hyperglycaemia of shear stress- but not acetylcholine-mediated dilatation in the iliac artery of the anaesthetized pig J. Physiol., May 15, 2006; 573(1): 133 - 145. [Abstract] [Full Text] [PDF]

				E. C. Eringa, C. D. A. Stehouwer, K. Walburg, A. D. Clark, G. P. van Nieuw Amerongen, N. Westerhof, and P. Sipkema Physiological Concentrations of Insulin Induce Endothelin-Dependent Vasoconstriction of Skeletal Muscle Resistance Arteries in the Presence of Tumor Necrosis Factor-{alpha} Dependence on c-Jun N-Terminal Kinase Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 274 - 280. [Abstract] [Full Text] [PDF]

				A. X. Freire, L. Bridges, G. E. Umpierrez, D. Kuhl, and A. E. Kitabchi Admission Hyperglycemia and Other Risk Factors as Predictors of Hospital Mortality in a Medical ICU Population Chest, November 1, 2005; 128(5): 3109 - 3116. [Abstract] [Full Text] [PDF]

				P. Plomgaard, K. Bouzakri, R. Krogh-Madsen, B. Mittendorfer, J. R. Zierath, and B. K. Pedersen Tumor Necrosis Factor-{alpha} Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation Diabetes, October 1, 2005; 54(10): 2939 - 2945. [Abstract] [Full Text] [PDF]

				M. Boschmann, S. Engeli, F. Adams, K. Gorzelniak, G. Franke, S. Klaua, U. Kreuzberg, S. Luedtke, R. Kettritz, A. M. Sharma, et al. Adipose Tissue Metabolism and CD11b Expression on Monocytes in Obese Hypertensives Hypertension, July 1, 2005; 46(1): 130 - 136. [Abstract] [Full Text] [PDF]

				R. Takeda, E. Suzuki, H. Satonaka, S. Oba, H. Nishimatsu, M. Omata, T. Fujita, R. Nagai, and Y. Hirata Blockade of Endogenous Cytokines Mitigates Neointimal Formation in Obese Zucker Rats Circulation, March 22, 2005; 111(11): 1398 - 1406. [Abstract] [Full Text] [PDF]

				E. Vila and M. Salaices Cytokines and vascular reactivity in resistance arteries Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1016 - H1021. [Abstract] [Full Text] [PDF]

				B. S. Luciano, S. Hsu, P. L. Channavajhala, L.-L. Lin, and J. W. Cuozzo Phosphorylation of Threonine 290 in the Activation Loop of Tpl2/Cot Is Necessary but Not Sufficient for Kinase Activity J. Biol. Chem., December 10, 2004; 279(50): 52117 - 52123. [Abstract] [Full Text] [PDF]

				S. P. Bagby Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease? J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2775 - 2791. [Full Text] [PDF]

				Y. Miyazaki, A. Mahankali, E. Wajcberg, M. Bajaj, L. J. Mandarino, and R. A. DeFronzo Effect of Pioglitazone on Circulating Adipocytokine Levels and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4312 - 4319. [Abstract] [Full Text] [PDF]

				R. T. de Jongh, E. H. Serne, R. G. IJzerman, G. de Vries, and C. D.A. Stehouwer Impaired Microvascular Function in Obesity: Implications for Obesity-Associated Microangiopathy, Hypertension, and Insulin Resistance Circulation, June 1, 2004; 109(21): 2529 - 2535. [Abstract] [Full Text] [PDF]