Short-term Acute Hyperinsulinemia and Prothrombotic Factors in Subjects with Normal Glucose Tolerance

Abstract

Some cytokines and proinflammatory mediators are considered markers of increased atherothrombotic risk. Few information is available on the effects of acute glucose and insulin variations on these markers of atherosclerosis. We assessed the acute effect of glucose and insulin on soluble CD40 ligand (sCD40L), IL-6, and P-selectin levels, evaluating their relationship with insulin sensitivity in normal glucose tolerance subjects (NGT). Twenty-four NGT subjects underwent a 3-h oral glucose tolerance test (OGTT) with measurements of sCD40L, IL-6, and P-selectin levels at 0, 90 and 180 min. Insulin sensitivity was assessed by the Oral Glucose Sensitivity Index (OGIS). To distinguish the role of glucose and insulin, eight subjects had the plasma glucose profile of the OGTT reproduced by a variable IV glucose infusion (ISO-G study) and nine underwent a euglycemic clamp. Lastly, a 3-h time-control (TC) study was performed in eleven subjects. A significant reduction of sCD40L was observed during OGTT and ISO-G study. This reduction was not due to time-related changes, since it was not observed in TC study. During the clamp, insulin induced a marked drop in sCD40L (from 4.89±1.34 to 1.60±0.29 ng/ml, p<0.05). In the pooled data from all studies, fasting sCD40L was indirectly related to LDL-cholesterol (r=−0.38; p=0.04), while IL-6 was directly related with BMI, fat mass, waist circumference, and P-selectin (p<0.05). sCD40L levels are downregulated during a short-term period of acute hyperinsulinemia, whether induced by oral or intravenous glucose administration or by insulin infusion, while it does not seem to affect P-selectin and IL-6.

Key words

insulin - sCD40L - IL-6 - P-selectin - OGTT

References

• 1 Tanne D, Haim M, Goldbourt U, Boyko V, Reshef T, Adler Y, Benderly M, Mekori YA, Behar S. CD40 ligand and risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.  Int J Cardiol. 2006;  107 322-326
• 2 Inwald DP, MacDowall A, Peters MJ, Callard RE, Klein NJ. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation.  Circ Res. 2003;  92 1041-1048
• 3 Desideri G, Ferri C. Effects of obesity and weight loss on soluble CD40L levels.  JAMA. 2003;  289 1781-1782
• 4 Patel JV, Lim HS, Nadar S, Tayebjee M, Hughes EA, Lip GY. Abnormal soluble CD40 ligand and C-reactive protein concentrations in hypertension: relationship to indices of angiogenesis.  J Hypertens. 2006;  24 117-121
• 5 Gokulakrishnan K, Deepa R, Mohan V, Gross MD. Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome--the Chennai Urban Rural Epidemiology Study.  Metabolism. 2006;  55 237-242
• 6 Ohashi Y, Kawashima S, Mori T, Terashima M, Ichikawa S, Ejiri J, Awano K. Soluble CD40 ligand and interleukin-6 in the coronary circulation after acute myocardial infarction.  Int J Cardiol. 2006;  112 52-58
• 7 Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients.  Circulation. 2005;  111 412-419
• 8 Varo N, Vicent D, Libby P, Nuzzo R, Calle-Pascual AL, Bernal MR, Fernandez-Cruz A, Veves A, Jarolim P, Varo JJ, Goldfine A, Horton E, Schönbeck U. Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones.  Circulation. 2003;  107 2664-2669
• 9 Wagner DD. New links between inflammation and thrombosis.  Arterioscler Thromb Vasc Biol. 2005;  25 1321-1324
• 10 Afshar-Kharghan V, Thiagarajan P. Leukocyte adhesion and thrombosis.  Curr Opin Hematol. 2006;  13 34-39
• 11 Tailor A, Cooper D, Granger DN. Platelet-vessel wall interactions in the microcirculation.  Microcirculation. 2005;  12 275-285
• 12 Koyama H, Maeno T, Fukumoto S, Shoji T, Yamane T, Yokoyama H, Emoto M, Shoji T, Tahara H, Inaba M, Hino M, Shioi A, Miki T, Nishizawa Y. Platelet P-selectin expression is associated with atherosclerotic wall thickness in carotid artery in humans.  Circulation. 2003;  108 524-529
• 13 Stumpf C, John S, Jukic J, Yilmaz A, Raaz D, Schmieder RE, Daniel WG, Garlichs CD. Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension.  J Hypertens. 2005;  23 995-1000
• 14 Li-Saw-Hee FL, Blann AD, Lip GY. A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation.  J Am Coll Cardiol. 2000;  35 1926-1931
• 15 Menown IB, Mathew TP, Gracey HM, Nesbitt GS, Murray P, Young IS, Adgey AA. Prediction of Recurrent Events by D-Dimer and Inflammatory Markers in Patients with Normal Cardiac Troponin I (PREDICT) Study.  Am Heart J. 2003;  145 986-992
• 16 Conway DS, Pearce LA, Chin BS, Hart RG, Lip GY. Plasma von Willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 1321 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors.  Circulation. 2002;  106 1962-1967
• 17 Yngen M, Norhammar A, Hjemdahl P, Wallen NH. Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty.  Diab Vasc Dis Res. 2006;  3 52-56
• 18 Andreozzi F, Laratta E, Cardellini M, Marini MA, Lauro R, Hribal ML, Perticone F, Sesti G. Plasma interleukin-6 levels are independently associated with insulin secretion in a cohort of Italian-Caucasian nondiabetic subjects.  Diabetes. 2006;  55 2021-2024
• 19 Andreozzi F, Laratta E, Procopio C, Hribal ML, Sciacqua A, Perticone M, Miele C, Perticone F, Sesti G. Interleukin-6 impairs the insulin signaling pathway promoting production of Nitric Oxide in human umbilical vein endothelial cells.  Mol Cell Biol. 2007;  27 2372-2383
• 20 Glund S, Krook AR. Role of interleukin-6 signalling in glucose and lipid metabolism.  Acta Physiol. 2008;  192 37-48
• 21 Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase.  Diabetes. 2006;  55 2688-2697
• 22 Soop M, Duxbury H, Agwunobi AO, Gibson JM, Hopkins SJ, Childs C, Cooper RG, Maycock P, Little RA, Carlson GL. Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans.  Am J Physiol Endocrinol Metab. 2002;  282 E1276-E1285
• 23 Heliovaara MK, Teppo AM, Karonen SL, Tuominen JA, Ebeling P. Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects.  Diabetes Obes Metab. 2005;  7 729-736
• 24 National Institutes of Health . The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII).  , NIH Publication No. 03-5233. EUA, 2003, 2–3
• 25 American Diabetes Association . Report of the Expert Committee on Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1997;  20 1183-1197
• 26 Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test.  Diabetes Care. 2001;  24 539-548
• 27 DeFronzo R, Tobin J, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 E214-E23
• 28 Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA. Obesity and insulin resistance in humans: a dose-response study.  Metabolism. 1990;  39 452-459
• 29 Vaidyula VR, Rao AK, Mozzoli M, Homko C, Cheung B, Boden G. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand.  Diabetes. 2006;  55 202-208
• 30 Coppola L, Verrazzo G, La Marca C, Ziccardi P, Grassia A, Tirelli A, Giugliano D. Effect of insulin on blood rheology in non-diabetic subjects and in patients with type 2 diabetes mellitus.  Diab Med. 1997;  14 959-963
• 31 Anfossi G, Mularoni EM, Burzacca S, Ponziani MC, Massucco L, Cavallo F, Trovati M. Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM.  Diabetes Care. 1998;  21 121-126
• 32 Vicennati V, Vottero A, Friedman C, Papanicolaou DA. Hormonal regulation of interleukin-6 production in human adipocytes.  Int J Obes Relat Metab Disord. 2002;  26 905-911
• 33 Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates interleukin-6 and tumor necrosis factor-α gene expression in human subcutaneous adipose tissue.  Am J Physiol Endocrinol Metab. 2004;  286 E234-E238
• 34 Blackburn P, Despres JP, Lamarche B, Tremblay A, Bergeron J, Lemieux I, Couillard C. Postprandial variations of plasma inflammatory markers in abdominally obese men.  Obesity (Silver Spring). 2006;  14 1747-1754
• 35 Heliövaara MK, Teppo AM, Karonen SL, Tuominen JA, Ebeling P. Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects.  Diabetes Obes Metab. 2005;  6 729-736
• 36 Targher G, Bonadonna RC, Alberiche M, Zenere MB, Muggeo M, Bonora E. Relation between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals: role of adipose tissue.  Diabetes Care. 2001;  24 1961-1966
• 37 Jilma B, Dallinger S, Hergovich N, Eichler HG, Richter V, Wagner OF. Effects of hyperinsulinemia on plasma levels of circulating adhesion molecules.  J Clin Endocrinol Metab. 2000;  85 1748-1751
• 38 Otsuka A, Azuma K, Iesaki T, Sato F, Hirose T, Shimizu T, Tanaka Y, Daida H, Kawamori R, Watada H. Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta.  Diabetologia. 2005;  48 2667-2674
• 39 Verna S, Wang CH, Li SH, Lonn E, Charbonneau F, Title LM, Anderson TJ. FATE Investigators . The relationship between soluble CD40 ligand levels and Framingham coronary heart disease risk score in healthy volunteers.  Atherosclerosis. 2005;  182 361-365
• 40 Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance.  Eur Cytokine Netw. 2006;  17 4-12

Correspondence