In vivo thromboxane-dependent platelet activation is persistently enhanced in subjects with impaired glucose tolerance
Corresponding Author
Francesca Santilli
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Correspondence
Francesca Santilli, Center of Aging Science and Translational Medicine (CESI-Met), “G. D'Annunzio” University Foundation, Via Luigi Polacchi, Chieti 66013, Italy.
Email: [email protected]
Search for more papers by this authorFrancesco Zaccardi
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Leicester Diabetes Centre, Leicester General Hospital, Leicester, United Kingdom
Search for more papers by this authorRossella Liani
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorGiovanna Petrucci
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorPaola Simeone
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorDario Pitocco
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorRomina Tripaldi
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorAlessandro Rizzi
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGloria Formoso
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorAlfredo Pontecorvi
Institute of Endocrinology, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
Search for more papers by this authorErmanno Angelucci
Department of Clinical Medicine, Chieti University Hospital, Chieti, Italy
Search for more papers by this authorFrancesca Pagliaccia
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorMaria Golato
Department of Clinical Pathology, Chieti University Hospital, Chieti, Italy
Search for more papers by this authorFrancesca De Leva
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorEster Vitacolonna
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorBianca Rocca
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorAgostino Consoli
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorCarlo Patrono
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorCorresponding Author
Francesca Santilli
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Correspondence
Francesca Santilli, Center of Aging Science and Translational Medicine (CESI-Met), “G. D'Annunzio” University Foundation, Via Luigi Polacchi, Chieti 66013, Italy.
Email: [email protected]
Search for more papers by this authorFrancesco Zaccardi
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Leicester Diabetes Centre, Leicester General Hospital, Leicester, United Kingdom
Search for more papers by this authorRossella Liani
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorGiovanna Petrucci
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorPaola Simeone
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorDario Pitocco
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorRomina Tripaldi
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorAlessandro Rizzi
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGloria Formoso
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorAlfredo Pontecorvi
Institute of Endocrinology, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy
Search for more papers by this authorErmanno Angelucci
Department of Clinical Medicine, Chieti University Hospital, Chieti, Italy
Search for more papers by this authorFrancesca Pagliaccia
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorMaria Golato
Department of Clinical Pathology, Chieti University Hospital, Chieti, Italy
Search for more papers by this authorFrancesca De Leva
Diabetes Care Unit, Catholic University School of Medicine and Fondazione Policlinico Universitario “A. Gemelli” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorEster Vitacolonna
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorBianca Rocca
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorAgostino Consoli
Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti “G. D'Annunzio” School of Medicine, Chieti, Italy
Search for more papers by this authorCarlo Patrono
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
Search for more papers by this authorAbstract
Background
Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)-dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown.
We investigated whether TXA2-dependent platelet activation, as reflected by 11-dehydro-TXB2 (TXM) urinary excretion, is comparably abnormal in IGT as in DM, is persistent over long-term follow-up, changes as a function of metabolic disease progression, and is influenced by food intake.
Methods
We prospectively investigated subjects with IGT (n = 48) and two control groups with DM diagnosed either less than 12 months (n = 60) or 12 months or more (n = 58).
Results
Baseline TXM excretion was comparable between subjects with IGT and DM, with no evidence of a circadian variation. During a 36-month follow-up, urinary TXM excretion was stable over time in the DM groups, while tended to increase in subjects with IGT. Increasing urinary TXM excretion over time was observed in the subjects who progressed to diabetes vs nonprogressors.
Conclusions
We conclude that TXA2-dependent platelet activation was at least as high in IGT as in patients with DM and further increased over time, especially in those who progressed to overt diabetes.
CONFLICT OF INTEREST
C.P. has received consulting and lecture fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline and Zambon, and institutional research grants from Bayer; he serves as Chairperson of the Scientific Advisory Board of the International Aspirin Foundation. No other potential conflicts of interest relevant to this article were reported.
Supporting Information
| Filename | Description |
|---|---|
| dmrr3232_Supporting Information.docxWord 2007 document , 219.8 KB |
Table S1. Baseline clinical characteristics of the two groups of study subjects Table S2. Baseline correlations between demographic, anthropometric and biochemical variables and the urinary excretion of 8-iso-PGF2α and 11-dehydro-TXB2, within each study group Table S3. Number of participants included at each time point Table S4. Correlations between two-hour, post-meal glucose variations (8-10 am, 1-3pm or 6-8 pm) and subsequent urinary 11-dehydro-TXB2 and 8-iso-PGF2α values Figure S1. Longitudinal changes of urinary 8-iso-PGF2α excretion in IGT vs. T2DM patients over time. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus - mechanisms, management, and clinical considerations. Circulation. 2016; 133(24): 2459-2502. https://doi.org/10.1161/CIRCULATIONAHA.116.022194
- 2Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006; 29(5): 1130-1139.
- 3Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007; 116(2): 151-157.
- 4Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010; 362(9): 800-811. https://doi.org/10.1056/NEJMoa0908359
- 5Huang Y, Cai X, Mai W, Li M, Hu Y. Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis. BMJ. 2016; 355: i5953. https://doi.org/10.1136/bmj.i5953
- 6Qiao Q, Pyorala K, Pyorala M, et al. Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur Heart J. 2002; 23(16): 1267-1275.
- 7Faerch K, Vistisen D, Johansen NB, Jorgensen ME. Cardiovascular risk stratification and management in pre-diabetes. Curr Diab Rep. 2014; 14(6): 493. https://doi.org/10.1007/s11892-014-0493-1
- 8Gillies CL, Abrams KR, Lambert PC, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007; 334: 299.
- 9Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003; 290(4): 486-494.
- 10Kaiser T, Sawicki PT. Acarbose for prevention of diabetes, hypertension and cardiovascular events? A critical analysis of the STOP-NIDDM data. Diabetologia. 2004; 47(3): 575-580. https://doi.org/10.1007/s00125-003-1318-y
- 11Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007; 357(24): 2482-2494.
- 12Davi G, Catalano I, Averna M, et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990; 322(25): 1769-1774.
- 13Santilli F, Formoso G, Sbraccia P, et al. Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus. J Thromb Haemost. 2010; 8(4): 828-837. https://doi.org/10.1111/j.1538-7836.2010.03742.x
- 14Davi G, Gresele P, Violi F, et al. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation. 1997; 96(1): 69-75.
- 15Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999; 99(2): 224-229.
- 16Santilli F, Davi G, Consoli A, et al. Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus. J Am Coll Cardiol. 2006; 47(2): 391-397.
- 17Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006; 295(14): 1681-1687.
- 18Coban E, Kucuktag S, Basyigit S. Platelet activation in subjects with impaired glucose tolerance. Platelets. 2007; 18(8): 591-594.
- 19Dogru T, Genc H, Tasci I, et al. Platelet aggregation is not enhanced in patients with prediabetes. Ups J Med Sci. 2007; 112(3): 338-346.
- 20Santilli F, Rocca B, De Cristofaro R, et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance". J Am Coll Cardiol. 2009; 53(8): 667-677.
- 21Patrono C, Morais J, Baigent C, et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol. 2017; 70(14): 1760-1776. https://doi.org/10.1016/j.jacc.2017.08.037
- 22Ciabattoni G, Pugliese F, Davi G, Pierucci A, Simonetti BM, Patrono C. Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man. Biochim Biophys Acta. 1989; 992(1): 66-70.
- 23 Standards of Medical Care in Diabetes—2019. 2. Classification and diagnosis of diabetes. Diabetes Care. 2019; 42(Supplement 1): S13-S28. https://doi.org/10.2337/dc19-S002
- 24Pagliaccia F, Habib A, Pitocco D, et al. Stability of urinary thromboxane A2 metabolites and adaptation of the extraction method to small urine volume. Clin Lab. 2014; 60(1): 105-111.
- 25Catella F, FitzGerald GA. Paired analysis of urinary thromboxane B2 metabolites in humans. Thromb Res. 1987; 47(6): 647-656.
- 26Wang Z, Ciabattoni G, Creminon C, et al. Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man. J Pharmacol Exp Ther. 1995; 275(1): 94-100.
- 27Ciabattoni G, Maclouf J, Catella F, FitzGerald GA, Patrono C. Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine. Biochim Biophys Acta. 1987; 918(3): 293-297.
- 28Brindle E, Fujita M, Shofer J, O'Connor KA. Serum, plasma, and dried blood spot high-sensitivity C-reactive protein enzyme immunoassay for population research. J Immunol Methods. 2010; 362(1-2): 112-120. https://doi.org/10.1016/j.jim.2010.09.014
- 29DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011; 108(Suppl 3): 3B-24B. https://doi.org/10.1016/j.amjcard.2011.03.013
- 30Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002; 25(7): 1129-1134.
- 31Trovati M, Mularoni EM, Burzacca S, et al. Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. Diabetes. 1995; 44(11): 1318-1322.
- 32Basili S, Pacini G, Guagnano MT, et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol. 2006; 48(12): 2531-2538.
- 33Davi G, Guagnano MT, Ciabattoni G, et al. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA. 2002; 288(16): 2008-2014.
- 34Davi G, Chiarelli F, Santilli F, et al. Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration. Circulation. 2003; 107(25): 3199-3203.
- 35Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002; 105(14): 1650-1655.
- 36Eikelboom JW, Hankey GJ, Thom J, et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation. 2008; 118(17): 1705-1712. https://doi.org/10.1161/CIRCULATIONAHA.108.768283
- 37Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012; 379(9833): 2279-2290. https://doi.org/10.1016/S0140-6736(12)60283-9
- 38Halvorsen B, Santilli F, Scholz H, et al. LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro. Diabetologia. 2016; 59(10): 2134-2144.
- 39 Standards of Medical Care in Diabetes. 5. Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2017; 40(Suppl 1): S44-S47.
- 40Ibrahim JG, Molenberghs G. Missing data methods in longitudinal studies: a review. Test (Madr). 2009; 18(1): 1-43.
- 41Mitchell JA, Knowles RB, Kirkby NS, et al. Kidney transplantation in a patient lacking cytosolic phospholipase A2 proves renal origins of urinary PGI-M and TX-M. Circ Res. 2018; 122(4): 555-559. https://doi.org/10.1161/CIRCRESAHA.117.312144
Citing Literature
