Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients

Alfonso Iorio; Marco Orsini Federici; Evangelia Mourvaki; Piero Ferolla; Marta Piroddi; Anna Stabile; Alessandra Timi; Roberta Celleno; Massimo Massi Benedetti

doi:10.1160/TH07-03-0201

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(03): 635-641
DOI: 10.1160/TH07-03-0201

Endothelium and Vascular Development

Schattauer GmbH

Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients

Alfonso Iorio

¹Section of Internal and Vascular Medicine

,

Marco Orsini Federici

²Section of Internal Medicine and Endocrine and Metabolic Sciences and

,

Evangelia Mourvaki

¹Section of Internal and Vascular Medicine

,

Piero Ferolla

²Section of Internal Medicine and Endocrine and Metabolic Sciences and

,

Marta Piroddi

³Section of Cellular Biochemistry; Department of Internal Medicine, University of Perugia, Perugia, Italy

,

Anna Stabile

¹Section of Internal and Vascular Medicine

,

Alessandra Timi

²Section of Internal Medicine and Endocrine and Metabolic Sciences and

,

Roberta Celleno

²Section of Internal Medicine and Endocrine and Metabolic Sciences and

,

Massimo Massi Benedetti

²Section of Internal Medicine and Endocrine and Metabolic Sciences and

› Author Affiliations

Abstract

Summary

Review of literature has shown an increased rate of thrombotic complications in diabetic patients with frequent episodes of hyperketonemia. However, the mechanisms by which ketosis promotes vascular disease in diabetic patients are unclear.It was the aim of this study to investigate early changes in haemostatic parameters and oxidative stress markers during the hyperketonemic status which follows the interruption of continuous subcutaneous insulin infusion (CSII) in type I diabetic patients. Eight CSII-treated type I diabetic patients underwent a 4-hour pump arrest. Blood glucose, insulin and 3-hydroxybutirate were measured to verify the metabolic response. A vein-occlusive (VO) test was performed for the determination of tPA and PAI-1 activities and their antigen levels before and after the CSII arrest. Coagulation factor VII and VIII were evaluated by one-stage PT and PTT method, respectively.TF, vWF, tPA and PAI-1 antigens were determined by ELISA, whereas tPA and PAI-1 activities using chromogenic methods. Plasma malondialdehyde (MDA) and protein carbonyl groups (PCG) levels were determined by HPLC and spectrophotometry, respectively. After the insulin deprivation phase, post-VO tPA antigen level significantly decreased (P=0.0391), whereas TF and post-VO PAI-1 activity and antigen levels significantly increased (P=0.0156 and P=0.0234, respectively). Plasma MDA and PCG levels were 1.88-fold and 1.74-fold higher than baseline values, respectively. In conclusion, the impairment of the fibrinolytic potential and the increases in TF, MDA and PCG levels may enhance the risk of both arterial and venous thrombosis during ketosis.Thus, early detection of hyperketonemia in DM patients could contribute to the prevention of life-threatening vascular events.

Keywords

Diabetes mellitus - fibrinolysis - hyperketonemia - oxidative stress - PAI-1

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References

References
1 Miles JM, Rizza RA, Haymond MW. et al. Effects of acute insulin deficiency on glucose and ketone body turnover in man: evidence for the primacy of overproduction of glucose and ketone bodies in the genesis of diabetic ketoacidosis. Diabetes 1980; 29: 926-930.
2 Schade DS, Eaton RP. The regulation of plasma ketone body concentration by counter-regulatory hormones in man. III. Effects of norepinephrine in normal man. Diabetes 1979; 28: 5-10.
3 Vignati L, Asmal AC, Black WL. et al. Coma in diabetes. In: Joslin’s Diabetes Mellitus. Lea & Febiger; Philaldephia: 1985: 526-552.
4 Clement S, Braithwaite SS, Magee MF. et al American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004; 27: 553-591.
5 Silverstein J, Klingensmith G, Copeland K. et al. American Diabetes Association. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 2005; 28: 186-212.
6 Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44-54.
7 Fattah MA, Shaheen MH, Mahfouz MH. Disturbances of haemostasis in diabetes mellitus. Dis Markers 2003; 19: 251-258.
8 Berrettini M, Parise P, Ricotta S. et al. Increased plasma levels of tissue factor pathway inhibitor (TFPI) after n-3 plynsaturated fatty acid supplementation in patients with chronic atherosclerotic disease. Thromb Haemost 1996; 75: 395-400.
9 Blann AD. Plasma von Willebrand factor, thrombosis, and the endothelium: The first 30 years. Thromb Haemost 2006; 95: 49-55.
10 Hoekstra T, Geleijnse JM, Schouten EG. et al. Plasminogen activator inhibitor-type I: its plasma determinants and relation with cardiovascular risk. Thromb Haemost 2004; 91: 861-872.
11 Thorand B, Baumert J, Doring A. et al. Association of cardiovascular risk factors with markers of endothelial dysfunction in middle-aged men and women. Results from the MONICA/KORA Augsburg Study. Thromb Haemost 2006; 95: 134-141.
12 Parise P, Hauert J, Iorio A. et al. Fibrinogen degradation products generation is the major determinant of platelet inhibition induced by plasminogen activators in platelet rich plasma. Fibrinolysis 1993; 7: 379-385.
13 Van der Meijden PE, Feijge MA, Giesen PL. et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost 2005; 93: 1128-1136.
14 el Khawand C, Jamart J, Donckier J. et al. Hemostasis variables in type I diabetic patients without demonstrable vascular complications. Diabetes Care 1993; 16: 1137-1145.
15 Thogersen AM, Jansson JH, Boman K. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-2247.
16 Vericel E, Januel C, Carreras M. et al. Diabetic patients without vascular complications display enhanced basal platelet activation and decreased antioxidant status. Diabetes 2004; 53: 1046-1051.
17 Lipinski B. Pathophysiology of oxidative stress in diabetes mellitus. J Diabetes Complications 2001; 15: 203-210.
18 Ileri NS, Buyukasik Y, Karaahmetoglu S. et al. Evaluation of the haemostatic system during ketoacidotic deterioration of diabetes mellitus. Haemostasis 1999; 29: 318-325.
19 Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 2002; 25: 593-598.
20 Krzentowski G, Scheen A, Castillo M. et al. A 6-hour nocturnal interruption of a continuous subcutaneous insulin infusion: 1. Metabolic and hormonal consequences and scheme for a prompt return to adequate control. Diabetologia 1983; 24: 314-318.
21 Castillo MJ, Scheen AJ, Lefebvre PJ. The degree/ rapidity of the metabolic deterioration following interruption of a continuous subcutaneous insulin infusion is influenced by the prevailing blood glucose level. J Clin Endocrinol Metab 1996; 81: 1975-1978.
22 Guerci B, Meyer L, Salle A. et al. Comparison of metabolic deterioration between insulin analog and regular insulin after a 5-hour interruption of a continuous subcutaneous insulin infusion in type 1 diabetic patients. J Clin Endocrinol Metab 1999; 84: 2673-2678.
23 Guerci B, Benichou M, Floriot M. Accuracy of an electrochemical sensor for measuring capillary blood ketones by fingerstick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients. Diabetes Care 2003; 26: 1137-1141.
24 Wieczorek I, Ludlam CA, MacGregor I. Venous occlusion does not release von Willebrand factor, factor VIII or PAI-1 from endothelial cells--the importance of consensus on the use of correction factors for haemoconcentration. Thromb Haemost 1993; 69: 91-93.
25 Levine RL, Williams JA, Stadtman ER. et al. Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 1994; 233: 346-357.
26 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254.
27 Fukunaga K, Takama K, Suzuki T. High-performance liquid chromatographic determination of plasma malondialdehyde level without a solvent extraction procedure. Anal Biochem 1995; 230: 20-23.
28 Esterbauer H, Lang J, Zadravec S. et al. Detection of malonaldehyde by high-performance liquid chromatography. Methods Enzymol 1984; 105: 319-328.
29 Byrne HA, Tieszen KL, Hollis S. et al. Evaluation of an electrochemical sensor for measuring blood ketones. Diabetes Care 2000; 23: 500-503.
30 Sowers JR, Lester MA. Diabetes and cardiovascular disease. Diabetes Care 1999; 22 (Suppl. 03) C14-20.
31 Orsini-Federici M, Akwi JA, Canonico V. et al. Early detection of insulin deprivation in continuous subcutaneous insulin infusion patients with type 1 diabetes. Diabetes Technol Ther 2006; 8: 67-75.
32 Davi G, Violi F, Catalano I. et al. Increased plasminogen activator inhibitor antigen levels in diabetic patients with stable angina. Blood Coagul Fibrinolysis 1991; 2: 41-45.
33 Lyon CJ, Hsueh WA. Effect of plasminogen activator inhibitor-1 in diabetes mellitus and cardiovascular disease. Am J Med 2003; 115 (08) 62S-68S Abstract.
34 Dellas C, Loskutoff Dj. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost 2005; 93: 631-640.
35 Maiello M, Boeri D, Podesta F. et al. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose. Diabetes 1992; 41: 1009-1015.
36 Pandolfi A, Iacoviello L, Capani F. et al. Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. Diabetologia 1996; 39: 1425-1431.
37 Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40: 405-412.
38 Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257-267.
39 Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med 1991; 10: 339-352.
40 Jain SK. Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. J Biol Chem 1989; 264: 21340-21345.
41 Mullarkey CJ, Edelstein D, Brownlee M. Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 1990; 173: 932-939.
42 Yim HS, Kang SO, Hah YC. et al. Free radicals generated during the glycation reaction of amino acids by methylglyoxal. A model study of protein-cross-linked free radicals. J Biol Chem 1995; 270: 28228-28233.
43 Jain SK, Kannan K, Lim G. Ketosis (acetoacetate) can generate oxygen radicals and cause increased lipid peroxidation and growth inhibition in human endothelial cells. Free Radic Biol Med 1998; 25: 1083-1088.
44 Jain SK, McVie R. Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients. Diabetes 1999; 48: 1850-1855.
45 Nishikawa T, Edelstein D, Du XL. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-790.
46 Rajeswari P, Natarajan R, Nadler JL. et al. Glucose induces lipid peroxidation and inactivation of membrane- associated ion-transport enzymes in human erythrocytes in vivo and in vitro. J Cell Physiol 1991; 149: 100-109.
47 Jain SK. In vivo externalization of phosphatidylserine and phosphatidylethanolamine in the membrane bilayer and hypercoagulability by the lipid peroxidation of erythrocytes in rats. J Clin Invest 1985; 76: 281-286.
48 Ceriello A, Giacomello R, Stel G. et al. Hyperglycemia- induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes 1995; 44: 924-928.