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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
1   Section of Internal and Vascular Medicine
,
Marco Orsini Federici
2   Section of Internal Medicine and Endocrine and Metabolic Sciences and
,
Evangelia Mourvaki
1   Section of Internal and Vascular Medicine
,
Piero Ferolla
2   Section of Internal Medicine and Endocrine and Metabolic Sciences and
,
Marta Piroddi
3   Section of Cellular Biochemistry; Department of Internal Medicine, University of Perugia, Perugia, Italy
,
Anna Stabile
1   Section of Internal and Vascular Medicine
,
Alessandra Timi
2   Section of Internal Medicine and Endocrine and Metabolic Sciences and
,
Roberta Celleno
2   Section of Internal Medicine and Endocrine and Metabolic Sciences and
,
Massimo Massi Benedetti
2   Section of Internal Medicine and Endocrine and Metabolic Sciences and
› Author Affiliations
Further Information

Publication History

Received 17 March 2007

Accepted after revision 21 May 2007

Publication Date:
28 November 2017 (online)

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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
 

  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 3 Vignati L, Asmal AC, Black WL. et al. Coma in diabetes. In: Joslin’s Diabetes Mellitus. Lea & Febiger; Philaldephia: 1985: 526-552.
    Google Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 6 Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44-54.
    CrossrefPubMedGoogle Scholar
  • 7 Fattah MA, Shaheen MH, Mahfouz MH. Disturbances of haemostasis in diabetes mellitus. Dis Markers 2003; 19: 251-258.
    PubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Blann AD. Plasma von Willebrand factor, thrombosis, and the endothelium: The first 30 years. Thromb Haemost 2006; 95: 49-55.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 17 Lipinski B. Pathophysiology of oxidative stress in diabetes mellitus. J Diabetes Complications 2001; 15: 203-210.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Levine RL, Williams JA, Stadtman ER. et al. Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 1994; 233: 346-357.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 28 Esterbauer H, Lang J, Zadravec S. et al. Detection of malonaldehyde by high-performance liquid chromatography. Methods Enzymol 1984; 105: 319-328.
    PubMedGoogle Scholar
  • 29 Byrne HA, Tieszen KL, Hollis S. et al. Evaluation of an electrochemical sensor for measuring blood ketones. Diabetes Care 2000; 23: 500-503.
    CrossrefPubMedGoogle Scholar
  • 30 Sowers JR, Lester MA. Diabetes and cardiovascular disease. Diabetes Care 1999; 22 (Suppl. 03) C14-20.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 37 Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40: 405-412.
    PubMedGoogle Scholar
  • 38 Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996; 19: 257-267.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 40 Jain SK. Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells. J Biol Chem 1989; 264: 21340-21345.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 45 Nishikawa T, Edelstein D, Du XL. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-790.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar