Elevated Circulating P-Selectin in Insulin Dependent Diabetes Mellitus

 

PDF Download Buy Article Permissions and Reprints

Summary

Based on findings that showed increased P-selectin expression on platelets and on choroidal microvessels of patients with insulin dependent diabetes mellitus (IDDM), we hypothesized that also plasma concentrations of circulating (c)P-selectin would be increased in these patients.

The aim of this study was to compare the plasma levels of cP-selec-tin between non-smoking patients with IDDM, treated with an intensified insulin therapy, and healthy controls. The study design was prospective, cross-sectional and analyst-blinded. Subjects were matched individually for sex, age and body mass index. Plasma levels of cP-selectin and of von Willebrand antigen (vWF-Ag) were determined by enzyme linked immunoassays.

Forty-two pairs were available for intergroup comparison. Median plasma concentrations of cP-selectin in patients with IDDM (285 ng/ml; interquartile range: 233-372) were on average 21% higher than those of controls (236 ng/ml; interquartile range: 175-296; p = 0.004). Also, median plasma levels of vWF-Ag were 10% higher in patients (96 U/dl; interquartile range: 82-127) than controls (87 U/dl; interquartile range: 70-104; p = 0.025). There was no correlation between plasma concentrations of cP-selectin and vWF-Ag levels in either group (p ώ0.05).

In conclusion, our results of increased cP-selectin levels are in line with increased P-selectin expression on platelets and on choroidal microvessels found in patients with IDDM. In view of the currently developed small molecule inhibitors of cell adhesion molecules, these independent observations together may provide a sound rationale to select P-selectin as a target for treating or preventing IDDM-associated micro- or macrovascular complications.

• References

• 1 Colwell JA. Vascular thrombosis in type II diabetes mellitus (editorial). Diabetes 1993; 42 (01) 8-11
  CrossrefPubMedGoogle Scholar
• 2 Tschoepe D, Roesen P, Esser J, Schwippert B, Nieuwenhuis HK, Kehrel B, Gries FA. Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Hemost 1991; 17 (04) 433-438
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Tschoepe D, Driesch E, Schwippert B, Nieuwenhuis HK, Gries FA. Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia. Diabetes 1995; 44: 890-894
  CrossrefPubMedGoogle Scholar
• 4 Colwell JA, Winocour PD, Halushka PV. Do platelets have anything to do with diabetic microvascular disease. Diabetes 1983; 32 (Suppl. 02) Suppl 14-19
  CrossrefPubMedGoogle Scholar
• 5 Vukovich TC, Schemthaner G, Knobi PN, Hay U. The effect of near-normoglycemic control on plasma factor VUI/von Willebrand factor and fibrin degradation products in insulin-dependent diabetic patients. J Clin Endocrinol Metab 1989; 69 (01) 84-89
  CrossrefPubMedGoogle Scholar
• 6 Patel KD, Zimmermann GA, Prescott SM, McEver RP, McIntyre TM. Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J Cell Biol 1991; 112 (04) 749-759
  CrossrefPubMedGoogle Scholar
• 7 Dunlop LC, Skinner MP, Bendall LJ, Favaloro EJ, Castaldi PA, Gorman JJ, Gamble JR, Vadas MA, Bemdt MC. Characterization of GMP-140 (P-se-lectin) as a circulating plasma protein. J Exp Med 1992; 175 (04) 1147-1150
  CrossrefPubMedGoogle Scholar
• 8 Wagner DD. The Weibel-Palade body: the storage granule for von Willebrand factor and P-selectin. Thromb Haemost 1993; 70 (01) 105-110
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Geng JG, Bevilacqua MP, Moore KL, McIntyre TM, Prescott SM, Kim JM, Bliss GA, Zimmerman GA, McEver RP. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature 1990; 343: 757-760
  CrossrefPubMedGoogle Scholar
• 10 Johnson-Tidey RR, McGregor JL, Taylor PR, Proston RN. Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. Am J Pathol 1994; 144 (05) 952-961
  PubMedGoogle Scholar
• 11 Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T. Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD 62). J Immunol 1993; 151 (06) 3267-3273
  PubMedGoogle Scholar
• 12 Dore M, Korthuis RJ, Granger DN, Entman ML, Smith CW. P-selectin mediates spontaneous leukocyte rolling in vivo. Blood 1993; 82 (04) 1308-1316
  PubMedGoogle Scholar
• 13 Yeo EL, Sheppard JA, Feuerstein IA. Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear stress conditions (an injury vessel wall model). Blood 1994; 83 (09) 2498-2507
  PubMedGoogle Scholar
• 14 Kaikita K, Ogawa H, Yasue H, Sakamoto T, Suefujig H, Sumida H. et al Soluble P-selectin is released into the coronary circulation after coronary spasm. Circulation 1995; 92: 1827-1830
  PubMedGoogle Scholar
• 15 Ikeda H, Takajo Y, Kazuya I, Takafumi U, Maki S, Noda T, Sugi K, Imaizumi T. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92: 1693-1696
  CrossrefPubMedGoogle Scholar
• 16 Chong BH, Murray B, Bemdt MC, Dunlop LC, Brighton T, Chesterman CN. Plasma P-Selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83 (06) 1535-1541
  PubMedGoogle Scholar
• 17 Wu G, Li F, Li P, Ruan C. Detection of plasma alpha-granule membrane protein GMP-140 using radiolabeled monoclonal antibodies in thrombotic disease. Haemostasis 1993; 23 (02) 121-128
  PubMedGoogle Scholar
• 18 Blann AD, Dobrotova M, Kubisz P, McCollum CN. Von Willebrand Factor, soluble P-Selectin, tissue plasminogen activator inhibitor in atherosclerosis. Thromb Haemost 1995; 74 (02) 626-630
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 McLeod DS, Lefer DJ, Merges C, Lutty GA. Enhanced expression of intercellular adhesion molecule-1 and P-Selectin in diabetic human retina and choroid. Am J Pathol 1995; 147 (03) 642-653
  PubMedGoogle Scholar
• 20 Bennett PH. The diagnosis of diabetes: new international classification and diagnostic criteria. Annu Rev Med 1983; 34: 295-309
  CrossrefPubMedGoogle Scholar
• 21 Waldhausl W. The physiological basis of insulin treatment - clinical aspects. Diabetologia 1986; 29: 837-849
  CrossrefPubMedGoogle Scholar
• 22 Jilma B, Hildebrandt J, Kapiotis S, Wagner OF, Kitzweger E, Mullner C, Monitzer B, Krejcy K, Eichler HG. Effects of estradiol on circulating P-selectin. J Clin Endocrinol Metab 1996; 81 (06) 2350-2355
  PubMedGoogle Scholar
• 23 Knobl P, Schemthaner G, Schnack C, Pietschmann P, Griesmacher A, Prager R, Muller M. Thrombogenic factors are related to uninary albumin excretion rate in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36 (10) 1045-1050
  CrossrefPubMedGoogle Scholar
• 24 Khawand CE, Jamart J, Donckier J, Chatelain B, Moriau M, Buysschaert M. Hemostasis variables in type I diabetic patients without demonstrable vascular complications. Diabetes Care 1993; 16 (08) 1137-1145
  CrossrefPubMedGoogle Scholar
• 25 Tschoepe D, Langer E, Schauseil S, Rosen P, Kaufmann L, Gries FA. Increased platelet volume - sign of impaired thrombopoiesis in diabetes mellitus. Klin Wochenschr 1989; 67 (04) 253-259
  CrossrefPubMedGoogle Scholar
• 26 Daniel S, O’Brien JR, John JA. Platelets in the prediction of thrombotic risk. Atherosclerosis 1982; 45 (01) 91-99
  CrossrefPubMedGoogle Scholar
• 27 Ceriello A, Giacomello R, Stel G, Motz E, Taboga C, Tonutti L, Falleti E, Bartoli E. Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes 1995; 44: 924-928
  CrossrefPubMedGoogle Scholar
• 28 Jilma B, Eichler HG, Vondrovec B, Breiteneder H, Kyrle PA, Kitzweger E, Kapiotis S, Speiser W. Effects of desmopressin on circulating P-selectin. BrJ Haematol 1996; 93: 432-436
  CrossrefPubMedGoogle Scholar
• 29 Johnston GI, Bliss GA, Newman PJ, McEver RP. Structure of the human gene encoding GMP-140, a member of the selectin family of adhesion receptors for leukocytes. J Biol Chem 1990; 265: 21381-21385
  PubMedGoogle Scholar
• 30 Katayama M, Handa M, Ambo H, Araki Y, Kawai Y, Watanabe K, Ikeda Y. Soluble P-selectin is present in normal circulation and its plasma level is elevated in patients with thrombotic thrombocytopenic purpura and haemo-lytic uraemic syndrome. Br J Haematol 1993; 84: 702-710
  CrossrefPubMedGoogle Scholar
• 31 Lorant DE, Topham MK, Whatley RA, McEver RP, McIntyre TM, Prescott SM, Zimmerman GA. Inflammatory roles of P-Selectin. J Clin Invest 1993; 92: 559-570
  CrossrefPubMedGoogle Scholar
• 32 Wierusz-Wysocki B, Wysocki H, Siekerka H, Wykretowicz A, Szcaepanik A, Klimas R. Evidence of polymorphonuclear neutrophils (PMN) activation in patients with insulin-dependent diabetes mellitus. J Leukocyte Biol 1987; 42: 519-523
  CrossrefPubMedGoogle Scholar
• 33 Freedman S, Hatchell D. Enhanced superoxide radical production by stimulated polymorphonuclear leukocytes in a cat model of diabetes. Exp Eye Res 1992; 55: 767-773
  CrossrefPubMedGoogle Scholar
• 34 Fasching P, Rohac M, Waldhausl W, Soregi G, Veitl M, Schneider B, Streli C, Wagner OF. Elevated concentrations of circulating adhesion molecules and their association with late diabetic complications in insulin-dependent and non-insulin-dependent diabetes mellitus. submitted
  PubMedGoogle Scholar
• 35 Lampeter ER, Kishimoto TK, Rothlein R, Mainolfi EA, Bertrams J, Kolb H, Martin S. Elevated levels of circulating adhesion molecules in IDDM patients and in subjects at risk for IDDM. Diabetes 1992; 41 (12) 1668-1671
  CrossrefPubMedGoogle Scholar
• 36 Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann AD. Increased levels of soluble adhesion molecules in type 2 (non-insulin dependent) diabetes mellitus are independent of glycaemic control. Thromb Haemost 1994; 72 (06) 679-684
  PubMedGoogle Scholar
• 37 Celi A, Pellegrini G, Lorenzet R, Blasi AD, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci 1994; 8767-8771
  PubMedGoogle Scholar