Horm Metab Res 2001; 33(12): 713-720
DOI: 10.1055/s-2001-19133
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Microvascular Permeability is Increased in Both Types of Diabetes and Correlates Differentially with Serum Levels of Insulin-Like Growth Factor I (IGF-I) and Vascular Endothelial Growth Factor (VEGF)

F. Brausewetter 1 , P. M. Jehle 1 , M. F. Jung 1 , B. O. Boehm 2 , J. Brueckel 2 , V. Hombach 1 , H. H. Osterhues 1
  • 1 Department of Medicine II, University of Ulm, Germany
  • 2 Department of Medicine I, University of Ulm, Germany
Further Information

Publication History

Publication Date:
18 December 2001 (online)

Vascular endothelial growth factor (VEGF) and insulin-like growth factor-I (IGF-I) both play a pivotal role in diabetic microangiopathy. This study assessed the relationship between capillary permeability as a marker of endothelial dysfunction and serum VEGF and IGF-I levels in normotensive diabetics. Subjects were 10 Type 1 (6/4, male/female, age: 30 [mean] ± 5 [SD] years, HbA1c: 7.5 ± 1.1 %), 13 Type 2 diabetics (9/4, m/f; 63 ± 7 years, 8.3 ± 1.8 %), and 24 age- and sex-matched control subjects. We determined nailfold capillary permeability by intravital fluorescence videomicroscopy after intravenous injection of sodium-fluorescein. Serum VEGF, free and total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and insulin levels were measured by specific immunoassays. Capillary permeability was increased in both types of diabetes patients compared to age- and sex-matched controls. In Type 1 diabetics, fluorescence light intensities increased over time, reaching significance 30 minutes after dye injection. Type 2 diabetics already revealed an early onset of elevated fluorescence light intensities after one minute. Capillary permeability showed a significant positive correlation with VEGF levels in Type 1 diabetics, (r = 0.76, p < 0.05; 20 min after dye injection) but with free IGF-I levels in type 2 diabetics (r = 0.65, p < 0.05; 5 min after dye injection). IGFBP-3 correlated negatively with capillary permeability in both diabetes types, whereas IGFBP-1 levels correlated positively in Type 2 patients. In conclusion, capillary permeability is increased in both types of diabetes mellitus. However, VEGF and IGF-I may differentially affect microvascular permeability depending on the diabetes type.

References

  • 1 Tooke J E. Microvascular haemodynamics in diabetes mellitus.  Clin Sci. 1986;  70 119-125
  • 2 Parving H H, Viberti G C, Keen H, Christiansen J S, Lassen N A. Haemodynamic factors in the genesis of diabetic microangiopathy.  Metabolism. 1983;  32 943-949
  • 3 Zatz R, Brenner B M. Pathogenesis of diabetic microangiopathy: The haemodynamic view.  Am J Med. 1986;  80 443-453
  • 4 Sandeman D D, Shore A C, Tooke J E. Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control.  N Engl J Med. 1992;  10 760-764
  • 5 Jaap A J, Tooke J E. Pathophysiology of microvascular disease in non-insulin-dependent diabetes.  Clin Sci. 1995;  89 3-12
  • 6 Jaap A J, Shore A C, Gartside I B, Gamble J, Tooke J E. Increased microvascular fluid permeability in young type I (insulin-dependent) diabetic patients.  Diabetologia. 1993;  36 648-652
  • 7 Valensi P, Cohen-Boulakia F, Attali J R, Behar A. Changes in capillary permeability in diabetic patients.  Clin Hemorheol Microcirc. 1997;  17 389-394
  • 8 Jaap A J, Hammersley M S, Shore A C, Tooke J E. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus.  Diabetologia. 1994;  37 214-216
  • 9 Parving H H, Nielsen F S, Bang L E, Smidt U M, Svendsen T L, Chen J W, Gall M A, Rossing P. Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy.  Diabetologia. 1996;  39 1590-1597
  • 10 Jaap A J, Shore A C, Gartside I B, Gamble J, Tooke J E. Capillary filtration coefficient in type 2 diabetes.  J Diabetes Complicat. 1994;  8 111-116
  • 11 Vane J, Änggard E, Botting R. Regulatory functions of the vascular endothelium.  N Engl J Med. 1990;  323 27-36
  • 12 Ferrara N, Houck K, Jakeman L, Leung D W. Molecular and biological properties of the vascular endothelial growth factor family of proteins.  Endocr Rev. 1992;  13 18-32
  • 13 Duh E, Aiello L P. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.  Diabetes. 1999;  48 1899-1906
  • 14 Williams B. Factors regulating the expression of vascular permeability/ vascular endothelial growth factor by human vascular tissues.  Diabetologia. 1998;  40 118-120
  • 15 Punglia R S, Lu M, Hsu J, Kuroki M, Tolentino M J, Keough K, Levy A P, Levy N S, Goldberg M A, D`Amato R J, Adamis A P. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I.  Diabetes. 1997;  46 1619-1626
  • 16 Bates D O, Lodwick D, Williams B. Vascular endothelial growth factor and microvascular permeability.  Microcirculation. 1999;  6 83-96
  • 17 Bar R S, Dake B L, Stueck S. Stimulation of proteoglycans by IGF-I and -II in microvessel and large endothelial cells.  Am J Physiol. 1987;  253 E21-E27
  • 18 Bar R S, Clemmons D R, Boes M, Busby W H, Booth B A, Dake B L, Sandra A. Transcapillary permeability and subendothelial distribution of endothelial and amniotic fluid insulin-like growth factor binding proteins in the rat heart.  Endocrinology. 1990;  127 1078-1086
  • 19 Bereket A, Lang C H, Wilson T A. Alterations of the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.  Horm Metab Res. 1999;  31 172-181
  • 20 Feldmann B, Jehle P M, Mohan S, Lang G E, Lang G K, Brueckel J, Boehm B O. Diabetic retinopathy is associated with decreased serum levels of free IGF-I and changes of IGF-binding proteins.  Growth Horm IGF Res. 2000;  10 53-59
  • 21 Chiarelli F, Spagnoli A, Basciani F, Tumini S, Mezzetti A, Cipollone F, Cuccurullo F, Morgese G, Verrotti A. Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications.  Diabet Med. 2000;  17 650-656
  • 22 Bollinger A, Jäger K, Roten A, Timeus C, Mahler F. Diffusion, pericapillary distribution and clearance of Na-fluorescein in the human nailfold.  Pflügers Arch. 1979;  382 137-143
  • 23 Bollinger A, Frey J, Jäger K, Furrer J, Seglias J, Siegenthaler W. Patterns of diffusion through skin capillaries in patients with long-term diabetes.  N Engl J Med. 1982;  307 1305-1310
  • 24 Jehle P M, Jehle D R, Mohan S, Böhm B O. Serum levels of insulin-like growth factor system components and relationship to bone metabolism in type 1 and type 2 diabetes mellitus patients.  J Endocrinol. 1998;  159 297-306
  • 25 Williams S A, Boolell M, MacGregor G A, Smaje L H, Wassermann S M, Tooke J E. Capillary hypertension and abnormal pressure dynamics in patients with essential hypertension.  Clin Sci. 1990;  79 5-8
  • 26 Curry F E, Michel C C. A fiber matrix model of capillary permeability.  Microvasc Res. 1980;  20 96-99
  • 27 Katz M a, McCuskey P, Beggs J L, Johnson P C, Gaines J A. Relationships between microvascular function and capillary structure in diabetic and non-diabetic human skin.  Diabetes. 1989;  38 1245-1250
  • 28 Ku D D, Zaleski J K, Liu S, Brock T A. Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.  Am J Physiol Heart Circul Physiol. 1993;  265 586-592
  • 29 Clermont A C, Aiello L P, Mori F, Aiello L M, Bursell S E. Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy.  Am J Ophthalmol. 1997;  124 433-446
  • 30 Aiello L P, Avery R L, Arrigg P G, Keyt B A, Jampel H D, Shah S T, Pasquale L R, Thieme H, Iwamoto M A, Park J E, Nguyen H V, Aiello L M, Ferrara N, King G L. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.  N Engl J Med. 1994;  331 1480-1487
  • 31 Aiello L P, Pierce E A, Foley E D, Takagi H, Chen H, Riddle L, Ferrara N, King G L, Smith L E. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.  Proc Natl Acad Sci. 1995;  92 10 457-10 461
  • 32 Nagai Y, Ando H, Nohara E, Yamashita H, Takamura T, Kobayashi K. Plasma levels of vascular endothelial growth factor in patients with acromegaly.  Horm Metab Res. 2000;  32 326-329
  • 33 Kranz A, Rau C, Kochs M, Waltenberger J. Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance.  J Mol Cell Cardiol. 2000;  32 65-72
  • 34 Rajaram S, Baylink D J, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulations and functions.  Endocr Rev. 1997;  18 801-831
  • 35 Bayes-Genis A, Conover C A, Schwartz R S. The insulin-like growth factor axis. A review of atherosclerosis and restenosis.  Circ Res. 2000;  86 125-130
  • 36 Balaram S K, Agrawal D K, Allen R T, Kuszynski C A, Edwards J D. Cell adhesion molecules and insulin-like growth factor-1 in vascular disease.  J Vasc Surg. 1997;  25 866-876
  • 37 Hansson H A, Jennische E, Skottner A. Regenerating endothelial cells express insulin-like growth factor-I immunoreactivity after arterial injury.  Cell Tissue Res. 1987;  250 499-505
  • 38 Schini-Kerth V B. Dual effects of insulin-like growth factor-I on the constitutive and inducible nitric oxide (NO) synthase-dependent formation of NO in vascular cells.  J Endocrinol Invest. 1999;  22 (5 Suppl.) 82-88
  • 39 Hussain M A, Studer K, Messmer E P, Froesch E R. Treatment with insulin-like growth factor alters capillary permeability in skin and retina.  Diabetes. 1995;  44 1209-1212
  • 40 Bastian S E, Walton P E, Belford D A. Paracellular transport of insulin-like growth factor-I (IGF-I) across human umbilical vein endothelial cell monolayers.  J Cell Physiol. 1997;  170 290-298
  • 41 Blum W F, Breier B H. Radioimmunoassay for IGFs and IGFBPs.  Growth Reg. 1994;  4 (Suppl 1) 11-19
  • 42 Jehle P M, Ostertag A, Schulten K, Schulz W, Jehle D R, Stracke S, Fiedler R, Deuber H J, Keller F, Boehm B O, Baylink D J, Mohan S. Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy.  Kidney Int. 2000;  57 423-436
  • 43 Arner P, Sjoberg S, Gjotterberg M, Skottner A. Circulating insulin-like growth factor I in type 1 (insulin-dependent) diabetic patients with retinopathy.  Diabetologia. 1989;  32 753-758
  • 44 Segev Y, Landau D, Marbach M, Shehadeh N, Flyvbjerg A, Phillip M. Renal hypertrophy in hyperglycemic non-obese diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I.  J Am Soc Nephrol. 1997;  8 436-444
  • 45 Pfeiffer A, Spranger J, Meyer-Schwickerath R, Schatz H. Growth factor alterations in advanced diabetic retinopathy: a possible role of blood retina barrier breakdown.  Diabetes. 1997;  46 (Suppl. 2) 26-30
  • 46 Bar R S, Boes M, Busby W H, Sandra A, Dake B L, Booth B A. Insulin differentially alters transcapillary movement of intravascular IGFBP-1, IGFBP-2 and endothelial cell IGF-binding proteins in the rat heart.  Endocrinology. 1990;  127 497-499
  • 47 Tooke J E, Lins P E, Ostergren J, Adamson U, Fagrell B. The effects of intravenous insulin infusion on skin microcirculatory flow in Type 1 diabetes.  Int J Microcirc Clin Exp. 1985;  4 69-83
  • 48 Flynn M D, Boolell M, Tooke J E, Watkins P J. The effect of insulin infusion on capillary blood flow in the diabetic neuropathic foot.  Diabet Med. 1992;  9 630-634
  • 49 Poldermann K H, Stehouwer C DA, van Kamp G J, Gooren L JG. Effects of insulin infusion on endothelin-derived vasoactive substances.  Diabetologia. 1996;  39 1284-1292
  • 50 Steinberg H O, Brechtel G, Johnson A, Fineberg N, Baron A D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.  J Clin Invest. 1994;  94 1172-1179
  • 51 Boes M, Booth B A, Sandra A, Dake B L, Bergold A, Bar R S. Insulin-like growth factor binding protein (IGFBP)4 accounts for the connective tissue distribuation of endothelial cell IGFBPs perfused through the isolated heart.  Endocrinology. 1992;  131 327-330
  • 52 Takahashi K, Ghatei M Y, Lam H C, O'Halloran D J, Bloom S R. Elevated plasma endothelin in patients with diabetes mellitus.  Diabetologia. 1990;  33 306-310
  • 53 Forst T, Kunt T, Pohlmann T, Goitom K, Engelbach M, Beyer J, Pfutzner A. Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.  J Clin Invest. 1998;  101 2036-2041
  • 54 Jehle P M, Fussgaenger R D, Kunze U, Dolderer M, Warchol W, Koop I. The human insulin analog insulin lispro improves insulin binding on circulating monocytes of intensively treated insulin-dependent diabetes mellitus patients.  J Clin Endocrinol Metab. 1996;  81 2319-2327

1 F. Brausewetter and P. Jehle contributed equally to the work

Priv. Doz. Dr. med. Peter M. Jehle

Department of Internal Medicine II
University of Ulm

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89081 Ulm
Germany


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Email: peter.jehle@medizin.uni-ulm.de