Inhibition of tumor necrosis factor-α-induced intercellular adhesion molecule-1 expression in diabetic rats:: role of insulin

Objective: The effects of insulin on intercellular adhesion molecule (ICAM)-1-mediated leukocyte adhesion and migration were investigated. Methods: Diabetic rats (alloxan, 42 mg/kg, i. v., 42 days), matching controls, and insulin (NPH, 2 IU/day for 12 days) treated diabetic rats were used. The internal spermatic fascia of the animals was used for direct vital microscopy of the microcirculation, and for quantitation of ICAM-1 expression by immunohistochemistry and reverse transcriptasepolymerase chain reaction (RT-PCR). Experiments were performed 2 h after the local injection of recombinant rat tumor necrosis factor-alpha (5 ng). Results: Relative to controls (C), diabetic (D) rats exhibited a reduced number of adhered (D: 2.2 +/- 0.4 and C: 14.1 +/- 0.6 cells/100 mu m venule length, P < 0.001) and migrated leukocytes (D: 1.1 +/- 0.3 and C: 6.3 +/- 0.6 cells/1,000 mu m(2), P < 0.001) accompanied by low expression of ICAM-1 in postcapillary venules (D: 18 +/- 4 and C: 51 +/- 7 arbitrary units, P < 0.001). There were no differences in ICAM-1 mRNA levels (D: 1.01 +/- 0.05 and C: 1.18 +/- 0.09 ICAM-1/GAPDH ratio, P > 0.05). Treatment of diabetic rats with insulin restored the number of adhered (10.9 +/- 1.2 cells/100 mu m venule length), and migrated leukocytes (4.0 +/- 0.3 cells/1,000 mu m(2)) as well as ICAM-1 expression (45 +/- 3 arbitrary units). Levels of mRNA for ICAM-1 remained unchanged after treatment (1.15 +/- 0.04 ICAM-1/GAPDH ratio). Conclusion: Insulin modulates TNF-alpha-induced ICAM-1 expression on microvascular endothelium controlling, therefore, leukocyte adhesion and migration.