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Insulin Suppresses Plasma Concentration of Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9

From the Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo, Buffalo, New York; and Kaleida Health, Buffalo, New York

Address correspondence and reprint requests to Paresh Dandona, MD, D.Phil, Diabetes-Endocrinology Center of WNY, 3 Gates Circle, Buffalo, NY 14209. E-mail: pdandona{at}kaleidahealth.org

OBJECTIVE—We recently demonstrated a potent anti-inflammatory and thus a potential antiatherogenic effect of insulin in human aortic endothelial cells and mononuclear cells at physiologically relevant concentrations. We have now further investigated the anti-inflammatory suppressive action of insulin on vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. VEGF and MMP-9 play a central regulatory role in angiogenesis, contribute to the pathogenesis of proliferative retinopathy, and have also been found to accelerate atherosclerosis.

RESEARCH DESIGN AND METHODS—Insulin was infused (2 IU/h) in 5% dextrose (100 ml/h) and KCl (8 mmol/h) into 10 fasting, obese, nondiabetic subjects for 4 h. Subjects were also infused with 5% dextrose without insulin and with saline on two separate occasions. Blood samples were obtained at 0, 2, 4, and 6 h.

RESULTS—Plasma insulin concentrations increased from a basal level of 12.5 ± 2.2 to 28.2 ± 3.3 µU/ml at 2 h and 24.4 ± 3.7 µU/ml at 4 h after insulin infusion. VEGF concentration decreased from 307.2 ± 163.8 pg/ml (100%) at 0 h to 73.5 ± 20.9% of the basal level at 2 h and 67.1 ± 23.2% at 4h. Plasma MMP-9 concentrations decreased from 375 ± 196.3 ng/ml (100%) at 0 h to 83 ± 22% of the basal level at 2 h and to 82 ± 21% of the basal level at 4 h (P < 0.05). Dextrose infusion alone did not change plasma VEGF concentration. However, plasma MMP-9 concentration increased significantly at 4 h following dextrose infusion alone (P < 0.05). Saline infusions without insulin caused no alteration in glucose, insulin, VEGF, or MMP-9.

CONCLUSIONS—These observations may have implications for a potential antiretinopathic and antiatherosclerotic effect of insulin in the long term.

Abbreviations: ICAM, intracellular adhesion molecule • MCP, monocyte chemoattractant protein • MMP, matrix metalloproteinase • NF-B, nuclear factor-B • VEGF, vascular endothelial growth factor

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