Elevated ambient glucose induces acute inflammatory events in the microvasculature: effects of insulin

We employed intravital microscopy of the rat mesenteric microvasculature to study the effects of local hyperglycemia on leukocyte-endothelial cell int eractions. Intraperitoneal injection of 6, 12.5, and 25 mmol/l D-glucose to the rat significantly and time-dependently increased leukocyte rolling and leukocyte adherence in, and leukocyte transmigration through mesenteric ve nules compared with control rats injected with Krebs-Henseleit (K-H) soluti on alone or given 25 mmol/l L-glucose intraperitoneally. The response elici ted by D-glucose was associated with significant attenuation of endothelial nitric oxide (NO) release, as demonstrated by direct measurement of NO rel ease in inferior vena caval segments isolated from rats exposed to 25 mmol/ l D-glucose for 4 h (P < 0.01 vs, vena caval segments from control rats). L ocal application of 0.05 U/min insulin for 90 min significantly attenuated glucose-induced leukocyte rolling, adherence, and migration (P < 0.01 from 25 mmol/l D-glucose alone). Immunohistochemical localization of P-selectin expressed on endothelial surface was significantly increased 4 h after expo sure of the mesenteric tissue to high ambient glucose (P < 0.01 vs. ileal v enules from rats injected with K-H solution alone or 25 mmol/l L-glucose). Insulin markedly inhibited endothelial cell surface expression of P-selecti n in ileal venules exposed to elevated ambient glucose in vivo (P < 0.01 vs . control rats injected with 25 mmol/l L-glucose). These data demonstrate t hat acute increases in ambient glucose comparable to those seen in diabetic patients are able to initiate an inflammatory response within the microcir culation. This inflammatory response to glucose is associated with upregula tion of the endothelial cell adhesion molecule P-selectin and can be blocke d by local application of insulin.