High-dose metformin (420 mg/kg daily p.o.) increases insulin sensitivity but does not affect neointimal thickness in the rat carotid balloon injury model of restenosis

ABSTRACT Objective Our laboratory has shown that insulin's effect to decrease neointimal thickness after arterial injury is greatly diminished in insulin resistant conditions. Thus, in these conditions, a better alternative to insulin could be to use an insulin sensitizing agent. Metformin, the most commonly prescribed insulin sensitizer, has a cardiovascular protective role. Therefore, the objective of this study was to investigate the potential benefit of metformin on neointimal area after arterial injury in a rat model of restenosis. Methods Rats fed with either normal or high fat diet and treated with or without oral metformin (420 mg/kg daily) underwent carotid balloon injury. Effects of metformin on clamp-determined insulin sensitivity, vessel AMPK (AMP-activated protein kinase) phosphorylation (activation marker) and neointimal area were evaluated. Results Metformin increased insulin sensitivity, but did not affect neointimal thickness in either the normal fat or high fat diet-fed rats. Furthermore, metformin activated AMPK in uninjured but not in injured vessels. Similarly, 10 mM metformin inhibited proliferation and activated AMPK in smooth muscle cells of uninjured but not injured vessels, whereas 2 mM metformin did not have any effect. Conclusion In rats, metformin does not decrease neointimal growth after arterial injury, despite increasing whole body insulin sensitivity.