Antihypertensive effects of metformin in fructose-fed hyperinsulinemic, hypertensive rats

In the present study, we examined the relationship between elevated insulin levels and hypertension in the fructose-hypertensive rat model, in which the rise in blood pressure is induced by feeding normal rats a fructose-enriched diet. Six-week-old Sprague-Dawley rats were divided into four experimental groups: control (C, n = 8), control metformin-treated (CT, n = 8), fructose-fed (F, n = 9) and fructose-fed, metformin-treated (FT, n = 10). Long-term oral metformin treatment (500 mg/kg/day) was begun in the CT and FT groups, and 1 week after the initiation of metformin treatment, the F and FT groups started receiving a 66% fructose diet. Metformin treatment prevented the increase in plasma insulin levels in the FT rats (FT, 32 +/- 4 microU; F, 51 +/- 7 microU-ml; P < .001) without any change in plasma glucose levels. Interestingly, metformin treatment also prevented the increase in systolic blood pressure in the FT group (FT, 143 +/- 2 mm Hg; F, 159 +/- 2 mm Hg; P < .001) but had no effect in the CT group (CT, 142 +/- 3 mm Hg; versus C, 141 +/- 2 mm Hg; P > .05). Restoration of plasma insulin levels in the FT group to levels that existed in the untreated F rats reversed the effect of metformin on blood pressure (FT plus insulin, 158 +/- 3 mm Hg; F, 160 +/- 3 mm Hg; P > .05). In conclusion, metformin prevents the hyperinsulinemia and hypertension that occur after feeding normal rats a fructose-enriched diet. Also, the antihypertensive effects of metformin can be reversed by raising the plasma insulin levels in the treated rats to those that exist in the untreated fructose-fed group, which suggests that hyperinsulinemia may contribute toward the increase in blood pressure in this model of experimental hypertension.