Insulin-resistance reduces botulinum neurotoxin-type A induced prostatic atrophy and apoptosis in rats

Botulinum neurotoxin-type A (BoNTA) is an emerging therapeutic option for the treatment of benign prostatic hyperplasia. Recent reports indicate increased incidence of benign prostatic hyperplasia in the insulin-resistant individuals. Insulin-resistance is associated with the compensatory rise in the plasma insulin, which is known to have growth-promoting effects. The present study investigated the effect of insulin-resistance on the effectiveness of BoNTA in inducing prostatic atrophy in rats. Sprague-Dawley rats (200–220 g), maintained on normal-pellet or high-fat diet, were injected in the ventral prostate with 200 μl of saline or the same volume containing 5U BoNTA at the end of 9 weeks and were sacrificed 3 weeks later. Ventral prostate was carefully isolated, weighed, fixed and stained to examine the cellular morphology, cell death and proliferation. High-fat diet produced insulin-resistance, hyperinsulinemia and prostatic enlargement in rats. BoNTA caused prostatic atrophy and apoptosis in both insulin-resistant and insulin-sensitive rats. However, the effect of BoNTA was more prominent in insulin-sensitive rats (apoptosis-2 fold, prostatic atrophy-3 fold) as compared to the insulin-resistant rats. Significant increase in the phosphorylation of ERK-1/2 and expression of the proliferating cell nuclear antigen was observed in the prostate of insulin-resistant rats. In the present investigation we report that diet-induced insulin-resistance activates mitogenic signaling of insulin, increases cellular proliferation and reduces BoNTA-induced prostatic atrophy and apoptosis in rats. Results of the present study indicate that the insulin-resistance can affect the therapeutic outcome of BoNTA.