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 (200-220g), maintained on normal-pellet or high-fat diet, were injected in the ventral prostate with 200μl of saline or the same volume containing 5U BoNTA at the end of 9weeks and were sacrificed 3weeks 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.