Insulin-Resistance and Benign Prostatic Hyperplasia

Research on insulin-sensitizers can pave the way to identifying a novel therapeutic strategy for the management of prostatic enlargement in insulin-resistant individuals….

Insulin-resistance is currently an increasing worldwide concern. Increased incidence of benign prostatic hyperplasia in the insulin-resistant and diabetic population strengthens the relationship between these two pathological conditions. During insulin-resistance, hyperinsulinemia develops to combat decreased responsiveness of the body towards insulin. Recent experimental and clinical research indicates that insulin plays an important role in the prostatic enlargement, and hyperinsulinemia appears to be the most appropriate explanation for the association between insulin-resistance and benign prostatic hyperplasia.

The present findings may attract the attention of urologists because, for the first time, we provide mechanistic evidence of how insulin-resistance and associated disorders such as obesity, dyslipidemia, sympathetic over activity and hyperinsulinemia together can promote the prostatic growth. Lifestyle and dietary habits have been known to be associated with the development and progression of prostatic hyperplasia. Simple experiments utilizing hypoinsulinemic (streptozotocin-treated) and hyperinsulinemic (high-fat diet) rats clearly demonstrates that, apart from age, chronic change in the systemic insulin level affects the growth of the prostate gland. Insulin-resistance associated secondary rise in insulin can stimulate prostatic growth through:

i) insulin-receptor mediated growth promoting effects and/or
ii) by augmenting the insulin like growth factor-1 receptor signaling.

Recently, it has been reported that insulin/insulin like growth factor signaling activates androgen signaling through direct interaction of the Foxo-1 with the androgen receptor. The hyperinsulinemia can also affect prostatic growth by affecting the androgen signaling in the prostate gland, which may involve,

i) increase in the androgen synthesis,
ii) decrease in the expression of sex-hormone binding globulin, and
iii) decrease in the inhibition of androgen signaling through direct interaction of Foxo-1 with the androgen receptor.

Further, insulin can increase the conversion of testosterone into dihydrotestosterone, which has long been acknowledged as the major controller of prostatic growth. Based on the experimental and epidemiological evidences, hyperinsulinemia can play a crucial role in prostatic enlargement. However, mechanistic investigations employing transgenic animal models which are known to develop hyperinsulinemia and obesity spontaneously with the progression of age, and the prostate-specific insulin receptor knockout animal can help to better understand the role of insulin in the pathogenesis of benign prostatic hyperplasia.

The compensatory hyperinsulinema might result in the over-activation of insulin signaling, to which different organs might show differential response either in nature and/or degree. In vasculature, over-activation of insulin signaling results in the increased expression of the adhesion molecules, resulting in the higher risk for hypertension and atherosclerotic plaque. In females, the role of insulin-resistance and associated hyperinsulinemia has been well established in the pathogenesis of polycystic ovary syndrome (PCOS). Insulin-sensitizing drugs such as metformin and pioglitazone are reported to have a beneficial effect in the treatment of PCOS. Although, alopecia and glucose metabolic disorder has been put forwarded as male equivalent for the PCOS, prostatic enlargement may be another one. These arguments favor the idea that research on insulin-sensitizers can pave the way to identifying a novel therapeutic strategy for the management of prostatic enlargement in insulin-resistant individuals.

Astrup, A., Book Review. New England Journal of Medicine, 2008. 359. 322-22.