TheProstate70:79^89(2010) IncreasedCellProliferationandContractilityof ProstateinInsulinResistantRats:Linking HyperinsulinemiaWithBenignProstateHyperplasia A. Vikram, { G. B. Jena, { and P. Ramarao* Departmentof Pharmacologyand Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Mohali,Punjab,India BACKGROUND. Obesity, dyslipidemia, Hyperinsulinemia, and insulin resistance (IR) are key features of metabolic syndrome and are considered as risk factors for benign prostatic hyperplasia (BPH) as well as type 2 diabetes. The present study was aimed to determine whether or not IR associated hyperinsulinemia contributes to the BPH. METHODS. Sprague – Dawley rats (9 weeks) were used in the study. Rats were kept on high fat diet (HFD) for the induction of hyperinsulinemia while hypoinsulinemia was induced by streptozotocin. Effect of HFD feeding on the testosterone-induced prostatic growth was evaluated. Pioglitazone (PG, 20 mg/kg) was used for the reversal of compensatory hyper- insulinemia and to examine the subsequent effect on the prostatic growth. RESULTS. Prostatic enlargement was observed in the HFD-fed rats. Significant increase in the cell proliferation markers confirmed the occurrence of cellular hyperplasia in the prostate of hyperinsulinemic rat. Enhanced a-adrenoceptor mediated contraction in the prostate of HFD- fed rats indicates augmented contractility of the gland. Higher level of phosphorylated-ERK suggests enhanced MEK/ERK signaling. HFD feeding has not led to change in the plasma testosterone level. However, testosterone treatment further augmented the prostatic growth in HFD-fed rats. PG treatment led to improved insulin sensitivity, decreased plasma insulin level and prostate weight, indicating the role of compensatory hyperinsulinemia in the prostate growth. CONCLUSIONS. The present investigation reports that HFD-feeding induced hyperinsuli- nemic condition leads to increased cellular proliferation, enhanced a-adrenoceptor mediated contraction, and enlargement of the prostate in rats. Prostate 70: 79 – 89, 2010. # 2009 Wiley-Liss, Inc. KEY WORDS: high fat diet; hyperinsulinemia; prostate; insulin resistance; streptozo- tocin; pioglitazone INTRODUCTION Prostatic hyperplasia is a highly prevalent condition of the prostate in aging men, characterized by aug- mented cell proliferation [1]. The major factors involved in prostatic hyperplasia is an increase in the smooth muscle tone and enlargement of the gland [2]. Prostatic hyperplasia is a highly prevalent disease in men and a number of reports indicate the incidence of 90% in the ninth decade of life [3,4]. The etiology of prostatic hyperplasia is multi-factorial, and its develop- ment and differentiation is affected by genetic [5], { Research Scholar. { Assistant Professor. *Correspondence to: P. Ramarao, Professor and Head, Department of Pharmacology and Toxicology, National Institute of Pharmaceut- ical Education and Research (NIPER), S. A. S. Nagar, Mohali, Punjab 160 062, India. E-mail: ramaraop@yahoo.com Received 29 June 2009; Accepted 3 August 2009 DOI 10.1002/pros.21041 Published online 29 September 2009 in Wiley InterScience (www.interscience.wiley.com). ß2009Wiley-Liss,Inc.