Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Mohali, Punjab, India.
Br J Pharmacol. 2010 Dec;161(8):1708-21. doi: 10.1111/j.1476-5381.2010.00994.x.
Increased incidence of benign prostatic hyperplasia among insulin-resistant individuals suggests a role for hyperinsulinaemia in prostatic enlargement. We have already reported increased cell proliferation and enlargement of prostate gland in insulin-resistant rats. The present study aimed to elucidate the molecular mechanisms underlying the reversal of prostatic enlargement in insulin-resistant rats by the peroxisome proliferator-activated receptor γ agonist pioglitazone.
Sprague-Dawley rats were fed a normal pellet or a high-fat diet for 12 weeks with or without pioglitazone (20 mg·kg(-1)). Subgroups of animals fed different diets were castrated. Effects of dietary manipulation and pioglitazone were measured on insulin sensitivity, lipid distribution, cell proliferation and apoptosis.
A high-fat diet led to the accumulation of fat in non-adipose tissues, insulin resistance, compensatory hyperinsulinaemia and prostatic enlargement in rats. Pioglitazone treatment altered fat distribution, improved insulin sensitivity and normalized lipid and insulin level in rats on the high-fat diet. The improved metabolic parameters led to decreased cellular proliferation and increased apoptosis in the prostate gland. High-fat diet feeding and pioglitazone treatment did not change plasma testosterone levels. However, significant prostatic atrophy was observed in castrated rats irrespective of dietary intervention.
Our results show a previously unexplored therapeutic potential of pioglitazone for prostatic enlargement under insulin-resistant condition and further suggest that targeting distribution of lipid from non-adipose tissue to adipose tissue and insulin signalling could be new strategies for the treatment of benign prostatic hyperplasia.
胰岛素抵抗个体中良性前列腺增生的发病率增加表明高胰岛素血症在前列腺增大中起作用。我们已经报道了胰岛素抵抗大鼠中前列腺细胞增殖增加和前列腺增大。本研究旨在阐明过氧化物酶体增殖物激活受体 γ 激动剂吡格列酮逆转胰岛素抵抗大鼠前列腺增大的分子机制。
Sprague-Dawley 大鼠喂食正常颗粒或高脂肪饮食 12 周，同时或不给予吡格列酮（20 mg·kg(-1)）。给予不同饮食的动物亚组被阉割。测量饮食干预和吡格列酮对胰岛素敏感性、脂质分布、细胞增殖和细胞凋亡的影响。
高脂肪饮食导致非脂肪组织脂肪堆积、胰岛素抵抗、代偿性高胰岛素血症和大鼠前列腺增大。吡格列酮治疗改变了脂肪分布，改善了胰岛素敏感性，并使高脂肪饮食大鼠的脂质和胰岛素水平正常化。改善的代谢参数导致前列腺中细胞增殖减少和细胞凋亡增加。高脂肪饮食喂养和吡格列酮治疗并未改变血浆睾丸激素水平。然而，无论饮食干预如何，阉割大鼠均观察到明显的前列腺萎缩。
我们的结果表明，吡格列酮在胰岛素抵抗情况下治疗前列腺增大具有以前未探索的治疗潜力，并进一步表明，将脂质从非脂肪组织靶向分布到脂肪组织和胰岛素信号可能是治疗良性前列腺增生的新策略。
