Pioglitazone attenuates prostatic enlargement in diet-induced insulin-resistant rats by altering lipid distribution and hyperinsulinaemia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Vikram
Ajit
A
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Mohali, Punjab, India.
Jena
Gopabandhu
G
Ramarao
Poduri
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002369:Castration / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000139:chemically induced* / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D011467:Prostate / Q000187:drug effects / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D013739:Testosterone; D000077205:Pioglitazone