PIOGLITAZONE INHIBITS THE DIABETOGENIC ACTION OF GROWTH-HORMONE, BUT NOT ITS ABILITY TO PROMOTE GROWTH

Analogs of thiazolidinedione improve the responsiveness of insulin-res istant animals to insulin. One such analog, pioglitazone [2-(5-ethyl-2 -pyridinyl)ethoxy]benzyl}thiazolidine -2,4-dione hydrochloride), when fed to insulin-resistant animals such as the obese (ob/ob) mouse, redu ces blood glucose and lipids and also lowers the plasma insulin level. Because GH can produce insulin resistance in humans and animals such as the ob/ob mouse, the present study was conducted to determine wheth er feeding pioglitazone can 1) inhibit the ability of GH to induce enh anced insulin resistance in obese mice, 2) ameliorate or reverse GH-in duced insulin resistance once it has been induced in ob/ ob mice, and 3) alter the ability of GH to promote growth in hypophysectomized rats . Female ob/ob mice were fed a control diet or a diet containing piogl itazone (20 mg/kg animal.day) for 4 days. During the last 3 days of th e feeding period, the mice also received a daily sc injection of eithe r saline or 200 mu g S-carboxymethylated human GH (RCM-hGH), which is a GH derivative having mainly diabetogenic activity. In control-fed mi ce, RCM-hGH increased blood glucose and plasma insulin levels, which i s an expected response to OH-induced insulin resistance. By contrast, the ability of RCM-hGH to increase blood glucose and plasma insulin le vels was totally blocked in pioglitazone-fed mice. To determine whethe r pioglitazone can ameliorate OH-induced insulin resistance once it ha s been established, ob/ob mice were treated sc with either saline or 2 00 mu g RCM-hGH for 3 days. Half of the saline-treated and half of the hormone-treated mice were then fed pioglitazone, whereas the remainin g animals were continued on the control diet. After 48 h on the diets, the blood glucose and plasma insulin levels of the RCM-hGH treated mi ce fed the control diet remained elevated with respect to those in the saline-treated controls. On the other hand, the blood glucose and pla sma insulin levels of the RCM-hGH treated mice fed pioglitazone were m arkedly reduced compared to those of the RCM-hGH-treated control-fed a nimals. Thus, these results suggest that pioglitazone can ameliorate O H-induced insulin resistance. To determine whether pioglitazone interf eres with the growth-promoting activity of GH, male hypophysectomized rats were fed pioglitazone or a control diet for 2 weeks and then give n a daily sc injection of 0, 10, or 50 mu g hGH for 9 days. Pioglitazo ne feeding was continued during this treatment. Weight gain in respons e to hGH did not differ between the control and pioglitazone-fed group s. There was also no difference in total food consumption (grams of ch ow per g rat) among the groups, and plasma triglyceride levels were si gnificantly lower in the rats fed pioglitazone. These findings indicat e that pioglitazone can counteract the diabetogenic action of GH witho ut affecting its ability to promote growth and suggest that such insul in-sensitizing agents might be used therapeutically to minimize the di abetogenic action of GH.