Pioglitazone inhibits the diabetogenic action of growth hormone, but not its ability to promote growth.
Analogs of thiazolidinedione improve the responsiveness of insulin-resistant animals to insulin. One such analog, pioglitazone (5-(4-[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, reduces 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 whether feeding pioglitazone can 1) inhibit the ability of GH to induce enhanced insulin resistance in obese mice, 2) ameliorate or reverse GH-induced 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 pioglitazone (20 mg/kg animal.day) for 4 days. During the last 3 days of the feeding period, the mice also received a daily sc injection of either saline or 200 micrograms S-carboxymethylated human GH (RCM-hGH), which is a GH derivative having mainly diabetogenic activity. In control-fed mice, RCM-hGH increased blood glucose and plasma insulin levels, which is an expected response to GH-induced insulin resistance. By contrast, the ability of RCM-hGH to increase blood glucose and plasma insulin levels was totally blocked in pioglitazone-fed mice. To determine whether pioglitazone can ameliorate GH-induced insulin resistance once it has been established, ob/ob mice were treated sc with either saline or 200 micrograms RCM-hGH for 3 days. Half of the saline-treated and half of the hormone-treated mice were then fed pioglitazone, whereas the remaining 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 mice fed the control diet remained elevated with respect to those in the saline-treated controls. On the other hand, the blood glucose and plasma insulin levels of the RCM-hGH treated mice fed pioglitazone were markedly reduced compared to those of the RCM-hGH-treated control-fed animals. Thus, these results suggest that pioglitazone can ameliorate GH-induced insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
Towns
R
R
Department of Physiology, University of Michigan, Ann Arbor 48109.
Kostyo
J L
JL
Colca
J R
JR
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D013006:Growth Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007016:Hypophysectomy; D007333:Insulin Resistance; D051379:Mice; D008820:Mice, Obese; D000077205:Pioglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D001786:Blood Glucose; D007004:Hypoglycemic Agents; C043442:S-carboxymethylsomatotropin; D013844:Thiazoles; D045162:Thiazolidinediones; D013006:Growth Hormone; D000077205:Pioglitazone