Effects of Troglitazone on hepatic and peripheral insulin resistance induced by growth hormone excess in rats.
Researchers: mm,Sugimoto M, Takeda N, Nakashima K, Okumura S, Takami K, Yoshino K, Hattori J, Ishimori M, Takami R, Sasaki A, Yasuda K
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
Source: Metabolism 1998 Jul;47(7):783-787
Summary: The purpose of the present study was to clarify whether troglitazone, a new insulin-sensitizing drug of the thiazolidinedione class, counteracts the insulin antagonistic effects of recombinant human (rh) GH on glucose metabolism in rats. Male Wistar rats weighing 184 to 226 g were treated either with rhGH (n = 8) or rhGH plus troglitazone (n = 8). rhGH (20 IU/kg body weight/d) was given by subcutaneous injection twice daily for 2 days. Troglitazone was given at 100 mg/kg/d orally for 5 days before and 2 days during rhGH. Saline was injected to the control rats (n = 7). Euglycemic clamp studies with an insulin infusion rate of 8 mU/kg/min were performed in these rats after an overnight fast. Hepatic glucose output (HGO), glucose infusion rate (GIR), and glucose disappearance rate (GDR) were measured. Fasting levels of plasma glucose (6.6 +/- 0.1, 6.1 +/- 0.3, 6.5 +/- 0.2 mmol/L), insulin (187.5 +/- 24.1, 206.4 +/- 24.1, 182.3 +/- 31.0 pmol/L), and serum free fatty acid (FFA) (1.58 +/- 0.18, 1.43 +/- 0.16, 1.61 +/- 0.25 mEq/L) were comparable among rats treated with rhGH, rhGH plus troglitazone, and controls, respectively. Basal HGO was also comparable among the three treatment groups. HGO was suppressed significantly during the hyperinsulinaemic glucose clamp in control rats, but not in rhGH rats. When troglitazone was coadministered with rhGH, suppressibility of HGO during the glucose clamp was comparable to that of controls. GIR (13.5 +/- 4.5 v 24.1 +/- 4.1 mg/kg/min) and GDR (18.1 +/- 5.8 v 30.3 +/- 5.2 mg/kg/min) were decreased by rhGH treatment compared with control values. They returned to normal levels in rats treated with both rhGH and troglitazone (GIR, 22.4 +/- 5.9; GDR, 24.7 +/- 7.1). From these results, it is evident that rhGH treatment impaired insulin’s ability to suppress HGO and stimulate peripheral glucose utilization. Troglitazone could block the insulin antagonistic effects of GH on hepatic glucose output and peripheral glucose utilization.
Discussion: The use of Growth hormone for growth hormone deficiency syndrome (GHd) has been practiced since 1958. Up until 1985, all growth hormone preparations came from pituitary extractions. In 1985 a case of Creutzfeld-Jacob disease was reported to have been caused by contaminated growth hormone administration. Since that time, 28 more cases of Creutzfeld-Jacob disease have been reported as a result of contaminated pituitary extract growth hormone administration. Since 1985, recombinant human growth hormone has been produced. This has greatly increased the availability and use of this hormone by non-GH deficient individuals. Everyone from life extensionists to bodybuilders have been using it to effectively change body composition and increase lean mass.
To date, recombinant human GH treatment in patients with or without GHD has produced relatively few side effects, however,glucose intolerance, postprandial hyperglycaemia, and insulin resistance are well known side effects of GH treatment in both animals and humans. GH has been shown to reduce peripheral glucose uptake and prevent insulin mediated decreases in hepatic (liver) glucose output. The majority of studies also indicate that GH administration can cause hyperinsulinaemia (elevated insulin levels). The long term effects on glucose metabolism from GH administration in non-GH deficient adults is not known.
Troglitazone is a thiazolidinedione derivative. It is an antidiabetic drug known to improve glucose metabolism. The mechanism by which troglitazone exerts its antihyperglycaemic effects have been suggested to involve almost every step in the insulin signaling pathway, including insulin receptor kinase, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and glucose transporters.
In the study above we see that coadministration of GH and troglitazone prevented any disturbances in glucose metabolism. Troglitazone therapy began 5 days before GH administration. This is because a lag period of up to 2 – 3 weeks has been reported to be necessary to see the full effects of the drug. Also of interest was the fact that coadministration of thiazolidinediones have been shown not to interfere with the growth promoting effects of GH therapy.
From the results of this study one may assume that coadministration of troglitazone and GH is preferable to GH alone. This strategy may turn out to be a necessary preventative measure taken by non-GH deficient adults using GH to minimize the short term and possible long term deleterious alterations in glucose metabolism. It may also serve as an alternative to using insulin with GH. Because GH can cause hyperinsulinaemia, taking additional insulin only worsens the effects of GH on insulin status. Hyperinsulinemia has been linked to the development of coronary heart disease and type-II diabetes. Anyone using androgens may already be susceptible to coronary heart disease due to altered blood lipid profiles. Adding insulin and GH only increases their risk of heart problems down the road.
Leave a Reply
You must be logged in to post a comment.