Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat

Abstract

. Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat. Am J Physiol Endocrinol Metab 291: E1212-E1219, 2006. First published June 27, 2006 doi:10.1152/ajpendo.00614.2005.-Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) in combination with acipimox (GH ϩ acipimox, 20 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) or fenofibrate (GH ϩ fenofibrate, 30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GHplus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects. growth hormone; acipimox; insulin; free fatty acids GROWTH HORMONE (GH) THERAPY of short normal children or children born small for gestational age (SGA) is often associated with unwanted side effects, such as impaired insulin sensitivity and an enhanced susceptibility, for the development of type 2 diabetes (5,12,22). Furthermore, GH treatment of children with idiopathic short stature or SGA does not lead to achievement of genetic height potential (9,15,31). GH is a lipolytic hormone that induces elevations in free fatty acid (FFA) concentrations, and it is speculated that worsening of insulin sensitivity is a consequence of enhanced omental lipolysis, leading either to alterations in intermediate metabolism or to alterations in membrane characteristics (6,27,32). Previous work in GH-deficient adults (35, 36) has sho...

Genetic disorders in the GH–IGF-I axis in mouse and man

“…In addition, the GH plus FFA regulator combination treatment significantly enhances linear body growth in SGA and control rats. The precise mechanism of this observation remains to be elucidated (100). Chronic excess of GH, as in acromegaly, is associated with insulin resistance and impairment of insulin receptor signal transduction.…”

Growth hormone reverses dyslipidemia in adult offspring after maternal undernutrition

“…In vehicle treated rats an equivalent volume of “saline” was injected at the same time. The dose of rhGH treatment were chosen according to the study of Vickers’ study 42 . Four experimental groups were created: AGA rats receiving rhGH treatment (AGA + rhGH, n = 8), AGA rats receiving NS treatment (AGA + NS, n = 8), SGA rats receiving rhGH treatment (SGA + rhGH, n = 8), and SGA rats receiving NS treatment (SGA + NS, n = 8).…”

Early Growth Hormone Intervention Improves Glucose Metabolism in Adult Rats Born Small for Gestational Age

“…Every morning at 9 am, all groups received a subcutaneous injection of GH (5 mg/kg/day) or the equivalent volume of NS for two weeks. The GH dose was chosen according to a study of Vickers et al [19]. Body weight and length (nose to anus) were determined weekly.…”