Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming

Abstract

Evidence from human clinical, epidemiological, and experimental animal models has clearly highlighted a link between the early life environment and an increased risk for a range of cardiometabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and overnutrition, spanning exposure windows that cover the period from preconception through to early infancy, clearly highlight an increased risk for a range of disorders in offspring in later life. This process, preferentially termed “developmental programming” as part of the developmental origins of health and disease (DOHaD) framework, leads to phenotypic outcomes in offspring that closely resemble those of individuals with untreated growth hormone (GH) deficiency, including increased adiposity and cardiovascular disorders. As such, the use of GH as a potential intervention strategy to mitigate the effects of developmental malprogramming has received some attention in the DOHaD field. In particular, experimental animal models have shown that early GH treatment in the setting of poor maternal nutrition can partially rescue the programmed phenotype, albeit in a sex-specific manner. Although the mechanisms remain poorly defined, they include changes to endothelial function, an altered inflammasome, changes in adipogenesis and cardiovascular function, neuroendocrine effects, and changes in the epigenetic regulation of gene expression. Similarly, GH treatment to adult offspring, where an adverse metabolic phenotype is already manifest, has shown efficacy in reversing some of the metabolic disorders arising from a poor early life environment. Components of the GH-insulin-like growth factor (IGF)-IGF binding protein (GH-IGF-IGFBP) system, including insulin-like growth factor 1 (IGF-1), have also shown promise in ameliorating programmed metabolic disorders, potentially acting via epigenetic processes including changes in miRNA profiles and altered DNA methylation. However, as with the use of GH in the clinical setting of short stature and GH-deficiency, the benefits of treatment are also, in some cases, associated with potential unwanted side effects that need to be taken into account before effective translation as an intervention modality in the DOHaD context can be undertaken.

Early onset and progression of non-alcoholic fatty liver disease in young monosodium l-glutamate-induced obese mice

“…[16][17][18][19] Noteworthy, early infant GH deficiency and hyperinsulinemia are thought to predispose to a range of late-in-life chronic conditions due to metabolic programming. 20 Thus, those gathered features support MSG obesity as a reliable model to study MetS-related comorbidities under the developmental origins of health and disease concept.…”

What is the evidence for beneficial effects of growth hormone treatment beyond height in short children born small for gestational age? A review of published literature

“…However, GH is an important modulator of insulin sensitivity [11] and may potentially worsen metabolic risk. Alternatively, as the phenotypic outcomes in subjects born SGA closely resemble those of individuals with untreated GH deficiency (GHD), including increased adiposity and reduced lean mass, data from animal models suggest that GH might potentially reverse the adverse effects of prenatal programming [12].…”

Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression

“…The IGF axis is crucial for biological functions, including cell growth and apoptosis. The IGF-induced signaling pathway constitutes several components, including the two ligands (IGF-I and IGF-II), corresponding receptors (IGF-1 and -2R) and IGFBPs, which serve key roles in modulating the activity of the IGF signaling pathway ( 27 ). IGFBP2 may associate with IGF to form a complex, which can readily translocate via the endothelial barrier, and reach local tissues to interact with integrin and elements of the extracellular matrix ( 28 ).…”