BackgroundInsulin growth factor 1 (IGF-1) has multiple effects on metabolism. Much evidence suggests that the deficiency of this hormone increases insulin resistance, impairs lipid metabolism, augments oxidative damage and deregulates the neuro-hormonal axis. An inverse relationship between IGF-1 levels and the prevalence of Metabolic Syndrome (MetS) with its cardiovascular complications has been identified. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. In order to elucidate such mechanisms, the aim of this work was to study, in mice with partial IGF-1 deficiency, liver expression of genes involved in glucose and lipid metabolism as well as serum levels of glucose, triglycerides and cholesterol, as well as liver malondialdehyde (MDA) levels, as a marker for oxidative damage.MethodsThree experimental groups were studied in parallel: Controls (CO), wild type mice (igf-1+/+); untreated heterozygous mice (Hz, igf-1+/−) and Hz (igf-1+/−) mice treated with low doses of IGF-1 for 10 days (Hz + IGF-1).ResultsA reduction of IGF-1 serum levels in the Hz group was found, which was normalized by IGF-1 therapy. Serum levels of glucose, triglycerides and cholesterol were significantly increased in the untreated Hz group as compared to both controls and Hz + IGF-1 groups. The expression of genes involved in gluconeogenesis, glycogenolysis, lipid synthesis and transport, and catabolism were altered in untreated Hz animals and the expression of most of them was normalized by IGF-1 therapy; MDA was also significantly increased in the Hz untreated group.ConclusionsThe mere partial IGF-1 deficiency is responsible for the reduction in the expression of genes involved in glucose and lipid metabolism, resulting in dyslipidemia and hyperglycemia. Such genetic alterations may seriously contribute to the establishment of MetS.

Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1’s effects on liver by comparing wild-type controls, heterozygous igf1+/−, and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.Electronic supplementary materialThe online version of this article (doi:10.1007/s13105-016-0545-x) contains supplementary material, which is available to authorized users.

BackgroundCell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl4)-induced liver damage compared to healthy controls (Wt Igf +/+). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/−).MethodsThree groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+) were included in the protocol: untreated controls (Wt). Controls that received CCl4 (Wt + CCl4) and Wt + CCl4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl4 + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/−) groups were studied: untreated Hz, Hz + CCl4, and Hz + CCl4 + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM.ResultsAn altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl4 + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl4. Moreover, there was a correlation between MDA levels and the histological damage score (Pearson’s r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma.ConclusionsIGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series (healthy and IGF-1-deficient mice) with acute liver damage, suggesting that low doses of IGF-1, in acute liver damage, could be a feasible therapeutic option.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1198-4) contains supplementary material, which is available to authorized users.

Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH) treatment failed to show any improvement. He was born premature and small for gestational age. Genital examination classified the patient as Tanner I–II with small penis and testicular size for his age. Biochemical analyses revealed normal GH levels with low serum insulin-like growth factor-1 (IGF-1). Molecular diagnosis confirmed several mutations in IGF1R and IGFALS, and so he was diagnosed with Laron Syndrome or GH insensibility and treated with IGF-1 substitutive therapy.Learning points:Evaluation of the GH/IGF-1 axis when short stature does not respond to conservative treatment must be included in the ordinary practice.Laron Syndrome real incidence should be calculated once undiagnosed cases arise, as treatment, due to lack of market, is unaffordable.Even when adulthood is reached, and no longitudinal growth can be achieved, still IGF-1 treatment in Laron Syndrome patients should be pursued as metabolic and protective derangements could arise.

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