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Glucagon decreases IGF-1 bioactivity in humans, independently of insulin, by modulating its binding proteins

Item Type:Article
Title:Glucagon decreases IGF-1 bioactivity in humans, independently of insulin, by modulating its binding proteins
Creators Name:Sarem, Z. and Bumke-Vogt, C. and Mahmoud, A.M. and Assefa, B. and Weickert, M.O. and Adamidou, A. and Baehr, V. and Frystyk, J. and Moehlig, M. and Spranger, J. and Lieske, S. and Birkenfeld, A.L. and Pfeiffer, A.F.H. and Arafat, A.M.
Abstract:CONTEXT: Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined. OBJECTIVE: The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. MATERIALS AND METHODS: In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. RESULTS: Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. CONCLUSIONS: Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway.
Keywords:Blotting, Western, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Enzyme-Linked Immunosorbent Assay, Forkhead Box Protein O1, Glucagon, Growth Hormone, Injections, Intramuscular, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Obesity, Statistics, Nonparametric
Source:Journal of Clinical Endocrinology and Metabolism
Publisher:Endocrine Society
Page Range:3480-3490
Date:1 September 2017
Official Publication:https://doi.org/10.1210/jc.2017-00558
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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