Journal Article

Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins

Spranger, Joachim, Adamidou, Aikatarini, Möhlig, Matthias, Frystyk, Jan, Arafat, Ayman M, Weickert, Martin O, Bumke-Vogt, Christiane, Lieske, Stefanie, Assefa, Biruhalem, Birkenfeld, Andreas L, Bähr, Volker, Pfeiffer, Andreas F H, Sarem, Zeinab, Mahmoud, Ayman M

2017

Overview

ContextDepending 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.ObjectiveThe 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 MethodsIn 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.ResultsDespite 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.ConclusionsOur 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.Our data have demonstrated that the IGFBP-1 and -2–mediated insulin-independent glucagon-induced decrease in IGF-1 bioactivity is a mechanism through which glucagon induces GH secretion.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Adult / AKT protein / Biological activity / Blotting, Western / Bone cancer / Clinical s / Diabetes mellitus / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - diagnosis / Diabetes Mellitus, Type 1 - drug therapy / Diabetes Mellitus, Type 1 - metabolism / Dose-Response Relationship, Drug / Double-Blind Method / Drug Administration Schedule / Enzyme-Linked Immunosorbent Assay / Female / Forkhead Box Protein O1 - drug effects / Forkhead Box Protein O1 - metabolism / Forkhead protein / FOXO1 protein / Gene expression / Glucagon / Glucagon - administration & dosage / Growth Hormone - drug effects / Growth Hormone - metabolism / Growth hormones / Hepatocytes / Humans / Injections, Intramuscular / Insulin / Insulin-Like Growth Factor Binding Proteins - drug effects / Insulin-Like Growth Factor Binding Proteins - metabolism / Insulin-like growth factor I / Insulin-Like Growth Factor I - drug effects / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factor-binding protein 1 / Insulin-like growth factor-binding protein 2 / Insulin-like growth factor-binding protein 3 / Insulin-like growth factors / Kinases / Lipid metabolism / Male / Nuclear transport / Obesity / Obesity - metabolism / Obesity - physiopathology / Osteosarcoma / Osteosarcoma cells / Phosphorylation / Protein transport / Proteins / Rapamycin / Sarcoma / Secretion / Statistics, Nonparametric / TOR protein