Zeinab Sarem1,2, Christiane Bumke-Vogt2, Ayman M Mahmoud1,3,4, Biruhalem Assefa1,3, Martin O Weickert5,6, Aikatarini Adamidou1, Volker Bähr1, Jan Frystyk7, Matthias Möhlig1, Joachim Spranger1,3,8, Stefanie Lieske9, Andreas L Birkenfeld9,10, Andreas F H Pfeiffer1,2, Ayman M Arafat1,2,3. 1. Department of Endocrinology, Diabetes, and Nutrition, Charité-University Medicine Berlin, Berlin 10117, Germany. 2. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal 14558, Germany. 3. Department of Endocrinology, Diabetes, and Nutrition, Center for Cardiovascular Research, Charité-University Medicine Berlin, Berlin 10115, Germany. 4. Division of Physiology, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62514, Egypt. 5. Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom. 6. Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom. 7. Medical Research Laboratory, Institute of Clinical Medicine, Faculty of Health Sciences, Aarhus University, Aarhus DK-8000, Denmark. 8. Department of Endocrinology, Diabetes and Nutrition, Experimental and Clinical Research Centre, Charité-University Medicine Berlin and Max-Delbrück Centre Berlin-Buch, Berlin 13125, Germany. 9. Section of Metabolic Vascular Medicine, Medical Clinic III, and Paul Langerhans Institute Dresden, Dresden University of Technology, Dresden 01069, Germany. 10. Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 8WA, United Kingdom.
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.
RCT Entities:
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 obeseparticipants, 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 humanosteosarcoma 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.
Authors: Per Ivarsen; Jian-Wen Chen; Ida Tietze; Jens Sandahl Christiansen; Allan Flyvbjerg; Jan Frystyk Journal: Growth Horm IGF Res Date: 2009-12-30 Impact factor: 2.372