Exp Clin Endocrinol Diabetes 2015; 123 - P04_10
DOI: 10.1055/s-0035-1547668

Glucagon decreases IGF-1 bioactivity in humans: A novel mechanism by which caloric restriction inhibits cancer development

Z Sarem 1, M Weickert 2, B Assefa 3, A Adamidou 4, V Bähr 4, J Frystyk 5, M Moehlig 6, J Spranger 7, A Pfeiffer 8, A Arafat 9
  • 1Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany; Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany
  • 2University Hospitals Coventry & Warwickshire NHS Trust; Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick
  • 3Department of Endocrinology, Diabetes and Nutrition at the Center for Cardiovascular Research (Ccr), Charité-University Medicine Berlin
  • 4Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany
  • 5Aarhus University Hospital; Dept. of Endocrinology; Dept. of Endocrinology
  • 6Charite-University Medicine; Dept. of Endocrinology, Diabetes; and Nutrition
  • 7Charité-Universitätsmedizin Berlin; Endocrinology, Diabetes and Nutritio
  • 8Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 9Charite University; Endocrinology, Diabetology; and Nutrition

Background: Caloric restriction is known to be one of the most potent dietary interventions in increasing life span and inhibiting cancer development, Moreover, accumulating evidence suggests the impact of insulin-like growth factor 1 (IGF-1) in tumorigenesis. In this study, we aimed to clarify the interaction between glucagon, a hormone secreted during fasting, and IGF-1 bioactivity.

Methods: In our study, we investigated GH-IGF-1 system responses to intramuscular glucagon administration in 13 patients withT1DM (6 males, 7 females; body mass index [BMI] 24.8 ± 0.95 kg/m2), 11 obese participants (OP; 5males, 6 females; BMI 34.4 ± 1.7 kg/m2), and 13 healthy lean participants (LP; 6 males, 7 females; BMI 21.7 ± 0.6 kg/m2). In vitro, using human osteosarcoma cells (U-2OS) and mouse primary hepatocytes, the impact of glucagon on forkhead box transcription factor O1 (FOXO1) translocation, an important modulator of IGFBP-1, the transcription of GH/IGF-1 system members and phosphorylation of Akt was further investigated.

Results: Glucagon significantly decreased IGF-1 bioactivity in all groups (P < 0.01), despite unchanged total IGF-1 and IGFBP-3 levels, whereas significant increase in IGFBP-1 and IGFBP-2 was observed (P < 0.01). In contrast to the transient increase in insulin levels in OP and LP, no change was observed in T1DM. As expected, glucagon induced a surge in GH in all subjects. In vitro, a significant nuclear FOXO1 translocation was induced dose-dependently by glucagon, despite no phosphorylation of Akt was detected. Gene expression of IGF-1, IGFBP-3, IGFBP-1 and IGFBP-2 after glucagon stimulation in mouse primary hepatocytes did not explain in vivo results.

Conclusion: These results indicate that glucagon decreases IGF-1 bioactivity in humans independently of endogenous insulin levels. This reduction may be related to higher levels of IGFBP-1 and IGFBP-2 but not to changes in total IGF-1 or IGFBP-3. Increasing nuclear FOXO1 import may explain the glucagon-mediated up-regulation of IGFBP-1, whereas more analysis regarding glucagon-induced IGFBP-2 is required. Furthermore, we speculate that glucagon-mediated reduced bioactive IGF1 may be responsible for the positive effect of fasting on tumorigenesis.