Oxyntomodulin Identified as a Marker of Type 2 Diabetes and Gastric Bypass Surgery by Mass-spectrometry Based Profiling of Human Plasma

• Published in: EBioMedicine 2016-05, Vol.7 (C), p.112-120
• Main Authors: Wewer Albrechtsen, Nicolai J., Hornburg, Daniel, Albrechtsen, Reidar, Svendsen, Berit, Toräng, Signe, Jepsen, Sara L., Kuhre, Rune E., Hansen, Marie, Janus, Charlotte, Floyd, Andrea, Lund, Asger, Vilsbøll, Tina, Knop, Filip K., Vestergaard, Henrik, Deacon, Carolyn F., Meissner, Felix, Mann, Matthias, Holst, Jens J., Hartmann, Bolette
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - blood; Diabetes Mellitus, Type 2 - blood; Dipeptidyl Peptidase 4 - blood; Disease Models, Animal; Gastric Bypass; GLP-1; Glucagon-Like Peptide 1 - blood; Gut hormones; Humans; Low-abundant peptides; Mass Spectrometry - methods; Mass-spectrometry; Mice; Oxyntomodulin - blood; Oxyntomodulin - isolation & purification; Proteomics; Proteomics - methods; Research Paper
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.03.034

Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1), is inactivated by the same protease (dipeptidyl peptidase-4) as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides. •In the pursuit of identifying metabolic peptides in humans we developed a streamlined mass-spectrometry based platform•Our platform was used to investigate a gut derived glucose and appetite regulatory peptide, oxyntomodulin•Levels of oxyntomodulin are reduced in subjects with type 2 diabetes and increased after gastric bypass surgery The human plasma comprises a variety of peptides with importance for metabolic health. Identification of such peptides has been exploited for developing glucose-lowering therapies, such as incretin-based therapy. We therefore developed a mass-spectrometry based platform for identification of peptides in humans and by applying this platform we characterized a peptide hormone oxyntomodulin secreted from the intestine in response to glucose. Our data suggest that oxyntomodulin is down-regulated in subjects with type 2 diabetes and up-regulated after bariatric surgery. In summary, the collected data indicate that oxyntomodulin may co-orchestrate appetite and glucose regulatory effects together with incretin hormones.