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

• 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 surgeryThe 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.

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.