Oxyntomodulin

Oxyntomodulin Identified as a Marker of Type 2 Diabetes and Gastric Bypass Surgery by Mass-spectrometry Based Profiling of Human Plasma.[Pubmed:27322465]

EBioMedicine. 2016 May;7:112-20.

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.

Oxyntomodulin analog and exendin-4 derivative lower plasma glucose in cattle.[Pubmed:27888738]

Domest Anim Endocrinol. 2017 Apr;59:30-36.

The present study was undertaken with the aim of examining whether and how exendin-4 (1-3) fragment, ie, Ex-4 (1-3) fragment, contributes to the regulation of glucose. An analog of Oxyntomodulin (OXM) ([Gly(2), Glu(3)]-OXM), a glucagon analog ([Gly(2), Glu(3)]-glucagon), and two derivatives of Ex-4 (glucandin and [Gly(2), Glu(3)]-glucandin) were synthesized by substituting with Gly(2), Glu(3) at the N-terminuses of OXM and glucagon and/or by attaching Ex-4 (30-39) amide at the C-terminus of glucagon. Effects of these peptides on plasma insulin and glucose concentrations were investigated in cattle by conducting 3 in vivo experiments. In all 3 experiments, 0.1% BSA saline was injected as a control. In experiment 1, glucandin (amino acid sequence was glucagon [1-29]-Ex-4 [30-39] amide) and [Gly(2), Glu(3)]-glucandin were injected at the dose rates of 5 mug/kg BW in 4-mo-old Holstein steers. Results showed that glucoregulatory effects of glucandin were similar to those of glucagon. [Gly(2), Glu(3)]-glucandin stimulated insulin secretion at 2 to 10 min and lowered glucose concentrations at 15 to 75 min. Experiment 2 was carried out to better understand the glucose-lowering potency of [Gly(2), Glu(3)]-glucandin, in comparison with Ex-4 and glucagon-like peptide-1 (GLP-1), using 4.5-mo-old Holstein steers. [Gly(2), Glu(3)]-glucandin was injected at dose rates of 0.3 mug/kg BW, 1.0 mug/kg BW, 3.2 mug/kg BW, and 6.4 mug/kg BW. Ex-4 and GLP-1 were injected at dose rates of 0.3 mug/kg BW. Results showed that the insulinotropic and glucose-lowering effects of [Gly(2), Glu(3)]-glucandin were not as potent as for Ex-4 and GLP-1, and the minimum effective dose of [Gly(2), Glu(3)]-glucandin to regulate plasma glucose concentrations was 3.2 mug/kg BW. In experiment 3, [Gly(2), Glu(3)]-OXM and [Gly(2), Glu(3)]-glucagon were injected at dose rates of 5 mug/kg BW in 5-mo-old Holstein steers. Both [Gly(2), Glu(3)]-OXM and [Gly(2), Glu(3)]-glucagon increased insulin concentration. [Gly(2), Glu(3)]-OXM potently lowered plasma glucose, but [Gly(2), Glu(3)]-glucagon did not change it. In summary, our findings clearly demonstrate that Ex-4 (1-3) fragment contributes to the regulation of glucose. [Gly(2), Glu(3)]-OXM and [Gly(2), Glu(3)]-glucandin are insulinotropic and glucose-lowering peptides. It was of interest that the substitution of the first 3 amino acids of OXM with Ex-4 (1-3) could reverse the upregulation of glucose by OXM into downregulation of glucose. In lowering glycemia, [Gly(2), Glu(3)]-OXM seemed almost as effective as Ex-4, and [Gly(2), Glu(3)]-glucandin was less profound than Ex-4. These findings contributed new insights into the hormonal regulation of glucose in ruminants. The action of [Gly(2), Glu(3)]-OXM and [Gly(2), Glu(3)]-glucandin might provide an advantage in glycemic control of insulin resistance in cattle and humans.

Characterization and quantification of oxyntomodulin in human and rat plasma using high-resolution accurate mass LC-MS.[Pubmed:27314304]

Bioanalysis. 2016 Aug;8(15):1579-1595.

BACKGROUND: A thorough understanding of the biological role of Oxyntomodulin (OXM) has been limited by the availability of sensitive and specific analytical tools for reliable in vivo characterization. Here, we utilized immunoaffinity capture coupled with high-resolution accurate mass LC-MS detection to quantify OXM and its primary catabolites. RESULTS: Quantification of intact OXM 1-37 in human and rat plasma occurred in pre- and post-prandial samples. Profiles for the major catabolites were observed allowing kinetic differences to be assessed between species. CONCLUSION: A validated assay in human and rat plasma was obtained for OXM 1-37 and its catabolites, 3-37 and 4-37. The value of full scan high-resolution accurate mass detection without selected reaction monitoring for low-abundance peptide quantification was also demonstrated.

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke.[Pubmed:27856285]

Exp Neurol. 2017 Feb;288:104-113.

Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB.

Peripheral oxyntomodulin reduces food intake and body weight gain in rats.[Pubmed:15001546]

Endocrinology. 2004 Jun;145(6):2687-95.

Oxyntomodulin (OXM) is a circulating gut hormone released post prandially from cells of the gastrointestinal mucosa. Given intracerebroventricularly to rats, it inhibits food intake and promotes weight loss. Here we report that peripheral (ip) administration of OXM dose-dependently inhibited both fast-induced and dark-phase food intake without delaying gastric emptying. Peripheral OXM administration also inhibited fasting plasma ghrelin. In addition, there was a significant increase in c-fos immunoreactivity, a marker of neuronal activation, in the arcuate nucleus (ARC). OXM injected directly into the ARC caused a potent and sustained reduction in refeeding after a fast. The anorectic actions of ip OXM were blocked by prior intra-ARC administration of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin(9-39), suggesting that the ARC, lacking a complete blood-brain barrier, could be a potential site of action for circulating OXM. The actions of ip GLP-1, however, were not blocked by prior intra-ARC administration of exendin(9-39), indicating the potential existence of different OXM and GLP-1 pathways. Seven-day ip administration of OXM caused a reduction in the rate of body weight gain and adiposity. Circulating OXM may have a role in the regulation of food intake and body weight.

Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide.[Pubmed:15068960]

Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G693-7.

Many peptides are synthesized and released from the gastrointestinal tract and pancreas, including pancreatic polypeptide (PP) and the products of the gastrointestinal L cells, glucagon-like peptide 1 (GLP-1), Oxyntomodulin, and peptide YY (PYY). Whereas their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behavior. This review considers the anorectic peptides PYY, PP, GLP-1, and Oxyntomodulin, which decrease appetite and promote satiety in both animal models and humans.

A new role for enteric glucagon-37: acute stimulation of glucose absorption in rat small intestine.[Pubmed:9237694]

FEBS Lett. 1997 Jun 30;410(2-3):515-9.

Glucagon-37 is secreted by intestinal L-cells following carbohydrate uptake. It is known to inhibit gastric acid secretion (hence also named Oxyntomodulin) and appears to increase intracellular cyclic AMP concentrations. Since cyclic AMP could enhance intestinal glucose absorption, a possible stimulatory effect of glucagon-37 on glucose transport was examined. Glucagon-37 acutely increased glucose absorption in the isolated, vascularly perfused small intestine and in isolated enterocytes of the rat. In these cells the stimulation by glucagon-37 could be completely blocked by the cAMP antagonist Rp-cAMPS and was therefore mediated by cAMP. The stimulation of intestinal glucose absorption by glucagon-37 appears to be a major new physiological function.

Bioactive enteroglucagon (oxyntomodulin): present knowledge on its chemical structure and its biological activities.[Pubmed:6283496]

Peptides. 1981;2 Suppl 2:41-4.

A bioactive form of enteroglucagon has been isolated from porcine jejuno-ileum according to its glucagon-like effect in liver. Enzymatic digestion followed by HPLC, dansylation and partial sequence analysis strongly suggests that this peptide contains the glucagon molecule (1--29) elongated at the C-terminal end by the octapeptide Lys-Arg-Asn-Lys-Asn-Ile-Ala-COOH and possibly modified in the N-terminal region. A specific action of bioactive enteroglucagon, increase in cAMP, has been found in the acid-secreting fundic part of the rat stomach. The term "Oxyntomodulin" is therefore proposed to describe this peptide.