Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Abstract

Abstract. Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg-' h-' into six volunteers to study its pharmacokinetics and effects on pentagastrinstimulated gastric acid secretion (100 ng kg-' h-I). The concentration of oxyntomodulin in plasma measured with a cross-reacting glucagon assay increased from 37+5 to 106+ 17and 301 k40pmol I-', respectively. The metabolic clearance rate was 5.2k0.7 ml kg-' min-' and the half-life in plasma was 12 & 1 min. Oxyntomodulin reduced the pentagastrin-stimulated acid secretion by 20 f 9% during the low-rate infusion ( P < 0.05) and by 76 f 10% during the high-rate infusion (P < 0.05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C-peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.

Small Molecule Allosteric Modulation of the Glucagon-Like Peptide-1 Receptor Enhances the Insulinotropic Effect of Oxyntomodulin

“…Of importance, differences in metabolic clearance of GLP-1(7-36)-NH 2 /(7-37) versus oxyntomodulin may enhance oxyntomodulin-mediated signaling at the GLP-1 receptor as a result of more rapid inactivation of GLP-1(7-36)-NH 2 /(7-37) by DPP-4 because it is a better DPP-4 substrate than oxyntomodulin (Zhu et al, 2003). The half-life of GLP-1(7-36)-NH 2 /(7-37) is 1 to 2 min (Siegel et al, 1999), whereas half-life estimates for oxyntomodulin range from 6 to 12 min Schjoldager et al, 1988;Kervran et al, 1990). Furthermore, infusion studies in humans confirm the metabolic actions of oxyntomodulin (Cohen et al, 2003), and new drug discovery approaches to develop long-acting analogs of oxyntomodulin are being pursued (Pocai et al, 2009;Santoprete et al, 2011).…”

Therapy for Obesity Based on Gastrointestinal Hormones

“…The effects of acute administration of oxyntomodulin in humans include inhibition of gastric emptying, gastric and pancreatic exocrine secretion, and food intake [60,62]. Also, repeated subcutaneous administration causes marked weight loss in obese subjects [63].…”

“…The peptide is rapidly degraded by DPP-4 and neprylsin with a half-life of approximately 12 minutes [60,61]. The effects of acute administration of oxyntomodulin in humans include inhibition of gastric emptying, gastric and pancreatic exocrine secretion, and food intake [60,62].…”

Metabolic Synchronization of the Liver Circadian Clock

“…Injections of OXM during fasting conditions almost abolishes gastric acid secretion after pentagastrin stimulation [198] or after refeeding in rodents [199]. Even in humans synthetic OXM inhibits pentagastrin-stimulated acid secretion [200]. GLP-1 and GLP-2 as well as glucagon show comparable but much weaker actions on gastric acid secretion [201][202][203][204].…”