Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes

Abstract

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of β-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

“…Glucagon receptor stimulation enhances energy expenditure by increasing oxygen consumption, lipid catabolism and thermogenesis amongst other factors [39]. Oxyntomodulin is an endogenous peptide secreted by the enteroendocrine cells of the intestine in response to oral nutrients, which acts as an agonist at both GLP-1 and glucagon receptors [40]. Indeed, the administration of oxyntomodulin reduces food intake and suppresses appetite [41] by activation of GLP-1 receptors [42] and increases energy expenditure via activation of the glucagon receptor [43].…”

No Guts, No Loss: Toward the Ideal Treatment for Obesity in the Twenty-First Century

“…In vitro experiments show that OXM is a full agonist at both the GLP-1 and glucagon receptors, albeit with reduced binding affinities of 10- and 100-fold respectively compared to the cognate peptides ( 70 , 71 ). Consistent with these receptor binding actions, research has shown that OXM potentiates glucose stimulated insulin secretion via the GLP-1 receptor and is an incretin in its own right ( 72 , 73 ). Dakin and colleagues showed that ICV injection of OXM into rats inhibits feeding.…”

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

“…The work using oxyntomodulin, a natural dual agonist for GLP-1R and GCGR, provides a blueprint for the potential therapeutic advantages of targeting both receptors simultaneously. Like GLP-1, oxyntomodulin stimulates insulin secretion by direct action on beta cells [75] and when administered systemically [76,77], and suppresses appetite leading to weight loss [78] [79].…”