Optimization of co‐agonism at GLP‐1 and glucagon receptors to safely maximize weight reduction in DIO‐rodents

Abstract

The ratio of GLP-1/glucagon receptor (GLP1R/GCGR) co-agonism that achieves maximal weight loss without evidence of hyperglycemia was determined in diet-induced obese (DIO) mice chronically treated with GLP1R/GCGR co-agonist peptides differing in their relative receptor agonism. Using glucagon-based peptides, a spectrum of receptor selectivity was achieved by a combination of selective incorporation of GLP-1 sequences, C-terminal modification, backbone lactam stapling to stabilize helical structure, and unnatural amino acid substitutions at the N-terminal dipeptide. In addition to α-amino-isobutyric acid (Aib) substitution at position two, we show that α,α'-dimethyl imidazole acetic acid (Dmia) can serve as a potent replacement for the highly conserved histidine at position one. Selective site-specific pegylation was used to further minimize enzymatic degradation and provide uniform, extended in vivo duration of action. Maximal weight loss devoid of any sign of hyperglycemia was achieved with a co-agonist comparably balanced for in vitro potency at murine GLP1R and GCGR. This peptide exhibited superior weight loss and glucose lowering compared to a structurally matched pure GLP1R agonist, and to co-agonists of relatively reduced GCGR tone. Any further enhancement of the relative GCGR agonist potency yielded increased weight loss but at the expense of elevated blood glucose. We conclude that GCGR agonism concomitant with GLP1R agonism constitutes a promising approach to treatment of the metabolic syndrome. However, the relative ratio of GLP1R/GCGR co-agonism needs to be carefully chosen for each species to maximize weight loss efficacy and minimize hyperglycemia.

Glucagon clearance is regulated by nutritional state: evidence from experimental studies in mice

“…Of particular note is our finding that nutritional state affects glucagon kinetics, since this may yield insights into the relative contribution of hyperglucagonaemia in diabetes, which may differ in fed or fasting conditions or after nutritional challenges. Moreover, the results reported in this work are especially relevant given recent reports proposing glucagon receptor activation as a novel therapy to stimulate energy expenditure in obesity, in particular when used in combination with glucagon-like peptide 1 [15]. The inhibition of glucagon levels after incretin therapy, known to contribute to its improvement of glycaemia [16], may also be influenced by nutritional factors.…”

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…As mentioned above, glucagon increases energy expenditure, thermogenesis, and lipolysis and reduces meal size by exerting a central satiety effect Habegger et al 2010). These observations have led to the development of a new series of drugs with dual agonistic action on glucagon and GLP-1 receptors, with the idea that the hyperglycemic effect of glucagon could be counteracted by the hypoglycemic effect of GLP-1 (Day et al 2009(Day et al , 2012Pocai et al 2009;Tan et al 2013). Recent observations suggest that the activation of glucagon receptor stimulates fibroblast growth factor 21 (FGF21) production and secretion by the liver and that FGF21 mediates, at least partly, the effects of glucagon on energy expenditure and lipid metabolism (Habegger et al 2013).…”

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

“…The relative affinity of OXM for GLP-1-and glucagon-Rs has not been fully verified, although studies do confirm that OXM has a much weaker affinity than the native peptides for these receptors [14]. Nonetheless, a dual effect is beneficial since activation of glucagon-Rs will induce catabolic effects that favour weight loss, while GLP-1R agonism will modulate glucose homeostasis [15]. Thus, it follows that modification of the structure of glucagon could yield useful therapeutic agents for obesity-related diabetes.…”