A novel GIP analogue, ZP4165, enhances glucagon‐like peptide‐1‐induced body weight loss and improves glycaemic control in rodents

Abstract

Aim: To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). Methods:The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice.Results: ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist.Conclusions: ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.

Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study

“…The present study is a human proof-of-concept study based on promising rodent studies showing synergistic energy intake and body weight-lowering effects from co-activation of the GIP and GLP-1 receptors, compared with GLP-1 alone [7][8][9]. The clinical data from the present study contrast these rodent findings.…”

“…In contrast, studies with GIP infusions have not revealed any independent effects on appetite, energy intake or REE in humans [6]. Surprisingly, rodent data have shown that GIP and GLP-1 receptor co-activation elicits a synergistic effect with regard to energy intake: potentiating the satiety-promoting and body weight-reducing effects of GLP-1 [7][8][9]. The interest in GIP and GLP-1 receptor coactivation emerged when Finan and colleagues showed, in diet-induced obese mice, that co-administration of GIP and GLP-1 receptor agonists decreased body weight and energy intake to a greater extent than that elicited by either agonist alone [7].…”

“…In line with the results obtained by Finan and colleagues, Gault and colleagues found in ob/ob mice that whereas daily administration of either liraglutide or N-AcGIP(Lys37Myr) alone did not alter body weight or energy intake, the combination (Lira-AcGIP) significantly reduced both body weight and energy intake [8]. In addition, Nørregaard et al showed that coadministration of liraglutide and a novel GIP receptor agonist resulted in significant reductions in energy intake and body weight in diet-induced obese mice compared with liraglutide alone [9]. Only one study has so far evaluated the effects of co-infusion of GIP and GLP-1 on appetite, energy intake and REE in humans and, because of a small sample size and thereby high risk of statistical type 2 error, no firm conclusions could be drawn [10].…”

CNS-targeting pharmacological interventions for the metabolic syndrome

“…While insulinotropic effects of GIP are well defined, controversy exists regarding its weight-lowering potential. Surprisingly, the pharmacological targeting of the GIP receptor (GIPR) by agonists (130,(136)(137)(138) as well as by antagonists (139,140) led to body weight loss in obese rodents. Notably, a recent study aimed at disentangling these contradictory observations by comparing the in vivo potency of several structurally diverse GIPR agonists with a potent long-acting antagonist (138).…”

RD Lawrence Lecture 2017 Incretins: the intelligent hormones in diabetes

“…Recent preclinical studies have shown that co‐administration or combination therapy with analogues of GIP and other gut hormones and/or analogues (e.g. GLP‐1) leads to improved metabolic outcomes . However, the development of combination therapies would not be perceived as being straightforward, especially concerning optimization of the most effective dose and suitable pharmaceutical formulation.…”