Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism

Abstract

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3–30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

The Novel Peptide Chm-273s Has Therapeutic Potential for Metabolic Disorders: Evidence from In Vitro Studies and High-Sucrose Diet and High-Fat Diet Rodent Models

“…The rationale of the use of 5 mg/kg as an initial dose for in vivo experiments is based on the previous studies of tetrapeptides missing additional modifications and improved stability profiles [ 55 , 56 ]. This dose is typical for initial studies of the peptides with metabolically relevant features [ 57 , 58 ]. Leptin administered at 1 mg/kg (i.p.)…”

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

“…This has led to the emergence of both GIPR agonizing peptides along with GIPR neutralizing antibodies [ 32 , 33 ] as potential therapeutics for obesity. While GIPR peptide antagonists have been shown to protect against DIO in ovariectomized female mice [ 14 ] and provide benefit on glucose homeostasis in preclinical studies [ [44] , [45] , [46] ] including our own ( Figure 6 C,D), the current literature largely reflects an inability of previous GIPR peptide antagonists to produce additive weight reduction in DIO rodents [ 27 , 45 ] or additively modulate appetite and energy expenditure in obese humans when combined with GLP-1R agonists [ 47 ]. The lack of efficacy in this regard may be due to differences in mouse models used, relative potency of either GIPR antagonists or GLP-1R agonists, or metabolic liabilities leading to degradation of the peptide antagonist as we demonstrate here ( Supplemental figure 2 ).…”

Glucose-Dependent Insulinotropic Polypeptide—A Postprandial Hormone with Unharnessed Metabolic Potential

“…GIPR-blocking antibodies have been shown to have beneficial effects when combined with GLP1R agonists in preclinical models of obesity, as discussed above. Attempts to use peptide-based GIPR antagonists have revealed limited additional effects when combined with liraglutide, reporting either no (110) or minor (160) additional changes in adiposity of DIO mice. Human GIP , a potent antagonist of the human GIPR, has been used in a number of physiological studies, revealing the importance of postprandial GIP for bone metabolism in addition to its incretin role, as discussed above-however, outcomes of chronic GIPR inhibition in humans are lacking.…”