Does glucose-dependent insulinotropic polypeptide receptor blockade as well as agonism have a role to play in management of obesity and diabetes?

Abstract

Recent approval of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, tirzepatide, for the management of type 2 diabetes mellitus (T2DM) has reinvigorated interest in exploitation of GIP receptor (GIPR) pathways as a means of metabolic disease management. However, debate has long surrounded the use of the GIPR as a therapeutic target and whether agonism or antagonism is of most benefit in management of obesity/diabetes. This controversy appears to be partly resolved by the success of tirzepatide. However, emerging studies indicate that prolonged GIPR agonism may desensitise the GIPR to essentially induce receptor antagonism, with this phenomenon suggested to be more pronounced in the human than rodent setting. Thus, deliberation continues to rage in relation to benefits of GIPR agonism vs antagonism. That said, as with GIPR agonism, it is clear that the metabolic advantages of sustained GIPR antagonism in obesity and obesity-driven forms of diabetes can be enhanced by concurrent GLP-1 receptor (GLP-1R) activation. This narrative review discusses various approaches of pharmacological GIPR antagonism including small molecule, peptide, monoclonal antibody and peptide-antibody conjugates, indicating stage of development and significance to the field. Taken together, there is little doubt that interesting times lie ahead for GIPR agonism and antagonism, either alone or when combined with GLP-1R agonists, as a therapeutic intervention for the management of obesity and associated metabolic disease.

Keywords: diabetes; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; obesity; polypharmacy; satiety.

Figure 1

A summary of the tissue-specific benefits of GIPR agonism and antagonism. In addition, the impact of combined GIPR antagonism combined with GLP-1R agonism is considered. Agonism is indicated by green ticks at the GPCR while antagonism is indicated by red crosses. Increases in the therapeutic effect in each instance are indicated by upward arrows and decreases and indicated by downward arrows.

Figure 2

A peptidic structure analysis of glucagon-like peptide-1 (GLP-1) (7–36), the dual GIP/GLP-1 receptor co-agonist tirzepatide and glucose-dependent insulinotropic peptide (GIP) (1–42). Structures for human, mouse and rat GIP(1-42) are provided. Amino acid residues are indicated by single-letter abbreviations. Residues shared with GIP(1–42) are shaded in blue, shared with GLP-1(7–36) are shaded in green, residues shared with both GLP-1 and GIP are indicated in orange and those unique to tirzepatide are shaded in grey. Additionally, species variations between GIP(1-42) are indicated in red. A 20-carbon fatty acid modification, namely eicosanedioic acid, is linked to Glu₂₀ with the full structure provided in gold lettering. ‘Aib’ residues indicate inclusion of 2-aminoisobutyric acid, a non-naturally occurring amino acid. Potency at human GLP-1 and GIP receptors (hGLP-1R and hGIPR, respectively) as well as at mouse and rat GIP receptors (mGIPR and rGIPR) are provided, where appropriate, based on EC50 values provided within the literature for each peptide (Sparre-Ulrich et al. 2016, Willard et al. 2020).