Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't

Abstract

The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.

Keywords: GIP; GLP-1; coagonist; diabetes; food intake; obesity.

FIGURE 1.

Schematic of different activation statuses of Gα_s-coupled G protein-coupled receptors (GPCR) in white adipose tissue, and the subsequent metabolic effects A: agonism of the Gα_s pathway, as mediated by a white adipocyte-specific Gα_s-coupled DREADD receptor, leads to enhanced cAMP/PKA mediated lipolysis and decreased lipogenesis in DIO mice. B: agonism of the Gα_s pathway, as mediated by white adipocyte-specific glucose-dependent insulinotropic polypeptide receptor (GIPR), has resulted in contradictory results, with reports of enhanced lipolysis and decreased lipogenesis akin to the Gα_s-coupled DREADD receptor, and opposing reports of enhanced lipogenic and decreased lipolytic effects; additionally, there has been conflicting evidence whether GIPR agonism in the white adipocyte increases intracellular cAMP. C: antagonism of the GIPR, which prevents ligand binding and subsequent Gα_s pathways activation, has suprisingly been linked to increases in lipolysis and decreases in lipogenesis. AC, adenylate cyclase.

FIGURE 2.

Schematic on the metabolic phenotype of conditional and global glucose-dependent insulinotropic polypeptide receptor (Gipr) knockout (KO) mice Simplified chart describing the role of tissue-specific GIPR knockouts on the degree of protection against body weight gain under chow and high-fat diet or its requirement for mediating GIPR-based pharmacological-induced weight loss. CNS, central nervous system; DIO, diet-induced obese; GLP-1R, glucagon-like peptide-1 receptor; RT/TN, room temperature/thermoneutral; VGAT, vesicular GABA amino acid transporter; WAT, white adipose tissue.

FIGURE 3.

Tirzepatide as a “super” glucagon-like peptide-1 receptor (GLP-1R) agonist? A–D: simplified schematic describing the alternative intracellular signaling and trafficking dynamics of the GLP-1R at the single receptor level or the global cellular level elicited by GLP-1R monoagonists such as GLP-1-(7-36NH₂) and semaglutide (A and B) or tirzepatide and exendin4-Phe1 (EX4-Phe1) (C and D). GLP-1R signaling and trafficking dynamics following ligand binding and receptor activation by mono-agonists such as GLP-1-(7-36)amide and semaglutide. A1: GLP-1R activation on the level of direct G-protein interaction is maximal, which includes maximal G protein-coupled receptor (GPCR)-mediated GDP to GTP exchange on the Gα_s subunit, and maximal recruitment of GDP-bound Gα_s to the GLP-1R for continued signaling. A2a: the “activated” GTP-bound Gα_s is subsequently recruited to adenylate cyclase where it stimulates the amplified production of cAMP. A2b: Simultaneously, β-arrestin is recruited to the GLP-1R to facilitate a braking mechanism on continued GDP-bound Gα_s recruitment to the ligand-bound GPCR to prevent further signaling. A3: internalization carries the GLP-1R away from the plasma membrane into the intracellular space, where it continues to transiently signal but also is redirected into desensitizing endolysosomal pathways. B: global schematic view at the cellular level of total GLP-1R dynamics resulting from the sum of unique single receptor signaling and trafficking dynamics elicited by GLP-1R agonists such as GLP-1-(7-36)amide and semaglutide. C: GLP-1R signaling and trafficking dynamics following ligand binding and receptor activation by “biased” GLP-1R agonists such as tirzepatide and EX4-Phe1. C1: GLP-1R activation on the level of direct G-protein interaction is minimal. C2a-C2c: maximal cAMP signaling efficacy (C2a) is achieved through minimal β-arrestin recruitment brake on signaling (C2b) and greater GLP-1R retention at the plasma membrane leading to less endolysosomal colocalization and higher receptor exposure to further extracellular ligands (C2c). D: global schematic view at the cellular level of total GLP-1R dynamics resulting from the sum of unique “biased” single receptor signaling and trafficking dynamics elicited by tirzepatide and exendin4-Phe1.