👤 Maria B N Gabe

The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment. Show less

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent. Show less

Enzymatic cleavage of endogenous peptides is a commonly used principle to initiate, modulate and terminate action for instance among cytokines and peptide hormones. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and the related hormone glucagon-like peptide-2 (GLP-2) are all rapidly N-terminally truncated with severe loss of intrinsic activity. The most abundant circulating form of full length GIP(1-42) is GIP(3-42) (a dipeptidyl peptidase-4 (DPP-4) product). GIP(1-30)NH Show less

In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with K Show less

Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR). Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. ClinicalTrials.gov (NCT03159741). Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30)NH Show less