The antiemetic actions of GIP receptor agonism

Abstract

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis.

INTRODUCTION

Nausea and Emesis Compromise Tolerability, Patient Quality of Life, and Prognosis in Disease Treatment

Nausea and vomiting are among the most frequently occurring symptoms in a myriad of diseases and treatments related to metabolic disorders. Given their prevalence and the severe negative impact on nutritional balance, quality of life, and disease prognosis (1, 2), an improved understanding and long-term control of nausea and vomiting remain a critical unmet need in many medical fields such as oncology, virology, immunology, and diabetology. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy [i.e., chemotherapy-induced nausea and vomiting (CINV)] (2). These side effects, which are still far too common and significantly underestimated in outpatient settings, have a profound negative impact on prognosis, quality of life, and the ability to adhere to treatment (3, 4). Despite progress in preventing and managing these side effects via serotonin type 3 receptor and neurokinin 1 receptor antagonists (3), CINV continues to be among the most distressing side effects among patients undergoing classical antineoplastic treatments (5). Studies indicate that between 30 and 80% of patients experience either acute or delayed CINV following chemotherapy, even with the use of modern antiemetic medications (6, 7). Nausea and vomiting often precede anorexia or the worsening of a preexisting anorectic state typically associated with cancer (8–10). Indeed, ∼50% of oncology patients receiving the emetogenic chemotherapeutic cisplatin, one of the most used antineoplastic agents, will manifest anorexia (10, 11).

Drug interventions for diabetes and obesity management (12, 13), including glucagon-like peptide-1 (GLP-1)-based agents, are prime examples of treatments that drive nausea/emesis. GLP-1 receptor agonists have had exceptional outcomes in both weight management and glucose control for almost two decades (14). The long-acting GLP-1 analog semaglutide shows reliable double-digit weight loss in overweight/obese, nondiabetic patients (15). While the success of semaglutide is remarkable, like all GLP-1-based therapeutics predecessors, semaglutide causes nausea and vomiting in a significant percentage of patients (∼20–40%). These side effects occur dose dependently, limiting the potential for higher dosages to achieve optimal glycemic and weight management. Nausea and emesis may also lead to treatment discontinuation, due to reduced dose tolerance in ∼10% of patients (15–19). Even with strategies to reduce side effects such as slow-dose escalation, patients reported malaise-related issues as the major reasons for treatment discontinuation (18, 20).

The prevalence and severity of malaise side effects across various medical fields and treatments emphasize the delicate balance that healthcare providers must strike between achieving optimal treatment and minimizing the discomfort that can accompany many medical conditions and highlight the need to develop not only more effective but also better tolerated treatments.

In this review, we will summarize recent advancements in the field of nausea and emesis management by highlighting the perhaps unexpected antiemetic actions of the glucose-dependent insulinotropic peptide receptor (GIPR) system and its potential as a novel therapeutic target that can be leveraged for the management of various forms of nausea and emesis occurring across medical fields. Additionally, the neuronal substrates engaged by the GIPR system, as well as the underlying molecular mechanism beyond its effects will be discussed.

Neural Substrates Mediating Nausea and Emesis

Improvements in pharmaceutical treatments that lessen emesis and nausea require a focus on the brainstem “vomiting center” (2, 21–24). This pivotal emetic “hub” referred to as the dorsal vagal complex (DVC) comprises three distinct yet interconnected nuclei: the nucleus tractus solitarius (NTS), the adjacent area postrema (AP), and the dorsal motor nucleus of the vagus. Physiological and pathological modulators of energy balance and emesis share many common neural substrates and anatomical nodes in the brain including the AP and NTS, from this point onward referred to as AP/NTS (2, 21, 22). Hence, the overlapping and divergent AP/NTS substrates that mediate nausea and emesis, and separately control food intake without malaise, require investigation.

The AP/NTS is the principal site of axonal convergence for vagal afferent projections originating from the gastrointestinal tract, while the presence of fenestrated capillaries within the AP allows neurons in the DVC to be reached by emetic/anorectic circulating agents that cannot readily cross the blood-brain barrier in other brain regions (21, 25). Increased neural activity within these nuclei correlates with emesis and nausea episodes (23, 26). For instance, chemotherapies, antidiabetic/obesity medications such as GLP-1 analogs, growth differentiation factor 15 (GDF15), lithium chloride, and other emetic agents all activate neurons in the AP/NTS (27–33). This activation subsequently propagates to other upstream targets within the central nervous system (CNS) linked to homeostatic and pathophysiological regulation of feeding, including the parabrachial nucleus and the central nucleus of the amygdala (27–31). However, the precise peripheral mediators operating within the AP/NTS in response to noxious stimuli, as well as the neuronal circuitry underpinning nausea, emesis, and anorexia, remain poorly characterized.

GLUCOSE-DEPENDENT INSULINOTROPIC PEPTIDE PHYSIOLOGY AND PHARMACOLOGY IN THE CONTEXT OF DIABETES AND OBESITY

The glucose-dependent insulinotropic peptide (GIP), also known as gastric inhibitory polypeptide, is a crucial hormone involved in the regulation of glucose homeostasis and insulin secretion. GIP is released from intestinal enteroendocrine K cells shortly after a meal begins (34) and has been historically characterized as an incretin for its role in regulating postprandial plasma glucose concentrations by stimulating insulin secretion (14, 35, 36). In fact, while GIP exerts its effects on various target tissues, its primary physiological role is the stimulation of insulin secretion from pancreatic β-cells in response to luminal glucose. Additionally, GIPR agonism promotes lipogenesis in adipose tissue, contributing to triglyceride storage. GIPR signaling also influences bone metabolism by enhancing insulin’s anabolic effects on osteoblasts, highlighting its multifaceted role beyond glycemic control. A complete review of GIP actions can be found here (37).

Despite a growing body of literature on GIP physiology, there still are limited and contentious preclinical and clinical data on the potential application of GIP analogs for the treatment of metabolic disease (see Refs. 38–41 for review). This ambiguity is partly due to initial findings suggesting the presence of a marked GIP resistance in type 2 diabetes mellitus (T2DM) patients (42), as well as conflicting results regarding the appetite-suppressing and weight-reducing effects of GIPR agonists when administered alone (38, 43–48). Additionally, more recent preclinical studies conducted using monoclonal antibodies to block the GIPR and more refined GIPR antagonists demonstrated body weight lowering capabilities, and similarly, GIPR constitutive knockout mice exhibited resistance to diet-induced obesity (48–50). These data collectively suggest that, paradoxically, both GIPR signaling activation and inhibition can induce comparable metabolic outcomes.

In contrast to contradictory evidence, the outcomes stemming from the study of GIP’s sister incretin, GLP-1, were much clearer. GLP-1 receptor (GLP-1R) agonism not only demonstrated sustained glucoregulatory effects in obese and diabetic patients but also showcased pronounced reductions in body weight (14). As a result, therapeutic strategies leveraging the GIP system were initially disregarded due to their comparatively modest biological and pharmacological impact when juxtaposed with the multiple and potent effects exhibited by GLP-1 analogs.

GLP-1/GIP DUAL AGONISM

In more recent years, enthusiasm for GIPR-based therapeutic approaches resurfaced as several preclinical studies and clinical trials were conducted by combining GIPR and GLP-1R agonism with surprisingly successful outcomes by demonstrating greater body weight loss and superior glycemic control compared to GLP-1R agonism alone (46, 51–54). These efforts culminated with the development of tirzepatide (originally named LY3298176), a long-acting dual “sequence-mixed” GIP and GLP-1 receptor agonist. The positive clinical results from tirzepatide treatments (54–56) paved the way for Food and Drug Administration (FDA) approval for T2DM treatment in May 2022 and its FDA approval for obesity treatment in November 2023 (sold under the brand name Mounjaro and Zepbound, respectively).

Preclinical evidence shows glucose-dependent insulin secretion and improved glucose tolerance with chimeric analogs that act on both GIP and GLP-1 receptors in mice (51). Chronic tirzepatide treatment in diet-induced obesity mice potently suppressed feeding body weight and food intake with a significantly greater effect than the GLP-1 receptor agonist dulaglutide (51). Early phase trials in T2DM patients indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist (51). Subsequent phase II clinical investigations of tirzepatide actions in T2DM patients show significant weight loss reductions, lower fasting insulin and triglycerides concentrations, and strong blood glucose lowering properties, as such that one-third of the patients treated with tirzepatide reached normoglycemia (indicated by a target of glycated hemoglobin A_1C of <5.7%) just after 6 mo of treatment (54). Crucially, tirzepatide demonstrated significantly higher effectiveness in normalizing glucose levels and in promoting weight loss when compared to GLP-1R monotherapy alone (51, 54, 55, 57). Several large-scale phase 3 clinical trials in T2DM (SURPASS) and obese (SURMOUNT) patients are currently ongoing (55, 56, 58–61). These trials have yielded favorable outcomes, not only supporting previous phase II results but also exceeding the performance of semaglutide and other GLP-1R monotherapies in terms of glucoregulation and body weight loss. This general metabolic improvement further underlines the beneficial actions of GIPR activation when combined with GLP-1-based therapeutics.

Another interesting feature of tirzepatide compared to other FDA-approved GLP-1R agonists is its tolerability profile, which allows for higher doses and could consequently increase efficacy in ameliorating many metabolic parameters (51, 54, 57). This prompted the exploration of the possibility that GIPR activation could not only have synergistic/additive effects on glycemic and body weight control but also antagonistic effects on malaise.

EVIDENCE OF GIP ANTIEMETIC PROPERTIES

A patent application filed by Tekada Pharmaceuticals first suggested a potential antiemetic effect of GIPR activation (62). In studies supporting this patent, GIPR agonism reduced conditioned taste avoidance (CTA) and emetic responses that usually occur following gut peptide PYY or cisplatin administrations in ferrets and beagles (62). These foundational results laid the groundwork for advancing our research (63–66), and given the neuronal overlap in pathways of sickness at the level of the DVC for various stimuli, this led us to speculate that GIP could not only enhance the actions of GLP-1 on glucose-handling and energy homeostasis but also antagonize GLP-1R emetic signal(s) by engaging an unknown mechanism(s) that ultimately reduces the incidence and severity of nausea and emesis characteristic of all current GLP-1R-based approaches.

GLP-1-Based Pharmacotherapy

In our laboratory, we first tested an acylated (C-20) long-acting, potent, and selective GIP (GIP-085) receptor agonist multiday action in rodents. Upon first proof of concept validations showing improved glucose clearance and increased circulating insulin levels that provided clear evidence of the insulin-stimulating actions of GIP-085 in rodents, we tested the ability of GIPR agonism to attenuate GLP-1R-induced malaise in rats. In species that lack the emetic-reflex, such as laboratory rats, pica behavior (i.e., ingestion of nonnutritive substances such as kaolin) is used as a validated proxy for nausea/malaise (67) in response to treatments that induce nausea and vomiting in humans, including GLP-1 analogs. Our results demonstrated that while GIP-085 treatment alone did not affect food intake and body weight, remarkably, when coadministered with a long-acting GLP-1R agonist it was able to reduce the acute pica behavior induced by GLP-1R activation (63). GIPR agonism also led to a small, yet significantly higher, food consumption that could be reflective of an overall reduced feeling of malaise experienced by the animals. Additionally, these results were also consistent with our exploratory data in mice showing significant attenuation of GLP-1R-induced conditioned taste avoidance (CTA) by GIPR agonism (63).

The house musk shrew (Suncus murinus) is a vomiting mammal that shows hypoglycemia, anorexia, and emetic sensitivity to various existing GLP-1R agonists (32, 68). We initially validated the effects of GIP-085 to reduce blood glucose through an intraperitoneal glucose tolerance test in this model. Similar to the rodent models, GIP-085 dose-dependently enhanced glucose clearance, underscoring its retained glucoregulatory potency in shrews (63). In addition, GIP-085 produced mild anorexia and body weight loss in the shrews, potentially highlighting species-specific differences in terms of GIP sensitivity. Importantly GIP-085 exhibited excellent tolerability in shrews, demonstrating almost negligible instances of emesis subsequent to administration. When coadministered with the GLP-1R agonist, the cotreatment did not affect the hypophagic and/or body weight lowering effect but remarkably, GIP-085 cotreatment was able to completely prevent GLP-1R induced emesis (63). The data collected in three different species provided the first evidence that GIPR may have antiemetic properties against GLP-1R agonists, highlighting their completely opposing effects in the context of emesis and nausea (63).

Chemotherapy

We have previously tested the effects of GIPR-085 in rats receiving a single injection of cisplatin. Consistent with our and other previous studies, a single dose of cisplatin in rats induces significant kaolin consumption (69–71), anorexia, and weight loss relative to vehicle injections, while there was no effect of GIPR-085 alone. Importantly, GIPR activation reduced pica behavior and partially rescued anorexia and body weight loss induced by cisplatin administration. In parallel experiments, musk shrews were utilized to examine whether GIPR agonism prevents CINV in the shrew similar to what we observed following GLP-1R agonism. In line with previous reports (72, 73), cisplatin treatment induced the expected emetic response along with significant anorexia and body weight loss. By contrast, pretreatment with the GIP-085 in the shrew strongly reduced the incidence and severity of emetic episodes caused by cisplatin, as well as delaying its insurgence. Specifically, GIPR agonism in the shrew reduced the number of emetic episodes by >50% compared to cisplatin-treated controls. Finally, using the ferret model, the gold standard preclinical model of CINV, we determined the effect of a systemically administered short-acting GIPR agonist (Ref. 64) on cisplatin-induced emesis. GIPR activation alone did not cause emesis, but pretreatment with the GIPR agonist prevented emesis and retching that occurred within the first 4 h of all cisplatin-treated ferrets, and only one ferret experienced emesis after GIPR agonism in the subsequent 4 h (65). Overall, these studies collectively demonstrate robust antiemetic properties of GIPR agonism in three species, including two mammalian species with emetic physiology recapitulating that of humans.

How Universal Is the Antiemetic Potential of GIPR Agonism?

The research into the antiemetic actions of GIPR agonism is in its early stages, and we have just begun to explore its full potential and therapeutic value. Nonetheless, there is growing evidence suggesting that GIPR agonism could be effective in preventing nausea and emesis induced by the gastrointestinal satiation signal PYY. The benefits of GIPR activation have been demonstrated in studies in mice, where GIPR agonism was proven effective in preventing PYY-induced CTA while simultaneously enhancing its hypoghagic effects (64). PYY has been extensively investigated for its potential therapeutic value as an antiobesity medication. However, its applicability in humans has been limited also in part due to a low therapeutic index and a high incidence of nausea and emesis at high pharmacological doses (74). Hence, if these findings continue to be confirmed and mechanisms understood, the coadministration of a GIPR agonist may render PYY-based approaches a more viable strategy for the treatment of obesity.

Lithium chloride is a commonly used toxin/stressor to study sickness neural pathways and behaviors as it reliably induces conditioned taste avoidance and aversion, as well as emesis (75–77). In mice, lithium chloride-induced avoidance is blocked by native GIP administration (78); however, GIP analogs show modest effects (64). Explanations for these incongruent results remain elusive. Growth differentiation factor 15 (GDF15) elevations have been linked to nausea and emesis (e.g., cancer, hyperemesis gravidarum, see Ref. 79 for review). An open question is whether nausea and emesis following GDF15 administration (32, 80) could be attenuated by GIPR agonism, as attenuation of GDF15-induced CTA has been inconsistently observed (64, 78).

Notably, all of the aforementioned studies assessed CTA, which is not necessarily a proxy for malaise, nor always correlated with nausea and emesis (see Refs. 81–83 for review). Therefore, more robust models of nausea and emesis are warranted in further studies to thoroughly assess the antiemetic properties of GIPR against these stimuli.

THE MECHANISM OF ACTION FOR GIPR AGONISTS IN BLOCKING EMESIS AND NAUSEA

The peripheral actions of GIP, including the increase in glucose-stimulated insulin secretion following administration of exogenous GIP, have been well characterized and are thought to be mediated, at least in part, by direct activation of GIPRs expressed on pancreatic β-cells (34, 84). Conversely, although GIPR expression within the CNS has been documented in the early 90s (85), only a few studies have investigated the central actions of GIP ligands on feeding behaviors. The renewed interest in the field has prompted studies closely examining the central effects of GIPR activation using modern genetic, molecular, and pharmacological tools (48, 63, 65, 78, 86–90) For a comprehensive review, refer to Refs. 91, 92). These aforementioned studies have shed light on the expression of GIPR in CNS regions historically known to play a role in the regulation of energy balance and metabolism (86, 89), including the AP and the NTS (63, 78, 93). It was somewhat unexpected, given the role of the AP/NTS in mediating GLP-1R effects, that GIPR hindbrain activation via ligand central delivery into fourth ventricle did not affect feeding (63). However, hindbrain GIPR activation was able to antagonize GLP-1R-induced kaolin intake in rats, replicating the effects of systemically delivered GIP agonists and thus suggesting the hindbrain as a key site for GIPR antiemetic actions. In line with these behavioral effects, GIPR agonism significantly reduced neuronal activation in the AP/NTS caused by both GLP-1 analogs and cisplatin in shrews and rats, respectively, supporting a role of the hindbrain in the antiemetic action of GIPR agonism (63, 65).

Single nuclei sequencing and RNA scope data provided further molecular evidence in support of this notion identifying transcriptomically distinct populations within the AP/NTS in respect to GLP-1R and GIPR (63, 65, 93, 94). Only a limited number of neurons were found to express both the GIP and the GLP-1 receptors, suggesting the presence of unique and distinct neuronal circuitries within the AP/NTS for GIPR- and GLP1-R-expressing cells. These data also imply that the ability of GIPR ligands to attenuate malaise behaviors following GLP-1R activation is not due to competing intracellular signaling processes from the ligands acting directly on the same neurons. In support of this hypothesis, these studies also revealed the inhibitory nature of hindbrain GIPR neurons, with the majority of the GIPR-expressing neurons located in the AP expressing the neurotransmitter GABA This suggests that GIPR signaling may exert a downstream local inhibitory modulation (Fig. 1). Indeed, Zhang and colleagues (78) showed that chemogenetic activation of GABA-ergic neurons suppresses conditioned taste avoidance induced by GDF15 and GIP administration counteract GDF15-induced conditioned avoidance; an effect that was prevented by specific ablation of hindbrain GIPR cells.

Figure 1.

We speculate that glucose-dependent insulinotropic peptide (GIP) analogs counteract emesis and nausea via direct modulation of the area postrema/nucleus tractus solitarius (AP/NTS) circuitry. Given the inhibitory nature of the GIP receptor (GIPR)-expressing neurons, one can hypothesize the existence of a local inhibitory network within the caudal hindbrain that could be exploited via GIPR activation to reduce emesis and nausea induced by various stimuli, thus offering a valuable opportunity to treat nausea and emesis across many medical conditions. GIPRA, GIPR agonist; DMV, dorsal motor nucleus of the vagus; CeA, central nucleus of the amygdala; LPBN, lateral parabrachial nucleus.

To provide deeper mechanistic and molecular insights underlying the behavioral and neuronal effects of GIPR signaling in CINV, we performed an unbiased systematic characterization of the AP/NTS cellular transcriptome using small nuclear RNA sequencing in rats following cisplatin or saline treatment (65). Differential gene expression analysis revealed ∼3,000 differentially expressed genes induced by cisplatin. Cisplatin treatment induced a profound alteration in the transcriptomic profile in two distinct nuclei clusters, one of them being the inhibitory GABA-ergic cluster that contains a high percentage of GIPR-expressing neurons. Downstream analysis of the gene expression alterations in these inhibitory neuronal populations was performed using the Kyoto Encyclopedia of Genes and Genomes and canonical pathway analyses with Ingenuity Pathway Analysis to understand how cisplatin affected direct and secondary neurobiological mechanisms. This analysis identified multiple dysregulated biological processes associated with the regulation of synapse and synaptic signaling and revealed significant downregulation of cAMP-response element binding protein signaling, calcium signaling, and synaptic long-term depression pathways in these inhibitory neurons. Collectively, these data suggest that this inhibitory neuronal population, which experienced pronounced transcriptome alterations after cisplatin treatment, would also be the primary site of action for the GIPR agonist that was shown to reduce emetic and anorexic effects on a multispecies basis. While further experiments are needed to provide additional and conclusive mechanistic explanations behind the antiemetic effects of GIPR signaling, altogether current literature suggests that GIPR activation may exert its antiemetic action by activating/restoring a missing basal excitatory neural input to the inhibitory neurons thus counteracting the excitatory effects of emetic agents.

CONCLUSIONS AND UNANSWERED QUESTIONS

The road that led to the characterization of modern antiemetics was marked by a series of serendipitous discoveries that eventually led to the repurposing of existing medications (95). Such is perhaps also the case with GIP, an incretin hormone with mild anorexigenic effects when compared to other gut hormones, which was initially overlooked in favor of more effective agents that regulate glucose homeostasis and control feeding behavior (38, 39). However, recent data suggest that GIPR/GLP-1R dual agonism (e.g., tirzepatide) achieves superior results in terms of body weight loss management and a better safety profile than GLP-1R agonism. Remarkably, and perhaps unexpectedly, there are also preclinical data collected in multiple different mammalian species that uncover a new role for the GIPR system. These studies demonstrate that GIPR signaling is capable of antagonizing malaise induced by various agents, including but not limited to GLP-1, PYY, and the chemotherapeutic agent cisplatin. Initial characterization of the neuronal and molecular circuitry engaged by GIP suggests that GIPR agonism exerts its antiemetic effects via direct central action in the hindbrain, where it increases the inhibitory tone in areas of the hindbrain critical for the mediation of emesis and nausea. Overall, this growing body of literature highlights a potential new clinical use for GIP analogs to increase the efficacy of current therapeutic regimes in many fields of medicine that are characterized by nausea and emesis.

Despite boasting an improved safety and tolerability profile, compared to GLP-1R agonist monotherapies (51, 53, 54, 57–59, 96), gastrointestinal adverse events such as nausea and vomiting were the most common adverse events following tirzepatide treatment. This discrepancy partly contradicts data stemming from preclinical models, which highlight a clear antiemetic action of GIPR agonism. Possible explanations for this could be that the dose range and/or the administration regime employed in the clinical trials was suboptimal and/or rooted in the pharmacodynamic profile of tirzepatide compared to the individual profile of the two single separate components. Additionally, it has been demonstrated that tirzepatide exhibits a bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1R internalization compared to native GLP-1 (97). Such experiments were conducted ex vivo in primary islets. Whether similar effects also occur in the CNS and whether they contribute to an enhanced “emetic” signaling via a biased GLP-1R activation remain to be elucidated. One certainty is that multiple GIPR agonists, when given “alone” as a separate component, were effective in mitigating various forms of emesis and nausea in preclinical models.

Despite significant advances in GLP-1 physiology and pharmacology, future investigations are needed to identify the site(s) of action of GLP-1 analogs in relation to their ability to penetrate the brain. Individual GLP-1R agonists seem to exhibit differential levels of brain penetrance, with exendin-4 displaying the highest, while acylated/conjugated variants like semaglutide and tirzepatide show more restricted blood-brain barrier penetrance (98–101). The existing literature clearly points to the AP/NTS as a critical site for not only the anorectic effects of the GLP-1R agonists but also the CNS site mediating nausea and emesis induced by systemically administered GLP-1R ligands. Thus it is not surprising to note that all FDA-approved GLP-1 ligands easily reach and activate neurons located in the AP/NTS, as well as neurons located in or in proximity to other circumventricular organs (e.g., the median eminence and the arcuate nucleus) (102). Nevertheless, it is reasonable to assert that the variability in brain penetrance may contribute to observed differences in magnitude and incidence of side effects across these GLP-1 analogs. Compounds with greater brain penetrance, in addition to reaching the AP/TS, could potentially directly activate upstream nodes of emetic circuitry also expressing GLP-1R, such as the lateral parabrachial nucleus and central nucleus of the amygdala. Nonpeptidergic small molecules, which inherently possess higher brain penetrance due to size and differential membrane absorption rates, may therefore be associated with increased incidence and severity of nausea and emesis in patients. Further studies and the collection of additional clinical data are necessary to comprehensively evaluate this possibility.

In addition, the extent and breadth of the GIPR agonist antiemetic effects remain to be investigated, as well as the capacity of GIPR agonism to attenuate other forms of malaise, including among others motion sickness, cyclic vomiting syndrome, and hyperemesis gravidarum. Although studies during pregnancy are inherently difficult to conduct, the use of GIPR-based drugs may also offer additional advantages in managing instances of gestational diabetes. Metabolic alternations seen in oncology patients share many similarities with those observed in T2DM patients (103), including insulin resistance and reduced glucose tolerance (104, 105). As GIP-based therapeutics do not cause hypophagia and exhibit antiemetic properties, GIPR monoagonism may represent an intriguing new approach for future investigations targeting cancer-induced insulin resistance.

GRANTS

This work was funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK128443 (to B.C.D.J. and M.R.H.).

DISCLOSURES

M.R.H. and B.C.D.J. have received research funding from Boehringer Ingelheim, Eli Lilly & Co., Gila Therapeutics, Pfizer Inc., and Novo Nordisk, which was not used in support of these studies.

AUTHOR CONTRIBUTIONS

T.B. prepared figures and drafted manuscript; B.C.D.J. and M.R.H. edited and revised manuscript; T.B., B.C.D.J., and M.R.H. approved final version of manuscript.