[581,795], although in contrast to GIP-induced cFos labelling in the hindbrain, there is a fairly limited colocalization with *GIPR*-Cre labelled cells [120]. Tanocytes in the ME further facilitate BBB transcytosis of circulating peptides [948], and while this may be crucial for liraglutide to inhibit food intake [949], no such transport has yet been demonstrated for GIP.

Both GLP-1R and GIPR agonists reach the hindbrain via the area postrema (AP) [580,581,944,945], but while GLP-1R agonists induce cFos neuronal activity in the AP and the nucleus tractus solitarius (NTS) [54], most GIPR agonists induce cFos activity primarily in the AP [581,932,950,951]. GIP-induced cFos activation in the AP is preserved in vagotomized mice, indicating that vagal afferents are not required for GIP-induced activation of AP neurons [951]. Expression of *Gipr* is further enriched in the AP [932,950], but scarce in the NTS and the nodose ganglion of the vagus nerve [580,932,950]. In the AP and the hypothalamus, neuronal expression of *Gipr* is largely limited to *Vgat*-expressing inhibitory GABAergic neurons [607,611,952], and specific deletion of *Gipr* in these neurons not only extinguishes GIP-induced cFos activity in the AP, ARC, and PVN, but also renders mice resistant to GIP-induced weight loss and inhibition of food intake [581]. The exact mechanisms by which GIPR signaling in GABAergic neurons decreases body weight and food intake in rodents remains to be determined, along with delineation of whether these effects are mediated via GIPR signaling in the AP, the hypothalamus or both. In any case, there is ample evidence indicating that the AP and the ME are first order signaling nodes that facilitate food intake inhibition through GIPR agonism in rodents (Figure 8). Efferent neurons regulating food intake project from the AP to the NTS, and further to the parabrachial nucleus (PBN) [953], the central amygdala (CeA) and the hypothalamus [580,950,954], all of which are implicated in the regulation of homeostatic and/or hedonic food intake [953,955,956]. Although the neurons in the PBN are primarily glutamatergic, and hence do typically not express *Gipr* [957], GIPR neurons project from the dorsal vagal complex (DVC) to the PBN [580], and peripherally injected acyl-GIP increases cFos activity not only on the AP, but also in the PBN [580], CeA [954] and the hypothalamus [581,587,795]. Chemogenetic activation of GIPR neurons in the DVC is sufficient to induce cFos activity in the PVH, and to reduce food intake in mice [580], suggesting that GIP decreases food intake by transmitting satiety signals from the AP to the PBN, CeA and the hypothalamus. The PVH also receives projections from the ARC, and while peripheral administration of acyl-GIP increases cFos activity in the ARC [581,795], chemogenetic activation of hypothalamic GIPR neurons decreases food intake in mice [587]. Viral-mediated knock-down of *Gipr* in the hypothalamus, however, does not extinguish superiority of GLP-1 and GIP co-therapy to yield greater weight loss and further inhibition of food intake relative to GLP-1R agonism alone [580]. Although these data suggest that hypothalamic GIPR signaling plays only a minor role in regulating food intake, viral-mediated gene knock-out is often incomplete and requires confirmation in genetic KO models. Moreover, the observation that a small fraction (<10%) of POMC neurons express *Gipr* [587], and that single peripheral administration of acyl-GIP increases cFos activity in a comparable subset of POMC neurons in the ARC [591] suggests involvement of the hypothalamus in the body weight lowering and food intake suppressing effects of GIP. Activation of ARC POMC neurons has further been shown after treatment of DIO mice with the long-acting GIPR agonist GIPFA-085 [936], but DIO mice with targeted deletion of *Gipr* in cells/neurons that express the *leptin receptor (Lepi)* do not show differences in body weight or food intake and remain fully sensitive to GIP-induced weight loss and inhibition of food intake [591]. Nonetheless, GIP and GLP-1 have recently been shown to inhibit AGRP

neuronal activity in fasted mice, and that GIP but not GLP-1 is required for full nutrient-induced silencing of AGRP neuronal activity [958]. In summary, there is increasing evidence indicating that long-acting GIPR agonists act centrally to decrease body weight and food intake in DIO mice via the hindbrain-hypothalamus axis, and these effects are mediated via GIPR signaling in GABAergic neurons, with potential implication on AGRP neurons.

While food intake inhibition through peripherally administered acyl-GIP is extinguished in mice with neuronal loss of *Gipr*, acyl-GIP-induced weight loss is in some studies partially preserved [795]. These data indicate that acyl-GIP not only decreases body weight through inhibition of food intake via CNS GIPR neurons, but potentially also by non-CNS mechanisms that are unrelated to food intake. In agreement with this are recent data showing that mice with adipocyte-specific over-expression of GIPR are lean and show decreased body weight when fed with a HFD [799]. Nonetheless, future clinical studies are needed to examine whether GIP effects on body weight and food intake translate to humans.

Infusion of native hGIP at physiological concentrations (0.8–1.5 pmol/ kg/min) for 5 h prior to or during a meal did not affect food intake, energy expenditure or plasma triglyceride removal in healthy humans [959]. In humans living with overweight/obesity, infusion of GIP at a dose of 4–6 pmol/kg/min for 4–5 h even abolished food intake inhibition of simultaneously infused GLP-1 [181], or revealed no effect relative to treatment with GLP-1 alone [960]. However, caution is warranted when extrapolating data from acute studies using native peptides to chronic studies using long-acting peptides that have been optimized for enhanced pharmacokinetic properties. In line with this notion, some studies in DIO mice show that acyl-GIP decreases food intake, at the earliest, after 6–8 h of peripheral bolus administration [581,795]. Moreover, two long-acting, selective GIPR agonists, LY3537021 and NNC0480-0389, were recently tested in healthy humans and in individuals with T2D. In a 34 week, phase 2 study in individuals with T2D, NNC0480-0389 lowered body weight by –4.3% compared to –10% in individuals receiving semaglutide and –2.7% in participants receiving placebo (EudraCT Number 2020-004863-14 - Clinical trial results - EU Clinical Trials Register). While the numerical weight loss seen with NNC0480-0389 did not reach statistical significance compared to placebo, two of the four tested doses of NNC0480-0389 in combination with semaglutide 2.4 mg resulted in significantly greater weight losses relative to semaglutide 2.4 mg alone; supporting a weight loss effect of the GIPRA. In a 4-week, phase 1 study, LY3537021 showed a placebo-adjusted decrease in body weight of up to –1.79 kg in healthy volunteers, and up to –2.78 kg in participants with T2D [961]. These data collectively suggest that the body weight lowering effects of GIPR agonism may to some extent translate from rodents into humans.

## 17.2. Use of GIPR agonists in unimolecular formats with GLP-1R agonists for the treatment of obesity and diabetes

With the spotlight on therapeutic exploitation of GLP-1 mimetics, plus doubts about effectiveness of GIPR agonism in humans with T2D, early preclinical studies with stable GIPR agonists had until very recently [961] not progressed to clinical development. However, in 2013, Matthias Tschöp and Richard DiMarchi reported the first unimolecular peptide co-agonists with similar affinities, efficacies and functional cAMP activity at the receptors for GIP and GLP-1 [177]. The rationale for the development of these GIPR:GLP-1R co-agonists was based not only on the assumption that the molecules would act at both target receptors to further improve glucose metabolism, as demonstrated earlier in ob/ob mice [287], but also on the then rather unexpected
observation that co-therapy with both peptides yielded greater weight loss and further inhibition of food intake relative to GLP-1R agonism alone in DIO rodents [177]. The first GIPR:GLP-1R co-agonists were based on the glucagon sequence, in which amino acid residues from GLP-1, GIP and exendin-4 were stepwise introduced to achieve near-balanced agonistic activity at GIPR and GLP-1R, while also protecting against DPP4 proteolysis and abolishing activity at the glucagon receptor (GCGR) [177].

The first generation of these DPP4 protected co-agonists was either pegylated or acylated with a C16 fatty acid, and exhibited superiority over liraglutide to decrease body weight and to improve glycemia in DIO and db/db mice, ZDF rats and cynomolgus monkeys [177]. The acylated molecule (known as MAR709, NN9709, RG7697, R06811135 or NN0090-2746) advanced to clinical development, but despite good tolerability and meaningful reduction in body weight and HbA1c in phase 1 trials [177,962,963], development was discontinued after a short phase 2a study, in which MAR709 showed, at the single tested dose, only moderate superiority over open-label liraglutide in people with T2D after 12-weeks of treatment [964]. While the short duration of treatment and the lack of a dose-escalation regime were distinct limitations of this clinical study [964], in DIO mice, MAR709 caused greater weight loss and further inhibition of food intake relative to treatment with a pharmacokinetically-matched GLP-1 backbone, and this superiority was extinguished in mice lacking GIPR in either the CNS [795] or more specifically in GABAergic neurons [581].

The GIPR:GLP-1R co-agonist tirzepatide (previously known as LY3298176) was first reported by Eli Lilly in 2018 [176]. The DPP4-protected molecule is based on the sequence of GIP, and contains a mixture of residues from GLP-1, GIP, and exendin-4. Tirzepatide has similar affinity and potency for cAMP production at the GIPR as native GIP, and 5-fold lower affinity and 13-fold lower potency for cAMP production at the GLP-1R compared to native GLP-1 in recombinant human cell lines overexpressing these receptors. The molecule has a C20 fatty diacid attached to render the molecule suitable for once-weekly (QW) dosing [176]. Although MAR709 and tirzepatide are potent full agonists at hGIPR, MAR709 maintained high potency at mGIPR, while tirzepatide has at least 10-fold lower potency at mGIPR. Consequentially, at a dose of 10 nmol/kg, MAR709 depends on CNS GIPR signaling to yield superior weight loss over GLP-1R agonism in DIO mice [581,795], whereas tirzepatide, when used at the same dose, does not decrease body weight in GLP-1R KO mice [965]. Nonetheless, at a dose of 10 nmol/kg, tirzepatide improves insulin sensitivity independent of body weight loss via GIPR [965], suggesting that tirzepatide at this dose has sufficient occupancy of mGIPR to affect glycemia but not body weight. Consistent with this are recent observations showing that the body weight lowering effect of tirzepatide is further enhanced in DIO mice when tirzepatide is given together with a long-acting GIPR agonist [966]. In another study, however, tirzepatide was shown to stimulate insulin secretion in isolated human islets predominantly via GIPR, but almost exclusively via GLP-1R in murine islets [967]. The species-specific differences in tirzepatide's potency at the murine vs. human GIPR warrant caution when extrapolating tirzepatide's metabolic effects from mice to humans. At the GLP-1R, tirzepatide and MAR709 further show notable differences to GLP-1, with both exhibiting different degrees of biased agonism at GLP-1R to favor cAMP production over β-arrestin recruitment relative to GLP-1, and delayed receptor internalization [548,549] and, in case of MAR709, enhanced receptor recycling [548]. At both of its target receptors, tirzepatide is further biased towards pERK1/2 relative to cAMP accumulation when compared to the respective endogenous peptide agonists GLP-1 and GIP [968]. While it remains to be determined

whether this biased agonism at the GLP-1R affects drug efficacy, depletion of β-arrestin in GIPR/GLP-1R expressing HEK293 cells increases ligand-induced cAMP/PKA signaling [555]. Tirzepatide and GIP further differentiate in their ability to induce phosphorylation of the human GIPR, with both peptides inducing phosphorylation of four serine residues at hGIPR and tirzepatide inducing an additional 5th serine residue phosphorylation [969].

Tirzepatide received FDA approval for the management of T2D in 2022, and for obesity in 2023. The glycemic effects of tirzepatide (at doses of 5, 10, or 15 mg QW) in individuals living with T2D and/or overweight/obesity were evaluated in the SURPASS 1-6 trials. In SURPASS-1, depending on the dose, up to 92% of participants receiving tirzepatide achieved an HbA1c below 7.0% after 40 weeks of treatment, compared to 19% in placebo treated controls, while up to 52% versus 1% achieved an HbA1c reduction below 5.7% [970]. Tirzepatide performed equally well in the SURPASS 2-6 trials, with superior reductions in HbA1c relative to treatment with semaglutide 1 mg [178], insulin degludec [971], insulin glargine [972,973], and insulin lispro [974], and with preserved efficacy and safety in individuals at risk for CV diseases [973]. In Japanese people living with T2D, tirzepatide decreased HbA1c by -2.8% after 52 weeks of treatment, relative to -1.3% in dulaglutide treated controls [975], and similar effects were observed in the SURPASS J-combo trial, in which tirzepatide was given as add-on therapy to sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors in Japanese people with poorly controlled T2D [976].

The multi-center SURMOUNT trials assessed the efficacy of tirzepatide for weight loss in people living with overweight and one or more complications or obesity. In SURMOUNT-1, tirzepatide led to a reduction in body weight after 72 weeks of treatment of up to -20.9% in non-diabetic individuals, compared to -3.1% in the placebo treated-controls [977]. In people with overweight/obesity and T2D, tirzepatide decreased body weight after 72 weeks treatment by -14.7% relative to -3.2% in placebo controls [978]. Although with minor variations, this level of weight loss is broadly confirmed across the SURPASS trials [178,970-976,979]. Moreover, tirzepatide reduced waist circumference, systolic and diastolic blood pressure, fasting insulin level, and lipid levels and more than 95% of the participants with prediabetes went into remission to normoglycemia, which seems to have additional beneficial effects on the prevention of type 2 diabetes [977,980]. In SURMOUNT-3, tirzepatide's effects were evaluated in people with overweight/obesity without T2D following intensive lifestyle intervention, demonstrating a reduction in body weight of -18.4% after 72 weeks with tirzepatide, compared to a +2.5% weight gain with placebo [981]. In SURMOUNT-4, individuals living with overweight/obesity were treated with tirzepatide for 36 weeks, followed by continuation with tirzepatide or switch to placebo for an additional 56 weeks [982]. After 36 weeks, the mean percent weight change was -20.9%. Individuals continued on tirzepatide showed an additional weight loss of -5.5%, for a total weight loss of -26.4%, while individuals switched to placebo gained 14.0% during the 56 week follow-up period [982]. In summary, along with the recent observation that the body weight lowering effects of GIP may to some extend translate to humans [961], GIPR:GLP-1R co-agonism has emerged as a valuable and highly effective strategy for the management of obesity and T2D, and with comparable safety relative to best-in-class GLP-1R agonists [178,970-976,979,983]. Notably, a head to head comparison of the efficacy of tirzepatide and semaglutide at their highest approved doses demonstrated a mean weight loss of 20.2% vs 13.2% for tirzepatide vs. semaglutide, respectively (https://investor.lilly.com/news-releases/news-release-details/lillyss-zepboundr-
tirzepatide-superior-wegovyr-semaglutide-head#: ~:text=Lilly's%20Zepbound%2C2%AE%20(tirzepatide)%20superior,13.7%25%20%7C%20Eli%20Lilly%20and%20Company). Consistent with these findings, individual trials assessing each drug alone show that tirzepatide at the highest approved dose of 15 mg QW outperforms semaglutide 2.4 mg QW to yield greater weight loss and further improvement of glucose control [971,977,978,984,985], and this has also been confirmed in a recent meta-analysis [986]. Comparing drug efficacies nonetheless remains challenging, since data related to receptor exposure in key target tissues are unavailable, and no human study has yet assessed tirzepatide effects upon blockade of GLP-1R. While the relative contribution of GIPR agonism to the metabolic efficacy of tirzepatide remains to be demonstrated, recent clinical data with two long-acting, selective GIPR agonists, LY3537021 and NNC0480-0389, support a potential body weight lowering effect of GIPR agonism in humans (see above).

The therapeutic potential of GIPR:GLP-1R co-agonism extends beyond managing T2D and obesity. A recent phase 2 study involving individuals with biopsy-confirmed metabolic-associated steatohepatitis (MASH) and moderate to severe fibrosis demonstrated that up to 62% of participants treated with tirzepatide achieved MASH resolution without worsening fibrosis, compared to only 10% in the placebo group after 52 weeks of treatment [987]. Additionally, 51% of individuals treated with tirzepatide showed an improvement of at least one fibrosis stage, compared to 30% of participants in the placebo group [987]. In a phase 3 trial involving individuals with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide decreased the number of apneas and hypopneas during an hour of sleep (apnea-hypopnea index, AHI) by -29.3 events per hour, relative to -5.5 events in placebo controls [988]. Along with further decreases in patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) levels and systolic blood pressure [988], these data prompted the FDA on December 20th 2024 to approve tirzepatide for the treatment of moderate-to-severe obstructive sleep apnea and obesity in adults. A recent clinical study assessing measured and patient self-reported alcohol drinking behavior further showed that individuals treated with tirzepatide (or semaglutide) for ≥30 days exhibit reduced alcohol cravings, desire to drink alcohol, and binge drinking episodes, which along with decreased Alcohol Use Disorders Identification Test (AUDIT) scores indicates that these medications may hold therapeutic value for also treatment of addictive behavior [989]. Whether this holds true for also drug addiction and nicotine use disorder, however, warrants further clarification.

## 17.3. Use of GIPR:GLP-1R:GCGR triple agonists for the treatment of obesity and diabetes

Expanding the concept of unimolecular incretin-based polyagonism, Tschöp and DiMarchi reported in 2015 the first acylated peptide with 10-fold higher potency for cAMP accumulation than the respective endogenous agonist at the receptors for GLP-1, GIP and glucagon [295]. The rational for adding glucagon receptor (GCGR) action to GIPR:GLP-1R co-agonism was anchored on the preclinical success of GLP-1R:GCGR agonism, which yielded superior weight loss with preserved (or even improved) glycemic benefits relative to GLP-1R agonism in obese rodents [294]. In keeping with glucagon's complementary pharmacology to decrease food intake, increase energy expenditure and enhance hepatic lipid utilization [745,990,991], the triagonist outperformed GIPR:GLP-1R co-agonism to further decrease body weight while improving glucose control and hepatic lipid metabolism in rodents [295]. The functional importance of each peptide entity was verified by genetic or pharmacological silencing of

each individual biological activity [295], and was further evident by the classical glucagon effects to increase energy expenditure and hepatic lipid utilization [295,992]. The triagonist further improved dyslipidemia and ameliorated hepatic steatosis in obese mice, and these effects were observed even at doses where the drug had only marginal effects on body weight and food intake [993]. A series of GIPR:GLP-1R:GCGR triagonists were additionally developed, each with notable differences in structure, duration of action, and activity at each target receptor [292,293,994–998]. The clinically most advanced triagonist is retatrutide (LY3437943), which is based on the GIP sequence with stepwise amino acid substitutions introduced to achieve triple agonism [176,997]. The molecule further includes non-natural amino acids at positions 2, 13, and 20, to protect from DPP4 recognition and to enhance the activity at the receptors for GIP and glucagon, while maintaining activity at the GLP-1R, and a C20 fatty-diacid was attached to lysine at position 17 to extend the circulating half-life through albumin binding. In recombinant human cell lines, retatrutide exhibits similar activity at GCGR and GLP-1R (~2–3 fold lower potency relative to GCG and GLP-1, respectively), but ~9-fold enhanced potency at GIPR relative to GIP [997]. In obese rodents, it decreases body weight with superior efficacy relative to treatment with tirzepatide [176]. In line with the thermogenic action of GCGR agonism, retatrutide increased energy expenditure, and this effect contributed 30–35% of the total weight loss in DIO mice and disappeared upon pharmacological inhibition of GCGR [997]. In Phase 1 clinical trials, retatrutide exhibited a safety profile comparable to dulaglutide [997,999]. Treatment-emergent adverse events (TEAEs) were mainly gastrointestinal and occurred in 63%, 60%, and 54% of participants treated with retatrutide, dulaglutide, and placebo, respectively [999]. Retatrutide dose-dependently decreased systolic/diastolic blood pressure by up to 12/2 mmHg, while mean pulse rate increased by up to +10 bpm during the last four weeks of treatment [999]. In phase 2 trials, retatrutide decreased body weight in individuals living with overweight/obesity after 48 weeks of treatment, and at the highest tested dose of 12 mg QW, by -24.2%, relative to -2.1% in placebo-treated controls, and with 26% of patients achieving weight loss >30% compared to 0% for placebo [1000]. Weight loss was associated with a decrease in plasma triglycerides and LDL cholesterol, and although heart rate dose-dependently increased by +7 bpm at week 24 when corrected for placebo, it declined to +5.7 by week 48 [1000]. Retatrutide also caused a dose-dependent decrease in liver fat, with up to 86% of individuals with metabolic dysfunction associated fatty liver disease reaching normal liver fat after 48 weeks of treatment [1001]. In individuals with T2D, retatrutide resulted in a decrease in HbA1c of up to -2.02% compared to -0.01% for placebo and -1.41% for the selective GLP-1R agonist dulaglutide, demonstrating that in the context of GLP-1R and GIPR agonism, activation of glucagon receptors does not impair glycemic control [1002]. In summary, incretin-based polyagonism has emerged as a powerful approach to extend the pharmacological potential of GLP-1R agonism, and with favorable tolerance and translation of metabolic effects from rodents to humans. Despite such major strides in the development and clinical use of these unimolecular polyagonists which target the GIPR, a number of stable GIPR monoagonist peptides are in preclinical development or phase 1 or 2 clinical trials. These include the yet unpublished XW-017 (Hangzhou Sciwind Biosciences Co), ZP6590 (Zealand) and several long-acting GIPR agonists, including NNC0480-0389 (Novo Nordisk), LY3537021 (Eli Lilly) [961], LY3532226 (Eli Lilly) and GIPFA-085 (Eli Lilly) [936]. Beneficial effects of these agents have been noted in conference presentations and most recently for LY3537021, which is reported to induce significant weight loss in subjects with T2D but
without nausea or vomiting [961], and NNC0480-0389, which in a phase 2 study in individuals with overweight/obesity and T2D enhanced weight loss relative to treatment with semaglutide 2.4 mg (EudraCT Number 2020-004863-14 - Clinical trial results - EU Clinical Trials Register). It is evident therefore that these GIP analogues can overcome the resistance reported when administering native GIP [144,151,152]. Nevertheless, it seems questionable whether any of these monoagonists in development will, when administered alone, prove superior to the clinical benefits of the established polyagonist peptides. One advantage could be less severe Gl-side effects, greater compliance and fewer discontinuations compared with GLP-1 agonism [1003]. Another possibility could be simple co-administration of these agents with long-acting analogues of other therapeutic peptides as advocated for CCK-8, GLP-1, OXM and PYY [1004,1005]. However, even then it might prove more attractive to develop appropriate unimolecular polyagonists and a GIP/xenin hybrid has already been shown to be effective in DIO rodents [440,1006]. Interestingly, dual GIP/GLP-2 agonists have also been developed for potential treatment of bone fragility and osteoporosis [819,847]. In contrast to peptide therapeutics, there has been little success in attempts to develop small molecule agonists acting at the GIPR. One exception is 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide (4H2BH) which appears to antagonize both GIP and glucagon action [1007].

## 17.4. Regulation of body weight and food intake, insulin action by GIPR antagonism and by unimolecular GIPR antagonism/GLP-1R agonism

The benefits of GIPR agonism can largely be attributed to weight loss and stimulation of insulin secretion [281,581,591,795]. It is therefore counterintuitive that GIPR signal inhibition also shows clear benefit in obesity and T2D. These include protection of *Gipr* deficient mice from diet-induced obesity and associated glucose intolerance [800,804–806,1008–1010], and amelioration of obesity and glucose intolerance in ob/ob and/or DIO mice by low molecular weight GIPR antagonists [1011,1012], Pro(3)GIP analogues [272,1013–1015], active or passive GIP vaccination [1016–1019], or targeted destruction of GIP-secreting K-cells [439]. Moreover, genetic *GIPR* variants that lead to decreased receptor function are associated with decreased BMI in humans [560,856,1020,1021]. The most extensively studied scenario concerns the antidiabetic effects of Pro(3)GIP described by the Coleraine group where, unlike GIPR agonists, amelioration of diabetes is associated with lower rather than raised insulin concentrations [272,280]. This is attributed to compromised effects of native GIP on adipose tissue resulting in clearance of triglyceride from adipose and liver stores, thereby substantially improving insulin sensitivity and alleviating insulin resistance. In such circumstances, insulin demand is less and any deficit in GIP action from the enteroinsular axis is not missed. As discussed later, an alternative view is that GIPR antagonism may result in the promotion of GLP-1 action. However, that does not necessarily fit with phenotype induced in these animal models where the major effect is to improve insulin action. Such action is not restricted to these scenarios or Pro(3)GIP and later studies published in 2015 using more specific GIPR antagonists, GIP(3-30)Cex-K(40)[PAL] and Pro(3)GIP(3-30)Cex-K(40)[PAL], similarly ameliorated insulin resistance and glucose intolerance in both DIO and db/db mice [169,1022]. However, how GIPR inhibition protects from obesity and associated insulin resistance remains puzzling, and may include increased lipid utilization [804], decreased intestinal nutrient uptake [1023], decreased food intake [805,1008], and/or increased energy expenditure [803,805]. In support of this, a recent study showed that the GIPR antagonist AT-7687 prevented weight gain when given as

monotherapy, in HFD-fed non-human primates [1024]. Although mice with adipose-specific loss of *Gipr* are not protected from diet-induced obesity [589,807,808], isoproterenol-induced lipolysis is increased in isolated GIPR-deficient white adipocytes [803]. Nonetheless, oral administration of lipids increases lipid storage in global *Gipr* deficient mice [803], which is in line with the observation that GIP induces lipolysis under conditions where insulin action is low to absent [597,598,769,794–796], and that mice with adipocyte-specific overexpression of *Gipr* show decreased fat mass and protection from diet-induced obesity [799].

In contrast to mice with adipose-specific loss of *Gipr* [589,807], mice with Nestin Cre-mediated neuronal loss of *Gipr* [795], or with deletion of *Gipr* specifically in inhibitory GABAergic neurons [581,966], show decreased body weight and fat mass when fed with a HFD, and this is paralleled by decreased food intake without changes in energy expenditure. However, although these data indicate that protection from diet-induced obesity in *Gipr* deficient mice originates, at least in part, from the lack of GIPR signaling in the CNS, the obesity-protecting phenotype of mice with neuronal loss of *Gipr* is rather mild and does not fully explain the resistance to weight gain seen after global *Gipr* deletion.

Protection from diet-induced obesity is paradoxically also observed in some studies with GLP-1R deficient mice [805,806]. Furthermore, chronic antagonization of GLP-1R decreases body weight gain during HFD-feeding with equal efficacy relative to antagonization of GIPR, and body weight gain is even further reduced upon adjunct antagonization of both incretin receptors [806]. Antagonism of either GIPR or GLP-1R enhances the sensitivity to the alternate incretin, as demonstrated *in vivo* by enhanced glycemic action of GIP following inhibition of GLP-1R [806] and by enhanced insulinotropic action of GLP-1 in the perfused GIPR-deficient pancreas [1025]. Other studies, however, show that genetic loss of either GIPR or GLP-1R does not enhance the insulin response to and plasma concentrations of the alternate incretin after oral glucose administration [1026–1028]. Nonetheless, consistent with the potential anti-obesity effect of GIPR signal inhibition, evident from early studies, are more recent reports showing that certain GIPR antagonists, or GIPR neutralizing antibodies, prevent HFD-induced weight gain, improve insulin sensitivity, and/or decrease body weight and food intake in DIO mice [939,1029,1030] and non-human primates [1024,1029], particularly when given in adjunct to GLP-1R agonism [1029,1031,1032].

AMG133 (maridebart cafraglutide, maritide, Amgen) is a bispecific hybrid that comprises two GLP-1R agonists moieties conjugated to a monoclonal anti-GIPR antagonist [1032,1033]. In DIO mice and non-human primates, AMG133 decreases body weight with superior efficacy relative to treatment with the respective monotherapies alone, and in DIO mice, drug-induced weight loss is superior to treatment with dulaglutide [1032]. Weight loss induced by AMG133 is primarily driven by inhibition of food intake, and is paralleled by improved insulin sensitivity, a decrease in blood glucose and a decrease in plasma levels of insulin, triglycerides and cholesterol [1032,1033]. In phase 1 trials, AMG133 was well tolerated, and a once monthly injection schedule over three months led to more than 10% weight loss in healthy human subjects [1033]. Although the relative contributions of blocking the GIPR vs. activating the GLP-1R cannot be ascertained in these clinical studies, these data have encouraged progression to phase 2 development. These data were recently corroborated by a study in non-human primates, showing that the peptide-based GIPR antagonist AT-7687 in combination with the GLP-1R agonist liraglutide results in greater weight loss relative to placebo as compared to treatment with liraglutide alone [1024].
The mechanisms of how GIPR antagonism decreases body weight and food intake remain elusive. Central immunoneutralization of GIPR was recently shown to decrease SOCS3, a negative regulator of leptin signaling, while central GIPR agonism had the opposite effect, hence indicating that GIPR antagonism may decrease body weight by improving leptin sensitivity [939]. Improvement of leptin sensitivity can, however, not fully explain protection from obesity in *Gipr* deficient mice, since lack of GIPR decreases body weight in obese leptin deficient ob/ob mice [804]. Mice with specific loss of *Gipr* in *Lepr* neurons are further not protected from diet-induced leptin resistance [591]. Another popular hypothesis is that GIPR agonism desensitizes the GIP receptor, and hence leads to functional antagonism [1034]. However, this is not supported by distinct differences in the metabolic phenotype induced by GIPR agonism vs. antagonism in various animal models of obesity-diabetes, with the latter intervention alleviating insulin resistance and inducing β-cell rest [169,272,1014,1015,1022]. The hypothesis, however, is anchored on the observation that repetitive GIPR stimulation decreases the sensitivity of the GIP receptor in DIO mice and in isolated adipocytes [592], and is supported by the phenotype of the common naturally occurring GIPR variant E354Q (rs1800437) with enhanced internalization rate and altered intracellular sorting [869–871], resulting in overall loss-of-function phenotypes [820,1035,1036]. Desensitization of GIPR by GIPR agonism, however, seems to be restricted to GIP effects on the islets, and does not occur for GIP's effect on CNS-mediated food intake suppression [1037]. Ligand-induced receptor desensitization has also been shown for GLP-1 in rat insulinoma INS-1 cells [617] and for both incretins in hamster β-cell HIT-T15 cells [616], but is not observed *in vivo* in healthy human subjects [158]. Here, it is, however, important to note that the desensitization of the GIPR is different from that of the GLP-1R, as GIPR internalization relies on arrestins [559], while that is not the case for the GLP-1R [558]. The same pattern goes for the cAMP production elicited by these two receptors, as the GIP receptor's Gs-mediated signaling is weakened in the absence of arrestins, while the opposite is observed for the GLP-1R [856]. Thus, from a molecular and cellular perspective, these two incretins are distinct when it comes to long-term agonist exposure. Prolonged treatment of DIO mice with acyl-GIP does, however, not decrease expression of *Gipr* in either the hypothalamus or the adipose tissue [795]. Yet, this could be due to a generally impairment of mouse GIPR in arrestin recruitment and receptor internalization compared to the human GIPR [562]. GIPR agonists and antagonists may also affect systemic energy metabolism via different central and/or peripheral mechanisms. While GIPR agonists depend on GABAergic GIPR neurons in the CNS to decrease food intake [581,966], GIPR antagonists may silence these or other neuronal populations to enhance the anorectic action of adjacent glutamatergic neurons. In line with such an assumption is the demonstration that a significant portion of food-intake inhibiting GLP-1R neurons are glutamatergic [612], and that GIPR antagonists primarily decrease food intake when given in adjunct to GLP-1 [1029,1031].

## 17.5. GIP effects on drug-induced emesis

Gastrointestinal (GI) discomfort, such as constipation, diarrhea, nausea and emesis are common adverse effects associated with the use of numerous pharmacotherapies, including antibiotics, antidepressants, opioids, chemo- or radiotherapy and GLP-1R agonists. Related to GLP-1R agonists, GI-adverse effects may occur in >50% of people at treatment initiation and represent the most frequent reasons for temporary or permanent treatment discontinuation [1038–1041]. Although GI-side effects associated with the use of

GLP-1R agonists are often for the majority of patients reported as transient and often resolve after 4–6 weeks of treatment without permanent drug withdrawal [1038–1041], they decrease the quality of life of the affected individuals and may prevent the use of higher doses otherwise required to optimize treatment outcome. Appreciably, GIPR agonism attenuates the emetic effects of GLP-1R agonism, as demonstrated by amelioration of GLP-1 induced pica behavior in rats, conditioned taste avoidance in mice and emesis in musk shrews [930] (Figure 8). In all of these animal models, the co-therapy of long-acting GIPR agonists and GLP-1R agonists reduced indices of malaise observed with GLP-1R agonism alone. GIP also decreases conditioned taste avoidance induced by treatment with PYY in mice [932] and attenuates chemotherapy-induced nausea and vomiting in ferrets and shrews [931]. Recent clinical studies show that the selective, long-acting GIPR agonists attenuate GI adverse events of GLP-1R agonists, providing evidence that anti-aversive effects of GIP may translate to humans [1003,1042]. The mechanisms by which GIPR agonism exerts its anti-emetic effects are not well understood but seem to reside in its ability to act on the hindbrain GIP receptor [1043].

Drug-induced emesis is for the most part mediated via the dorsal vagal complex (DVC), which comprises the AP, the NTS and the DMV [1043–1046], hindbrain areas also implicated the regulation of body weight and satiety by the incretin hormones. Similar to the incretins, many emetic drugs elicit cFos neuronal activation in the AP and the NTS [1047–1050] and ablation of the AP in cats or dogs abolishes emesis induced by radiation- and chemotherapy [1051,1052] nicotine [1053], PYY [1054], and apomorphine [1052]. GIP further suppresses conditioned flavor avoidance in mice by inhibiting GDF15/GFRAL responsive excitatory neurons in the AP, and these effects vanish when *Gipr* is deleted in a specific cluster of AP inhibitory neurons [951]. In the NTS, the emetic chemotherapeutic cisplatin induces cFos activity in GLP-1R neurons, and blockade of these neurons using the GLP-1R antagonist exendin 9-39 attenuates cisplatin-induced anorexia, weight loss and pica in rats [1047]. Pharmacological blockade of GLP-1R further attenuates lithium chloride (LiCl)-induced cFos activation in the AP, NTS, and PBN [1055] and further attenuates LiCl-induced dopamine suppression in the VTA [1056]. The emetic effect of PYY is paralleled by increased cFos activation in the PBN and GIP treatment decreases PYY-induced cFos activation in this area [932]. In line with a role of hindbrain GIPR signaling in the anti-emetic effect of GIPR agonism is the observation that central (i.c.v.) administration of GIP into the 4th ventricle of rats decreases kaolin intake induced by systemic GLP-1 treatment in rats [930], and that GIPR agonism attenuates GLP-1-induced cFos neuronal activation in the AP and NTS of rats and shrews [930].

Notably, the anorectic and aversive effects of GLP-1R agonism seem to be mediated by a heterogenous group of neurotransmitter/neuropeptide-expressing neurons in the DVC. Of relevance to GLP-1-mediated effects on nausea and malaise, it is interesting to note that GLP-1R expressed on a subset of CCK/glutamatergic neurons in the AP and NTS co-express the receptor complex Gfral-Ret for the emetogenic cytokine GDF15. Although these neurons are not directly targeted by GIPR agonism (as they do not co-express the GIPR), GIP ameliorates GLP-1-induced conditioned taste avoidance in mice, and this is paralleled by reduced GLP-1 induction of cFos activity in these CCK/glutamatergic neurons [950]. The antiemetic effect of GIPR agonism is undoubtedly an appreciable merit, which may have contributed to the near comparable tolerability of tirzepatide and semaglutide at the highest approved doses, i.e. 15 mg for tirzepatide versus 2.4 mg for semaglutide.
# 18. GIP EFFECTS ON NEURODEGENERATIVE DISEASES

The first data indicating that GIPR agonism has neuroprotective effects in the brain date back to 2005, where studies in rats showed that GIP stimulates proliferation of hippocampal progenitor cells *in vitro* and *in vivo* [122,1057]. The rate of progenitor cell proliferation in the hippocampal dentate gyrus correlates positively with the expression of *Gipr* in the hippocampus [122], and is accordingly decreased in *Gipr* deficient mice [122,925]. Treatment with [D-Ala₂]GIP further improves mitochondrial function while decreasing autophagy and apoptosis in human neuroblastoma SH-SY5Y cells exposed to rotenone, a pesticide and inhibitor of complex 1 of the mitochondrial electron transfer chain, that can induce Parkinson's disease (PD) in humans [1058]. In line with these data, GIP promotes neuronal survival in cultured cerebellar granule neurons by inhibiting apoptosis [606,1059], and mice deficient for *Gipr* show impaired learning and memory, along with reduced synaptic plasticity in the hippocampus [925], a key region that is implicated in spatial learning and memory [1060,1061] and involved in the development of neurodegenerative diseases [929]. Conversely, transgenic mice overexpressing *Gipr* show enhanced exploratory behavior, increased motor performance and improved working memory [1062], while treatment of wildtype mice or rats with [D-Ala₂] GIP enhances learning, synaptic plasticity and neurogenesis in the hippocampus [923,1063]. In line with these data, central (icv) administration of GIP prevents spatial memory impairments induced by icv infusion of β-amyloid oligomers [1064]. Expression of *Gipr* further increases after nerve injury in the lumbar dorsal root ganglia [1065] and spinal cord [1066] which, along with the observation that regeneration of the crushed sciatic nerve is impaired in *Gipr* deficient [1065], implies that GIPR agonism may promote axonal repair and regeneration after neuronal injury. In 12 month old APP/PS1 mice, a transgenic mouse model for AD [284,1067], treatment with [D-Ala₂] GIP protects from impairment of learning and memory, and these effects are paralleled by reduced synaptic loss, preservation of synaptic plasticity, decreased amyloid plaque formation and amelioration of inflammation, oxidative stress, and DNA damage [1068,1069]. The beneficial effects of [D-Ala₂]GIP to decrease synaptic loss and inflammation are preserved in 19 month old APP/PS1 mice [1070], suggesting that GIPR agonism may be beneficial even in more advanced stages of the disease. GIPR agonism also decreases central inflammation in aged wildtype mice, and improves synaptic plasticity in the hippocampus of aged wildtype and APP/PS1 mice, hence indicating that GIPR agonism ameliorates the disease- and age-related loss of synapses [1070]. In APP/PS1 mice, GIP-induced improvement of learning and memory is paralleled by enhanced *in vivo* long-term potentiation (LTP) in the hippocampus, reduced brain β-amyloid deposition, lower astrocyte and microglia activation and decreased expression of IL-1β, TNFα and NF-κB [1071]. In agreement with this, GIPR agonism reduces in APP/PS1 mice the number of β-amyloid plaques, central inflammation and ER stress, while preventing the decline in neuronal progenitor cell proliferation and cognitive impairment [941,1068].

Neuroprotective effects of GIPR agonism have also been shown in animal models of Parkinson's Disease (PD). In mice treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), a chemical that blocks mitochondrial activity and induces Parkinson-like symptoms in humans [1072], [D-Ala₂]GIP improves motor activity, protects synapses in the substantia nigra from the MPTP-induced toxicity, decreases central inflammation and normalizes cAMP/PKA/CREB signaling in the substantia nigra [1073]. The latter is consistent with the observation that [D-Ala₂]GIP increases cAMP/PKA/CREB signaling

in the hippocampus of APP/PS1 mice [1071]. Normalization of motor activity and protection of dopaminergic neurons is further observed after GIP treatment in mice subjected to low dose MPTO treatment, a treatment regime that is considered to more realistically mimic PD in mice [1074]. In this study, [D-Ala₂]GIP reduced chronic inflammation, oxidative stress and levels of lipid peroxidation, while increasing the expression of brain-derived neurotrophic factor (BDNF) [1074], a key central growth factor implicated in neuronal protection [1075-1077]. GIP protection against MPTP toxicity has also been shown in other studies, along with the demonstration that this effect can be antagonized using (Pro³)GIP [1078]. Reduction of oxidative stress by GIPR agonism is paralleled by decreased central levels of malondialdehyde and dopamine, and increased levels of glutathione, hence markers indicative of improved oxidative stress control [1078]. In rats centrally treated with 6-OHDA, a toxin that selectively destroys dopaminergic neurons, continuous infusion of GIP reduces 6-OHDA toxicity and improves motor impairments [1079].

A minor neuroprotective effect was also recently shown for tirzepatide in APP/PS1 mice [1080], and in human neuroblastoma SHSY5Y cells, where tirzepatide stimulated the expression of biomarkers indicative of neuronal growth (CREB, BDNF) and differentiation (MAP2, GAP43) while decreasing the expression of markers indicative of apoptosis (BCL-2 and BAX) [1081]. Unfortunately, however, this study did not assess the effects of GLP-1R agonism alone [1081], which seems crucial given that some studies show GLP-1R agonism to exhibit neuroprotective effects in patients with AD or PD [1082-1088]. Long-term treatment with liraglutide, however, did not affect β-amyloid plaque load in two transgenic mouse models for AD [1089], and tirzepatide was recently shown to not improve brain function in 5XFAD and APP/PS1 mice [1090]. It warrants clarification whether limitations of liraglutide and tirzepatide to cross the blood-brain barrier may have constituted a limitation of these studies [1091]. Other GIPR:GLP-1R co-agonists evaluated for their effects in animal models of AD or PD include DA1-JC, a C16 fatty acid acetylated co-agonist [177], DA3-CH, the non-acylated version of DA1-JC, as well as DA4-JC and DA5-CH, which are further optimized for enhanced BBB permeability [946,1091,1092]. In SH-SY5Y cells, DA1-JC decreases rotenone-induced cellular stress with greater significance over placebo relative to GLP-1R or GIPR agonism alone, but without significance of DA1-JC over the respective receptor monoagonists [1058]. DA1-JC also protects from MPTP-induced toxicity in mice [1093,1094] and from 6-OHDA toxicity in rats [1095,1096], and these effects are paralleled by reduced motor impairments, increased neuronal protection, and/or decreased central inflammation [1093-1096], albeit without superiority of DA1-JC to GLP-1R or GIPR monoagonist controls [1073,1097]. Similar neuroprotective effects are observed using DA3-CH in APP/PS1 mice [1098], and in MPTP treated mice, DA3-CH shows superiority to liraglutide to reverse MPTP-induced motor impairment, neuronal damage and activation of microglia and astrocytes [1099]. In mice treated with MPTP [1092,1100], or rats treated with 6-OHDA [1101,1102], GIPR:GLP-1R co-agonists optimized for BBB penetration (DA4-JC and/or DA5-CH) show greater dopaminergic neuron protection and decreased inflammation and/or apoptosis relative to liraglutide, semaglutide or the less BBB permeable co-agonist DA1-JC. Similar beneficial effects of DA4-JC on motor performance and/or inflammation are observed in APP/PS1 mice, in which DA4-JC was superior to liraglutide in improving memory formation and LTP in the hippocampus [1103], and further in rats treated icv with streptozotocin [1104], a model for sporadic AD [1105,1106]. In agreement with these data, DA4-JC was superior to liraglutide in reducing β-amyloid plaques, reversing memory loss, enhancing synaptic plasticity in the
hippocampus, and lowering central pro-inflammatory cytokine levels in APP/PS1/Tau mice [1107]. Improved motor performance is further observed in A53T mice after treatment with DA5-CH, albeit without significance over treatment with liraglutide [1108]. In summary, GIPR agonism improves motor performance and memory while decreasing central inflammation and apoptosis in a variety of rodent models for AD and PD, and these effects are preserved, or even enhanced relative to GLP-1R agonism using GIPR:GLP-1R co-agonists, particularly when using molecules that have been optimized for enhanced BBB permeability [927].

## 19. SUMMARY AND OUTLOOK

The isolation of GIP and the subsequent recognition of its role as an insulin-releasing incretin hormone generated much interest and research effort. This was nevertheless eclipsed by the advent of molecular biology and the emergence plus subsequent therapeutic exploitation of GLP-1. However, recent years have witnessed a strong resurgence of interest in GIP biology which has not only established GIP as the major incretin hormone but has also uncovered it's many important pleiotropic metabolic effects. Synthesized by intestinal K-cells as pro-GIP and processed by PC1/3, the active form GIP(1-42) is secreted in response to nutrients with possible modulation by neural and hormonal factors. In the blood, it is rapidly inactivated by DPP4, but important physiological effects are mediated rapidly though GIP receptors present on the various target cells. Key actions include enhancing glucose-stimulated insulin secretion, promoting β-cell survival/growth, modulating lipid storage/lipolysis in adipose tissue, reducing body weight through centrally mediated appetite suppression, alleviating drug-induced nausea, lowering peripheral and central inflammation, and promoting both cognition and bone formation. In consequence, changes in the secretion and/or action of GIP have been shown to make important contributions to pathogenesis of obesity-diabetes plus a range of other disorders. GIP insensitivity as encountered in T2DM is not irreversible, so therapeutic enhancement of GIP action through DPP4 inhibition or design of stable GIP analogues is possible. Although not fully understood, both GIP agonism and antagonism surprisingly benefit obesity-diabetes but neither approach is superior to the substantial benefits of recently introduced unimolecular peptides targeting both GIP and GLP-1 receptors. Such agents are now well-established for treating obesity and T2D in humans, and therapies combining GIPR antagonism with GLP-1R agonism have also shown promising results in clinical studies. Although research on GIP continues to generate conflicting views, modifying GIPR signaling has now emerged fully as a strong drug partner in the therapy of various diseases. These include disturbances of energy, glucose and lipid metabolism but benefits may extend in the future to treatment of neurodegenerative, bone and reproductive disorders.

## ACKNOWLEDGEMENTS

This work was funded by the European Union within the scope or the European Research Council ERC-CoG Trusted no.101044445, awarded to TDM. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the awarding authority can be held responsible for them. TDM further received funding from the German Research Foundation (DFG TRR296, TRR152, SFB1123 and GRK 2816/1) and the German Center for Diabetes Research (DZD e.V.). DJD is supported in part by operating grants from the CIHR, a Banting and Best Diabetes Centre-Novo

Nordisk Chair in incretin biology and a Sinai Health Novo Nordisk Fund in regulatory peptides. M.R.H. receives research funding from Boehringer Ingelheim, Pfizer, Gila Therapeutics, and Eli Lilly & Co. MMR is supported by the Novo Nordisk Foundation (NNF21OC0070347) and by EFSD/Lilly European Diabetes Research Programme. DW is an NHMRC Leadership Fellow (grant #2026300). PRF is funded by Diabetes UK, EFSD, Northern Ireland HPSS and Invest Northern Ireland. AEA is supported by the EFSD/Novo Nordisk Foundation Future Leaders Award (NNF21SA0072744).

## CRediT AUTHORSHIP CONTRIBUTION STATEMENT

**Timo D. Müller:** Writing — original draft, Conceptualization. **Alice Adriaenssens:** Writing — review & editing. **Bo Ahrén:** Writing — review & editing. **Matthias Blüher:** Writing — review & editing. **Andreas L. Birkenfeld:** Writing — review & editing. **Jonathan E. Campbell:** Writing — review & editing. **Matthew P. Coghlan:** Writing — review & editing. **David D'Alessio:** Writing — review & editing. **Carolyn F. Deacon:** Writing — review & editing. **Stefano DelPrato:** Writing — review & editing. **Jonathan D. Douros:** Writing — review & editing, Conceptualization. **Daniel J. Drucker:** Writing — review & editing. **Natalie S. Figueredo Burgos:** Writing — review & editing. **Peter R. Flatt:** Writing — review & editing, Writing — original draft. **Brian Finan:** Writing — review & editing. **Ruth E. Gimeno:** Writing — review & editing. **Fiona M. Gribble:** Writing — review & editing. **Matthew R. Hayes:** Writing — review & editing. **Christian Hölscher:** Writing — review & editing. **Jens J. Holst:** Writing — review & editing. **Patrick J. Knerr:** Writing — review & editing. **Filip K. Knop:** Writing — review & editing. **Christine M. Kusminski:** Writing — review & editing. **Arka-diusz Liskiewicz:** Writing — review & editing. **Guillaume Mabilleau:** Writing — review & editing, Conceptualization. **Stephanie A. Mowery:** Writing — review & editing. **Michael A. Nauck:** Writing — review & editing. **Aaron Novikoff:** Writing — review & editing. **Frank Reimann:** Writing — review & editing. **Anna G. Roberts:** Conceptualization. **Mette M. Rosenkilde:** Writing — review & editing, Writing — original draft. **Ricardo J. Samms:** Writing — review & editing, Conceptualization. **Philip E. Scherer:** Writing — review & editing. **Randy J. Seeley:** Writing — review & editing. **Kyle W. Sloop:** Writing — review & editing. **Christian Wolfrum:** Writing — review & editing, Conceptualization. **Denise Wootten:** Writing — review & editing. **Richard D. DiMarchi:** Writing — review & editing. **Matthias H. Tschöp:** Writing — review & editing.

## DECLARATION OF COMPETING INTEREST

DJD has served as a consultant or speaker within the past 12 months to Amgen, AstraZeneca, Boehringer Ingelheim, Kallyope and Novo Nordisk Inc. Neither DJD or his family members hold issued stock directly or indirectly in any of these companies. DJD holds non-exercised options in Kallyope. S.A.M, J.D.D., B.F., and P.J.K. are shareholders and former employees of Novo Nordisk. RJS has received research support from Novo Nordisk, Fractyl, Astra Zeneca, Congruence Therapeutics, Eli Lilly, Bullfrog Al, Glysend Therapeutics and Amgen. RJS has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Fractyl, Structure Therapeutics, Crinetics, Amgen and Congruence Therapeutics. RJS has equity in Bullfrog Al and Rewind. MMR and JJH are co-founders and shareholders of Antag Therapeutics and Bainan Biotech. MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. DW is shareholder and on the scientific advisory board of Septerna Inc. and
a co-founder and shareholder of Dacra therapeutics. MRH receives research SRA fundining from Boehringer Ingelheim, Eli Lilly & Co., Pfizer, Gila Therapeutics, and Novo Nordisk. MRH is a named inventor of patents pursuant to work that is owned by Syracuse University and the University of Pennsylvania. MRH is a founding scientists and shareholder of Coronation Bio. Inc. FMG and FR have received research support from Eli Lilly and AstraZeneca. FKK has served on scientific advisory panels, been part of speaker's bureaus for, served as a consultant to, owns stocks in and/or received research support from 89bio, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Norgine, Novo Nordisk, Sanofi, ShouTi, SNIPR Biome, Zealand Pharma and Zucara. FKK is a co-founder of and minority shareholder in Antag Therapeutics. FKK is currently employed by Novo Nordisk; the present work was done independent of Novo Nordisk. CH is a named inventor on patents that cover GIP or dual GLP-1/GIP receptor agonists as treatments for AD/PD. He is the CSO of Kariya Pharmaceutics Ltd. JJH appears on advisory boards for Novo Nordisk. SDP has served as president of EASD/European Foundation for the Study of Diabetes (EFSD) (2020–2022) and is current president of Fondazione Menarini; has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as advisor for Abbott, Amarin Corporation, Amplitude, Applied Therapeutics, AstraZeneca, Biomea Fusion, Eli Lilly & Co., EvaPharma, Menarini International, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Laboratori Guidotti, Menarini International, Merck Sharpe & Dohme, and Novo Nordisk. PRF has served as consultant for Amgen, Ipsen, Novo Nordisk, Sanofi, Zealand and is co-founder and shareholder of Dia Beta Labs. MHT is a member of the scientific advisory board of ERX Pharmaceuticals, Cambridge, Mass. He was a member of the Research Cluster Advisory Panel (ReCAP) of the Novo Nordisk Foundation between 2017 and 2019. He attended a scientific advisory board meeting of the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, in 2016. He received funding for his research projects by Novo Nordisk (2016–2020) and Sanofi-Aventis (2012–2019). He was a consultant for Bionorica SE (2013–2017), Menarini Ricerche S.p.A. (2016), and Bayer Pharma AG Berlin (2016). As former Director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum München (2011–2018), and since 2018, as CEO of Helmholtz Zentrum München, he has been responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia, worldwide, including but not limited to pharmaceutical corporations like Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BiOSyngen, and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including diabetes related patent portfolios of Helmholtz Zentrum München as, e.g., WO/2016/188932 A2 or WO/2017/194499 A1. MHT confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gaserbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme,

NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gaserbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. MAN has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly & Co., Medtronic, Merck, Sharp & Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (ShouTi, Gaserbrum). He has received grant support from Merck, Sharp & Dohme. He has also served on the speakers' bureau of Eli Lilly & Co., Merck, Sharp & Dohme, Medscape, Medical Learning Institute, and NovoNordisk. TDM receives funding from Novo Nordisk and has received speaking fees from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Merck, AstraZeneca, Mercodia and Berlin Chemie AG. TDM further holds stocks from Novo Nordisk and Eli Lilly. BA has served as a speaker within the past 12 months to Mankind and Novartis and is a shareholder of Astra Zeneca, Eli Lilly and Novo Nordisk AS. R.J.S., M.P.C., K.W.S., B.F. and R.E.G. are employees of Eli Lilly and Company and may own company stock.

## DATA AVAILABILITY

No data was used for the research described in the article.

## DEDICATION

This review is dedicated to the memory and research of all pioneers who have contributed to the present knowledge of GIP, and in particular the giants John Brown, Viktor Mutt, Ray Pederson, Werner Creutzfeldt and Vincent Marks.

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