Physiology and clinical applications of GIP

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.

Graphical Abstract

Introduction

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretins, which are peptide hormones released from enteroendocrine cells into circulation in response to nutrient ingestion to potentiate glucose-stimulated insulin secretion [1-3]. GIP was initially identified as an intestinal hormone with a gastric inhibitory effect [4] and named gastric inhibitory polypeptide, and was later reported to be capable of potentiating glucose-stimulated insulin secretion in human [5-8]. Further research showed that GIP infusion at concentrations comparable to those observed after oral glucose intake increased glucose-stimulated insulin secretion to levels similar to those recorded following an oral glucose tolerance test [9]. Given that the gastric inhibitory effect of GIP has proven to be negligible in humans, GIP is now recognized as a hormone responsible for incretin effect together with GLP-1 and the acronym was modified to represent “glucose-dependent insulinotropic polypeptide.”

GIP is secreted by GIP-producing enteroendocrine cells (i.e., K cells), which are localized mainly in the upper small intestine [10, 11]. GIP (1–42) exhibits a notably brief plasma half-life of only a few minutes in healthy individuals, primarily due to rapid inactivation by dipeptidyl peptidase-4 (DPP-4), generating GIP (3–42) [12]. GIP binds to the GIP receptor (GIPR) [13-15], which is expressed on the surface of pancreatic β-cells, stimulating insulin secretion [16]. In addition to its expression in pancreatic β-cells, GIPR has been reported to be expressed in many other organs, including the gut, white and brown adipose tissue, heart, pituitary, and inner layers of the adrenal cortex, bone, and several regions in the brain, contributing to various extrapancreatic effects of GIP [17-21].

Despite the widespread use of GLP-1-based therapies for type 2 diabetes (T2D), therapeutic applications targeting GIP for metabolic disorders have seen little progress until recently. However, this situation has changed dramatically with emerging evidence highlighting the metabolic benefits of dual GLP-1 receptor (GLP-1R) and GIPR agonists. In this article, we review basic findings on the mechanism of GIP secretion and action, as well as future prospects for obesity and diabetes treatment through the regulation of GIP signaling.

1. GIP secretion

Classically, GIP-producing enteroendocrine cells (EECs) have been referred to as K cells, but recent reports have shown that these cells also produce other enteroendocrine hormones, including cholecystokinin (CCK) and GLP-1 [22, 23], and a revision of this nomenclature has been advocated [24, 25]. However, since no universally accepted designation currently exists, we use the conventional term ‘K cell’ in this article. It has been demonstrated that GIP concentrations rise during the postprandial period [26, 27], indicating that GIP-producing K cells respond to macronutrient intake [28, 29].

1.1. Sugars

GIP secretion is stimulated by the oral consumption of glucose through the sodium-coupled glucose transporter 1 (SGLT1) [30-32], which utilizes the sodium gradient across the membrane as the driving force for glucose uptake into cells. Based on the glucose sensing mechanism in GLP-1-producing cells [33-35], it is assumed that the subsequent depolarization of the K cell membrane potential activates voltage-dependent Ca²⁺ channels (VDCCs), leading to an increase in intracellular Ca²⁺ levels that facilitates vesicular exocytosis [29]. Glucose-stimulated GIP secretion was completely abolished in SGLT1 KO mice [36], and patients with T2D who received pretreatment with licogliflozin, an SGLT1/2 inhibitor, exhibited diminished GIP secretion following oral glucose administration [37], supporting the significance of SGLT1 in glucose-stimulated GIP secretion.

In contrast, fructose, which crosses the cell membrane via glucose transporter 5 (GLUT5) [38], is not an effective stimulant of GIP secretion in either rodent models or healthy human subjects under normal condition [39]. However, some GIP response was observed following oral fructose administration to diabetic mice [40] or ob/ob mice [41].

Expression of adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel subunits (sulphonylurea receptor 1 [SUR1] and inward-rectifier potassium channel 6.2 [Kir6.2]) has also been confirmed in K cells, and the addition of tolbutamide, a K_ATP channel inhibitor, enhanced GIP release in primary mouse intestinal cultures [31]. An in vivo experiment showed that neither glimepiride, a sulfonylurea, nor diazoxide, a K_ATP-channel opener, affected glucose-stimulated GIP secretion in healthy mice. However, diazoxide inhibited GIP secretion in response to oral glucose load in diabetic mice, suggesting that the K_ATP channel contributes to glucose-induced GIP secretion only in the diabetic state [42]. Nevertheless, GIP secretion is not enhanced in individuals with T2D treated with glibenclamide [43], indicating that the contribution of K_ATP channels to GIP secretion in vivo, especially in humans, is minimal.

Sucralose, an artificial sweetener, has been reported to stimulate GIP secretion through sweet-sensing taste type 1 receptor 2 and 3 (T1R2/T1R3) in GLUTag cells [44]. However, in an isolated perfused rat small intestine, the sweet taste receptor (STR) inhibitor gurmarin failed to attenuate glucose-induced GIP secretion, and sucralose did not stimulate GIP secretion [45]. Additionally, GIP release was not stimulated by sucralose administration in primary cultures of adult mouse small intestine [31] or by oral ingestion of artificial sweeteners in human subjects [46, 47]. In view of these findings, it is considered unlikely that STRs are directly involved in the sugar detection mechanism of K cells [29]. However, since STR activation has been reported to upregulate SGLT1 expression [44, 48], it is possible that chronic STR activation may affect GIP secretion via SGLT1 upregulation. Further investigation is required.

1.2. Lipids

Dietary lipid is a particularly strong stimulant of GIP secretion [49]. The peak increase in GIP levels in response to a high-fat meal (450 kcal containing 33.3% fat) is three times higher than that observed during a 75 g oral glucose tolerance test (OGTT) in healthy subjects, indicating that GIP is robustly stimulated by fat content in a mixed meal [50]. Additionally, lipid administration to the duodenum of healthy subjects induces greater GIP secretion than isocaloric glucose administration [51], suggesting an important role for GIP in the regulation of lipid metabolism.

G protein-coupled receptor (GPR) 120 (free fatty acid receptor [FFAR] 4) and GPR40 (FFAR1), which are known as long-chain fatty acid (LCFA) receptors, are expressed in K cells and involved in GIP secretion in response to fat intake [29, 31, 52-54]. GIP secretion in response to lard oil was markedly impaired in GPR120 knockout (KO) mice, as well as in wild-type mice administered a GPR120 antagonist [53]. However, the GIP response to the oral administration of olive oil or corn oil was much more strongly suppressed in GPR40 KO mice than in GPR120 KO mice [54, 55], suggesting that the contributions of GPR40 and GPR120 may differ depending on the fatty acid composition of the oil. Additionally, double KO of GPR40 and GPR120 more effectively eliminated the GIP response to the oral administration of corn oil compared to single KO of either receptor in murine models [54, 56], suggesting that both GPR40 and GPR120 are important in fat-stimulated GIP secretion [29]. Both GPR40 and GPR120 are expressed in cholecystokinin (CCK)-producing cells, and CCK secretion is reduced in both GPR40 KO and GPR120 KO mice. Administration of a CCK agonist restores reduced fat-induced GIP secretion in GPR120 KO mice, but not in GPR40 KO mice, suggesting that GPR120 regulates fat-induced GIP secretion via CCK, a hormone that regulates bile release and subsequent triglyceride digestion [54] (Fig. 1) (the importance of bile in GIP secretion is discussed below). Furthermore, intestine-specific GPR120 KO mice exhibited reduced GIP secretion and CCK activity after a single administration of long-chain triglyceride (LCT), and mild improvements in obesity and marked amelioration of insulin resistance and hepatic steatosis under high-LCT diet feeding [57].

Fig. 1. Schematic representation illustrating potential mechanisms of fat-induced GIP secretion via GPR40 and GPR120, showing involvement of CCK and bile. GPR, G protein-coupled receptor; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide.

It has been demonstrated that medium-chain triglyceride (MCT) inhibits LCT-induced GIP secretion in mice by antagonizing GPR120 expressed in CCK-producing cells [58]. Regarding the chronic effects of MCT oil, long-term MCT consumption did not induce GIP hypersecretion, and suppressed fat mass and body weight gain compared to an LCT diet [59]. Identifying and applying materials that suppress LCT-induced GIP hypersecretion, such as MCTs, may therefore prevent the onset and progression of diet-induced obesity.

GPR119 is activated by monoacylglycerides (MAGs), which are generated within the gut lumen as a result of triglyceride digestion [60]. The GPR119 agonist AR231453 significantly stimulated GIP secretion in WT mice but not in GPR119 KO mice [61]. The significance of GPR119 in postprandial lipid detection by K cells is underscored by the observation that the GIP response to an olive oil gavage was markedly diminished in GPR119 KO mice [55]. The relevance of GPR40/GPR120 and GPR119 in fat-stimulated GIP secretion remains unclear, as fat-induced GIP secretion is almost abolished in GPR40/GPR120 double KO mice.

While the intraluminal delivery of bile acids stimulated GIP secretion in rats [62], chenodeoxycholic acid (CDCA), one of the primary bile acids and an agonist of G-protein-coupled bile acid receptor-1 (GPBAR-1), attenuated rather than enhanced postprandial GIP secretion in human subjects [63]. Thus, it is not clear whether stimulation of GIP secretion by bile is mediated by GPBAR-1. GIP secretion in bile duct-ligated mice after lard administration was found to be almost completely abolished, indicating that lipid digestion and micellisation of fatty acids in the presence of bile are essential for GIP secretion associated with lipid intake (Fig. 1) [64].

The results of several studies suggest the importance of lipid absorption in GIP secretion [28, 29]. Genetic deletion of monocaylglyceride-acyltransferase-2 (MGAT2) and diacylglyceride-acyltransferase-1 (DGAT1), enzymes involved in the stepwise re-esterification of MAGs to triacylglycerides (TAGs) inside intestinal epithelial cells, results in a reduced GIP-response to oral oil gavage [65]. Currently, there is no evidence to suggest that fatty acids are metabolised in K cells. Regarding the mechanism of fatty-acid uptake into K cells, a proposed pathway is protein-mediated transport, although quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of K cells revealed relatively low expression of fatty acid transport protein (FATP) isoforms and CD36 [64]. Supporting the involvement of fatty acid binding in K cells, it has been reported that fatty-acid binding protein 5 (FABP5), an intracellular fatty-acid transport protein, is expressed in GIP-producing cells and that fat-induced GIP secretion is significantly attenuated in FABP5 KO mice [64, 66].

As for the effects of chronic fat intake on GIP secretion, the expression of regulatory factor X 6 (Rfx6) and pancreatic and duodenal homeobox 1 (Pdx1), important transcription factors involved in GIP expression [67-69], was found to be increased in GIP-producing cells in high-fat diet (HFD)-induced obese mice, suggesting a possible mechanism for GIP hypersecretion in obesity [68, 70].

1.3. Proteins/Amino acids

In human subjects, protein meals were found to have no effect on GIP secretion [71]. However, intraduodenal administration of an amino acid mixture effectively stimulates GIP release in healthy individuals [72]. In isolated loops of rat small intestine, L-Amino acids stimulated GIP secretion, which was blocked by a calcium-sensing receptor (CaSR) inhibitor and augmented by the CaSR agonist [73]. Several studies revealed that exposure to phenylalanine [74], tryptophan [75], and arginine [76] can modulate GIP secretion through the CaSR in a pig model.

2. GIP action

GIPRs are expressed in many organs other than pancreatic β-cells, and GIP possesses a range of functions besides stimulating insulin release [1, 29]. This article outlines the mechanisms of GIP action in pancreatic endocrine cells, white adipose tissues, and the central nervous system, which are particularly important in metabolic regulation.

2.1. GIP and Pancreatic β-Cells

The secretion of insulin from pancreatic β-cells in response to glucose involves a rise in the intracellular ATP/adenosine diphosphate (ADP) ratio, leading to cell depolarization through ATP-sensitive K⁺ (K_ATP) channels [77], which then triggers the entry of Ca²⁺ ions via voltage-dependent Ca²⁺ channels (VDCCs) [78-80]. Upon binding of GIP to GIPRs located on the membranes of pancreatic β-cells, phosphorylation of the Gαs subunit of GIPRs activates adenylate cyclase, facilitating the conversion of ATP into cyclic adenosine monophosphate (cAMP) [15]. The resulting increase in intracellular cAMP activates protein kinase A (PKA) and exchange protein activated by cAMP 2 (Epac2). The PKA antagonist Rp-8-BrcAMPS attenuated GIP-induced insulin secretion from mouse pancreatic β-cells [81], indicating the essential role of PKA in the insulinotropic action of GIP [82]. Epac2, on the other hand, has been shown to enhance the rate of secretory vesicle fusion [82, 83] by activating Ras-related protein 1 (Rap1) [83]. Furthermore, Rap1 activation has been demonstrated to occur exclusively in the presence of glucose alongside the administration of GIP, GLP-1, or 8-Bromo-cAMP, a PKA activator [83], reinforcing the association between Rap1 signaling pathways and incretin action, as well as the subsequent cAMP accumulation.

Besides its insulinotropic effects, GIP has also been documented to play a role in preserving pancreatic β-cell volume [29, 84]. GIP reduces apoptosis in mouse pancreatic β-cells by enhancing the expression of the antiapoptotic gene B-cell/CLL lymphoma 2 (Bcl-2) through the PKA-mediated formation of a phosphorylated cAMP response element-binding protein (CREB) and target of rapamycin complex 2 (TORC2) complex. This complex binds to the cAMP response element 1 of the Bcl-2 promoter, upregulating Bcl-2 transcription [85]. Additionally, GIP triggers the RAC-alpha serine/threonine-protein kinase (AKT)/protein kinase B (PKB) signaling pathway, leading to phosphorylation and nuclear export of forkhead box protein O1 (Foxo1), thereby attenuating the expression of the proapoptotic BCL2-associated X (Bax) gene [86]. GIP promotes β-cell proliferation by activating the Raf-Mek1/2-ERK1/2 signaling pathway via cAMP/PKA/Rap1 [87] and inducing the transcription of the cyclin D1 gene, an important regulator of the cell cycle, via multiple signaling pathways [88].

2.2. GIP and Pancreatic α-Cells

It has been reported that α-cells express GIPR in both mice and humans [89, 90] and that GIP stimulates glucagon secretion in an α-cell line [91], isolated rat α-cells [89], perifused mouse islets [92], perfused rat pancreas [93], and during systemic infusion in humans [94]. In healthy subjects, GIP stimulates glucagon secretion only during fasting and hypoglycemic conditions [94]. In perfused mouse islets, GIP significantly enhances amino-acid induced glucagon secretion, and glucagon secretion after a mixed meal test is significantly impaired in α-cell-specific GIPR KO mice, indicating a significant role of GIP in the regulation of amino acid-stimulated glucagon secretion [95].

2.3. GIP and White Adipose Tissue

It has been shown that GIP secretion during a 75 g oral glucose tolerance test in Japanese normal glucose-tolerant subjects positively correlates with body mass index (BMI) of the subjects [96]. Both GIP secretion from GIP-producing cells [68, 97] and insulin secretion from pancreatic β-cells in response to GIP [98] are enhanced in HFD-induced obese mice. Studies using whole-body GIPR KO mice [99], GIP-secretion-deficient mice [100], whole-body administration of GIPR antagonists (see below), and GIP immunoneutralization [101] have shown that fat accumulation and insulin resistance associated with high-fat intake are suppressed by inhibition of GIP signaling. Based on these findings, it is suggested that increased GIP secretion during HFD feeding plays an important role in the progression of obesity and insulin resistance. However, since insulin promotes fat accumulation by increasing lipoprotein lipase (LPL) activity in adipocytes, and GIP has also been demonstrated to increase triglyceride uptake into adipocytes via LPL activation in vitro [102], it remains unclear whether increased GIP secretion under high fat intake enhances fat accumulation through a direct effect on adipocytes or indirectly through increased insulin levels resulting from GIP-stimulated pancreatic β-cells.

The diet-induced obesity (DIO)-resistant phenotype of conventional GIPR KO mice could be partially restored by reintroducing GIPR in adipose tissue using the aP2 promoter [103], and adipocyte-specific GIPR KO (GIPR^adipo–/–) mice exhibited a marginally greater resistance to DIO compared to their wild-type counterparts [104]. However, assessment of body composition in both of these studies revealed that the absence of GIPR signaling in adipocytes contributes to reduced lean mass, but not fat mass. GIPR^adipo–/– mice showed significant reductions in interleukin-6 (IL-6) mRNA expression in adipocytes, blood IL-6 levels, triglyceride accumulation in the liver, and systemic insulin resistance [104]. These results suggest that GIP is a thrifty hormone that efficiently stores nutrients absorbed from the intestinal tract. When an HFD is consumed, GIP promotes fat accumulation by increasing insulin secretion and enhances insulin resistance through increased IL-6 production from adipocytes and subsequent systemic inflammation (Fig. 2).

Fig. 2. Potential mechanisms by which GIP hypersecretion under HFD conditions induces insulin resistance and hepatic steatosis. IL-6, interleukin-6; GIP, glucose-dependent insulinotropic polypeptide; GIPR, GIP receptor; IR, insulin receptor; LPL, lipoprotein lipase.

In GIP secretion-deficient mice, age-related fat accumulation and insulin resistance are reduced, suggesting that GIP is also involved in age-related fat accumulation and the progression of insulin resistance [105]. It has been demonstrated that the number of GIP-producing cells, GIP content, and Pdx1 expression in GIP-producing cells increase in aged mice, while acquired Pdx1 knockdown using an intestine-specific gene transfer (iGT) technique decreases GIP gene expression and GIP content in GIP-producing cells and ameliorates GIP secretion after oral glucose loading. These findings suggest that Pdx1 may be involved in the age-related increase in GIP secretion [105]. On the other hand, no inhibitory effect of GIP deficiency on fat accumulation has been observed in ob/ob mice, a model of overeating [106]. In ovariectomized mice, a postmenopausal disease model, GIP deficiency was found to suppress weight gain and subcutaneous and visceral fat accumulation, as well as reduce insulin resistance [107]. Further studies are required to determine the source of the differential effects of GIP signaling on obesity promotion by HFD, overeating, and menopause.

A long-acting GIPR agonist modulates adipose tissue function differentially in the fasted and fed states by cooperating with insulin [108]. In the fed state, GIPR agonism enhances insulin signaling, promotes glucose uptake, and increases the conversion of glucose to glycerol. Conversely, in the fasted state, GIPR agonism stimulates lipolysis under conditions of reduced insulin levels. Recently, sustained activation of GIP signaling in adipocytes has been reported to increase lipid oxidation, thermogenesis, and energy expenditure through sarco/endoplasmic reticulum calcium-ATPase (SERCA)-mediated futile calcium cycling pathways in adipocytes [109].

2.4. GIP and the Central Nervous System (CNS)

Emerging evidence suggests that GIP analogs may exhibit neuroprotective properties in murine models of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease [110]. In addition to its neuroprotective properties, GIP has been shown to influence the regulation of food consumption and body weight through mechanisms operating within the central nervous system (CNS).

It has been reported that GIPR-Cre–driven reporters are widely expressed in the mouse CNS, including key feeding centers of the hypothalamus [111]. Chemogenetic activation of GIPR-expressing neurons in the mouse hypothalamus reduces food intake [111], and both intracerebroventricular and peripheral administrations of a GIPR agonist result in reduced food intake, accompanied by increased activity of hypothalamic neurons involved in food intake regulation in WT but not in GIPR KO mice [112]. These findings suggest that GIPR activation in the CNS functions as an anorexigenic signal. On the other hand, centrally administered GIPR antagonists have been shown to attenuate body weight gain and food intake [113], and HFD-fed CNS-GIPR KO mice show decreased body weight and improved glucose metabolism [112]. The mechanisms explaining this seemingly contradictory phenomenon remain unclear.

A recent report demonstrated that GIPR neurons located in the hypothalamus, area postrema (AP), and nucleus of the solitary tract (NTS) exhibit distinct variations in their connectivity, transcriptomic characteristics, peripheral accessibility, and mechanisms involved in appetite regulation. These findings indicate that the interaction of various regulatory mechanisms should be taken into account when studying the impact of GIP pharmacology on feeding behavior [114].

3. GIP-Based Obesity-Diabetes Treatment

3.1. GIPR Antagonists

It has been reported that the insulinotropic effect of GIP is severely compromised in patients with obesity-diabetes [115], although the effect is partially restored after optimization of glucose regulation through intensified insulin therapy [116]. On the other hand, as noted above, loss of physiological GIP signaling in mice has been shown to reduce obesity and insulin resistance caused by HFD intake [99, 100]. Thus, a number of GIPR antagonists are being developed for the treatment of obesity-diabetes [117]. Long-term administration of (Pro³)GIP to obese mice on an HFD was found to reduce body weight by about 8% compared to controls, without affecting food intake, and decrease casual blood glucose levels during the course of treatment and attenuated insulin levels during an oral glucose tolerance test [118]. GIP (3–30)NH₂, a truncated and amidated form of GIP, has been shown to act as a GIPR antagonist in healthy subjects. GIP (3–30)NH₂ significantly suppressed GIP-stimulated insulin secretion during a hyperglycemic clamp [119] and the GIP-induced increase in adipose tissue blood flow was almost completely abolished by GIP (3–30)NH₂ administration [120]. It also has been reported that SKL-14959, a small molecule compound, exhibits GIPR antagonist activity and that long-term administration of SKL-14959 to mice significantly suppresses fat accumulation and weight gain during HFD feeding [121].

As GIP is known to effect both bone mass maintenance as well as insulin secretion, there is concern regarding the impact of suppressing GIP signaling on bone mass as well as glucose tolerance. GIPR KO mice and GIP secretion-deficient mice exhibit hyperglycemia with decreased insulin secretion during OGTT [100, 122] as well as decreased bone mass [100]. On the other hand, GIP-green-fluoresent-protein (GFP)-knock-in (GIP^gfp/+) mice, in which GIP secretion is attenuated to half that of WT mice, exhibit no decrease in bone mass compared to wild-type mice, with no significant difference in blood glucose or insulin levels during OGTT after 8 weeks of HFD, although slight glucose intolerance was observed under a normal diet [18, 100]. As the clinical application of GIPR antagonist progresses in the future, the possibility of side effects, including worsening of glucose tolerance and osteoporosis, needs to be carefully examined.

Very recently, a phase 1, randomized, double-blind, placebo-controlled clinical trial involving obese patients indicated that AMG 133 (maridebart cafraglutide), a GIPR antagonist conjugated to GLP-1R agonist, demonstrated an acceptable safety and tolerability profile, as well as a significant dose-dependent reduction in body weight [123]. Future trials are required to comprehensively examine the combined effects of GIP antagonism and GLP-1 agonism on blood glucose levels and body weight in individuals with T2D.

3.2. GIPR agonists

In contrast to the results inferred from the obesity-promoting effects of GIP, it has been shown that transgenic mice overexpressing GIP exhibit a significant decrease in weight gain after ingestion of an HFD, suggesting that chronic elevation of GIP levels well above physiological concentrations may exert a centrally mediated suppressive effect on appetite [124]. GIPR agonists have been shown to offer certain metabolic advantages; the administration of N-acetyl-GIP and N-pyroglutamyl-GIP resulted in an attenuation of hyperglycemia in ob/ob mice [125], and several other GIP analogues have been reported to improve glucose tolerance in both lean and obese mice [126-128]. However, the effects of GIPR agonism on body weight and glycaemic control are generally modest, and the efficacy in humans has not yet been demonstrated. A recent study has shown that a long-acting GIPR agonist improves the gastrointestinal tolerability of liraglutide, a selective GLP-1R agonist, in healthy volunteers [129].

3.3. GIP/GLP-1 Receptor Dual Agonists

The initial discovery of a GIP/GLP-1 receptor dual agonist occurred in 2013, demonstrating markedly enhanced glucose-lowering and insulin-releasing capabilities compared to selective GLP-1R agonists in obese and leptin receptor-deficient murine models, as well as in human subjects [130]. NNC0090–2746 (RG7697), a fatty acid–modified dual GIPR and GLP-1R agonist, was evaluated in clinical trials involving participants with T2D, indicating notable enhancements in glucose tolerance and weight reduction when compared to those who received a placebo [131].

Tirzepatide, formerly known as LY3298176, is a 39-amino-acid long peptide with biased GIPR over GLP-1R action, binding more strongly to GIPR than to GLP-1R [132]. At present, tirzepatide is the leading GLP-1/GIP dual agonist and has been approved for marketing in many countries, including the US, Europe and Japan, for the treatment of T2D.

The SURPASS program, a series of phase III clinical trials, was conducted to assess the therapeutic efficacy (glycemic control and body weight reduction), safety, and tolerability of tirzepatide in people with T2D. The studies in the SURPASS program were similarly designed in terms of tirzepatide dosages, beginning with an initial dose of 2.5 mg administered weekly, followed by increments of 2.5 mg every four weeks until the final randomized treatment doses of 5, 10, or 15 mg of tirzepatide were achieved. The SURPASS1-6 trials reported to date have clearly demonstrated very strong HbA1c-lowering and weight-reducing effects of tirzepatide compared with placebo and control drugs [133-139].

Some SURPASS trials conducted on Japanese subjects with T2D and comparatively lower body mass index (BMI) have also substantiated the significant efficacy of tirzepatide. The SURPASS-J mono trial assessed the efficacy and safety of tirzepatide compared with dulaglutide in Japanese subjects with T2D [140]. The least square mean (LSM) change in HbA1c from baseline at week 52 was –2.4%, –2.6% and –2.8% with tirzepatide 5 mg, 10 mg, and 15 mg, respectively, versus –1.3% with dulaglutide. Tirzepatide was associated with dose-dependent reductions in body weight with a LSM difference of –5.8 kg (–7.8% reduction), –8.5 kg (–11.0% reduction), and –10.7 kg (–13.9% reduction) for 5 mg, 10 mg, 15 mg, of tirzepatide, respectively, compared with –0.5 kg (–0.7% reduction) for dulaglutide. The safety and glycaemic efficacy of tirzepatide as an additional treatment for Japanese subjects with T2D who were not achieving adequate glycemic control with various oral antihyperglycaemic monotherapies (SURPASS-J combo trial) were similar to those observed in the SURPASS-J mono trial [141].

The findings from a large, cardiovascular event-driven safety trial, which compares tirzepatide and dulaglutide among 12,500 participants in the SURPASS-CVOT trial, are expected to be published in the near future.

Tirzepatide has very recently received approval in Japan, as well as in the US and Europe, for the treatment of obesity. In the SURMOUNT-1 and SURMOUNT-3 trials, a high dose of tirzepatide (15 mg), administered subcutaneously once a week, led to approximately a 20% reduction in body weight among non-diabetic adults with a BMI ≥27 kg/m² after two years of treatment [142, 143]. In the SURMOUNT-2 study, the weight reduction was 14.7%, recorded among individuals with T2D and a BMI ≥27 kg/m² [144]. The SURMOUNT-OSA study demonstrated that tirzepatide reduced the apnea hypopnea index (AHI), body weight, hypoxic burden, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure, and also improved sleep-related patient-reported outcomes in individuals with moderate-to-severe obstructive sleep apnea and obesity [145]. In the SYNERGY-NASH trial, a phase 2 study involving participants with metabolic dysfunction–associated steatohepatitis (MASH) and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo in achieving resolution of MASH without worsening fibrosis [146]. The SUMMIT trial demonstrated that treatment with tirzepatide reduced the risk of a composite of cardiovascular-related deaths or worsening heart failure, compared with placebo, and improved the health of patients with heart failure with preserved ejection fraction and obesity [147]. Currently, large-scale randomized clinical trials are underway to assess tirzepatide’s efficacy in facilitating weight loss among children with a BMI at or above the 85th percentile for age and sex (SURMOUNT-ADOLESCENTS trial).

3.4. GIP/GLP-1/Glucagon Receptor Triple Agonists

Retatrutide, a long-acting agonist targeting glucagon, GIP, and GLP-1 receptors, has been tested in clinical trials involving human participants. In a phase 2 trial conducted in individuals with T2D and a BMI ranging from 25 to 50, retatrutide showed significant reductions in HbA1c levels at 24 weeks, and dose-dependent reductions in body weight at 36 weeks [148]. In addition, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight in individuals with a BMI ≥27 kg/m² [149]. Phase 3 randomized controlled trials (RCTs) are expected to provide additional insights into the long-term efficacy and safety profile of once-weekly subcutaneous retatrutide.

Conclusions

The effect of GIP on systemic metabolic regulation, especially fat accumulation, body weight and appetite, may differ between physiological and pharmacological concentrations in the bloodstream (Graphical Abstract). Thus, there has been limited progress in developing pharmacological interventions for obesity-diabetes that leverage the metabolic effects of GIP. In recent years, GIP/GLP-1 receptor dual agonists and GIP/GLP-1/glucagon receptor triple agonists, which co-stimulate multiple hormone receptors including GIPR, continue to be reported to exert remarkable anti-obesity and hypoglycaemic effects when compared to agonists of the GLP-1R alone, and are now being applied in clinical practice. However, the intracellular signaling pathways and the primary organ responsible for metabolic regulation through the concurrent activation of multiple hormone receptors remain unclear. For the successful clinical implementation of these newly developed multiple hormone receptor agonists, it is essential to elucidate their fundamental mechanisms of action, and at the same time to confirm their efficacy and safety in real-world applications.

Graphical Abstract. Effects of physiological and pharmacological GIP blood concentrations on systemic metabolism regulation. GIP, glucose-dependent insulinotropic polypeptide; GIPR, GIP receptor.

Disclosures

N.I. received clinical commissioned/joint research grant from asken, scholarship grant from Sumitomo Pharma, Mitsubishi Tanabe Pharma and Nippon Boehringer Ingelheim, and honoraria for lectures from Novo Nordisk Pharma, Sumitomo Pharma, Eli Lilly Japan and Mitsubishi Tanabe Pharma. N.H. received honoraria for lectures from Novo Nordisk Pharma, Mitsubishi Tanabe Pharma. S.Y. has no conflict of interest.

Author Contributions

S.Y. drafted the manuscript, and all authors reviewed, edited and approved the manuscript.