Revitalizing GIP: Therapeutic Potential in Metabolic and Neurodegenerative Disorders

The Revitalization of GIP Research

The main intestinal incretins in the human body are GLP-1 and GIP, which enhance insulin secretion in a glucose-dependent manner and help lower postprandial blood glucose levels. With the development of GLP-1 receptor agonists, these agents have been widely adopted in the treatment of patients with type 2 diabetes and obesity due to their superior hypoglycemic and weight loss effects.^1,2 Furthermore, GLP-1 receptor agonists have demonstrated clinically significant cardiovascular and renal benefits, including reduction of major adverse cardiovascular events and retardation of chronic kidney disease progression.^3,4 As a result, the majority of research and attention is concentrated on GLP-1,⁵ while the therapeutic potential of GIP was underappreciated based on earlier perceptions of its limitations. However, this perspective is evolving as recent research revises our understanding of GIP’s own metabolic benefits, particularly in synergistic combination therapies. GIP was the first incretin to be identified, but it has not gained widespread clinical application for various reasons. Primarily, this is because in individuals with type 2 diabetes (T2DM),^6,7 GIP levels are not substantially diminished, yet GIP receptor signaling is impaired, rendering exogenous GIP supplementation ineffective.⁸ Secondly, GIP continues to stimulate the secretion of glucagon in patients with high blood glucose levels, which was thought to potentially exacerbate hyperglycemia in T2DM.⁹ Thirdly, notable differences exist in GIP signaling pathways between humans and rodents. For instance, while (Pro3) GIP acts as a full agonist at the human GIP receptor (GIPR), it exhibits only partial agonist activity in rodents.¹⁰ Notably, the aforementioned species-specific differences in GIPR pharmacology, along with potential variations in tissue-specific receptor distribution and downstream signaling between rodents and humans, present significant translational challenges. These disparities necessitate cautious interpretation of preclinical findings and underscore the importance of robust clinical validation for GIP-targeted therapies. Collectively, these factors have limited research on GIP. However, an increasing number of studies have revealed the regulatory roles of GIP in various systems, such as adipose tissue, the central nervous system, and the cardiovascular system. Recently, the clinical success of GLP-1/GIP dual receptor agonists has brought GIP research into the spotlight once again,¹¹ demonstrating how co-activation of GLP-1R can potentiate insulin secretion, modulate glucagon action, and overcome the relative GIPR signaling deficiency observed in T2DM, thereby addressing the historical limitations of GIP monotherapy.

GIP is mainly synthesized and secreted by K cells located in the proximal small intestine and jejunum. This 42-amino-acid peptide is strongly stimulated by ingested glucose/carbohydrates and triglycerides, whereas proteins have a comparatively weaker effect on its secretion.^12,13 Although the specific mechanism by which K cells regulate GIP synthesis remains unclear, it has been observed that dietary fat can transiently enhance GIP secretion by activating the free fatty acid receptor GPR120 on the surface of K cells. This further induces an increase in GIP gene expression through the transcriptional regulator RFX6, ultimately leading to extra-production and secretion of GIP.^14,15 Similar to GLP-1, the presence of food in the small intestine after a meal stimulates GIP secretion. Once released into the bloodstream, GIP is quickly hydrolyzed by dipeptidyl peptidase-4 (DPP-4), with a half-life of 4–5 minutes, and is then eliminated from the kidney¹⁶(Figure 1). GIP exerts its physiological effects by binding to GIP receptors, which are G protein-coupled receptors that are widely distributed in the pancreas, adipose tissue, brain, and other tissues (Table 1 and Figure 2).

Table 1 The Similarities and Differences in the Actions of GLP-1 and GIP on Target Organs or Tissues

Figure 1 Synthesis and metabolism of GIP. Various nutrients from food enters the small intestine and stimulates GIP secretion. After GIP being released into the blood, it is quickly hydrolyzed by dipeptidyl peptidase-4 (DPP-4), with a half-life of 4–5 minutes, and is then eliminated from the kidney.

Figure 2 Major GIP targets. GIP exerts its effects by binding to GIP receptors, which are widely distributed in the pancreas, adipose tissue, brain, gastrointestinal tract, cardiovascular system, bone, etc. Especially, after GIP stimulates pancreatic α cells to secrete glucagon in hyperglycemic state, it can further promote insulin secretion by pancreatic β cells through communication between α and β cells. The specific mechanism is still unclear. The role of GIP in regulating food intake is contradictory on animals and humans. GIP does not reduce energy intake in overweight/obese individuals, but GIP injected into the central nervous system and periphery can reduce body weight and food intake in wild-type mice.

The Physiological Function of GIP

The Role of GIP in the Pancreas and Its Effects on Insulin/Glucagon Secretion

In pancreatic islet β cells, GIP binds to GIP receptor (GIPR) and promotes insulin secretion in a glucose-dependent manner, thereby reducing postprandial blood glucose levels. Animal experiments have shown that subcutaneous injection of a GIP analogue (ZP4165, GIPR agonist), increases insulin levels and improves glucose tolerance.¹⁷ In contrast, administration of muGIPR-Ab, a GIPR antagonist, decreases insulin levels and does not improve glucose tolerance.¹⁸ Studies on healthy volunteers have found that GIP significantly stimulates insulin secretion by more than double in a hyperglycemic state but does not have a significant effect on insulin secretion at fasting or hypoglycemic states.¹⁹ In addition, research by Nauck MA et al suggests in healthy individuals, GIP contributes up to 44% of postprandial insulin secretion.²⁰ The specific mechanism is that after GIP binds to GIP receptors, which increases intracellular calcium concentration through the cAMP/PKA and cAMP/Epac pathways, thereby triggering insulin release and increasing insulin secretion in pancreatic β cells. This pathway also participates in the promotion of insulin release by GLP-1 in β cells.¹⁶ In pancreatic α cells, GIP similarly regulates glucagon secretion in a glucose-dependent manner. In 1978, R.A. Pederson et al discovered that GIP stimulates glucagon secretion in isolated rat pancreatic tissue when glucose levels are below 5.5 mmol/L.²¹ Subsequently, Christensen, M. et al confirmed that GIP has no significant effect on glucagon secretion in a hyperglycemic state but can significantly increase glucagon secretion levels in a normal or hypoglycemic state^19,22 (Table 2). However, other studies found infusion of GIP under high glucose conditions in type 2 diabetes patients can still promote glucagon secretion.^23,24 To address this phenomenon, researchers have demonstrated through cell and animal experiments that after GIP stimulates pancreatic α cells to secrete glucagon, it can further promote insulin secretion by pancreatic β cells through communication between α and β cells, thereby participating in the maintenance of blood glucose homeostasis.²⁵ This finding revises the simplistic view of GIP-stimulated glucagon secretion as uniformly detrimental in T2DM. Instead, it reveals a nuanced role where glucagon release, within the context of intact islet paracrine communication, can be part of a coordinated response that ultimately benefits glucose regulation.

Table 2 GIP’s Different Effects in High vs Low Blood Glucose Conditions

The Role of GIP in the Feeding Center

In the central nervous system, GIP is involved in regulating cognition, appetite, and vomiting. GIP plays a neuroprotective role in the pathological changes of degenerative diseases such as Alzheimer’s disease and Parkinson’s disease, which is similar to GLP-1, and can improve the cognitive, learning, and memory abilities of animal models.^16,26,27 GIPR is distributed in several regions of the hypothalamus, including the paraventricular nucleus, dorsomedial nucleus, ventromedial nucleus, and arcuate nucleus. Direct activation of these receptors has been shown to reduce food intake in animal study.²⁸ The latest animal studies²⁹ suggest that central nervous system (CNS) GIPR knockout mice can resist high-fat diet-induced obesity, showing a reduction in food intake, weight loss, and improved glucose metabolism. Injection of acylated GIP into the central nervous system and periphery can reduce body weight and food intake in wild-type mice, but this effect is not significant in CNS-GIPR knockout mice, suggesting that GIPR in the central nervous system plays a key role in controlling energy intake. Earlier experiments have also shown that antagonizing central GIPR in mice, for example via intracerebroventricular infusion of the antagonist GIP(6–30)NH2, can protect against neural leptin resistance induced by a high-fat diet.³⁰ However, a discrepancy in the effects of GIP on food intake exists between animal and human studies: human experiments have shown no significant difference in ad libitum food intake following GIP infusion.^31,32 This interspecies divergence may stem from several factors, including differences in dosage, administration route (peripheral infusion in humans vs central or peripheral injection in animals), physiological state, and potentially distinct neural circuitry or GIPR signaling efficacy within central appetite-regulating centers. Further research is needed to reconcile these findings.

The area postrema and solitary nucleus are important components of the vomiting center, both of which express GIP and GLP-1 receptors.³³ The GIPR is mainly expressed in GABAergic neurons. Administration of a short-acting GIPR agonist into the fourth ventricle (targeting GIPR-expressing cells in the hindbrain only) attenuates the vomiting behavior induced by systemic administration of a GLP-1 receptor agonist in rats. This effect is similar to the reduction in vomiting behavior induced by co-administration of GIP and GLP-1 receptor agonists systemically in rats, suggesting that hindbrain GIPR-expressing GABAergic neurons contribute to the antiemetic effect of GIP.^33–35 This also partially explains why the dual GIP and GLP-1 receptor agonist, Tirzepatide, can reduce gastrointestinal side effects such as nausea and vomiting more than GLP-1 receptor agonists alone.³³

The Role of GIP on White Adipose Tissue and Ectopic Fat Deposition

Physiologically, white adipose tissue serves as a critical “buffer zone” for dietary triglycerides. During fasting, it breaks down triglycerides and releases free fatty acids; while after meals, it stores triglycerides. When excess nutrients are ingested, ectopic lipid accumulation may occur.³⁶ GIP is involved in regulating this process. In lean and healthy subjects during the high-insulin high-glucose clamp, GIP increases adipose tissue blood flow, promotes the absorption of triglycerides by white adipose tissue, and facilitates the uptake of free fatty acids (FFAs) and glucose, increasing triglycerides storage in adipose tissue.^37,38 Animal experiments have shown that GIP promotes the hydrolysis of chylomicrons and other lipoproteins by increasing the activity of lipoprotein lipase (LPL), which facilitates the absorption and storage of triglycerides in adipose tissue, while reducing plasma levels of triglycerides and free fatty acids, thus reducing ectopic fat deposition.^9,39 In summary, GIP may improve energy storage by promoting the expansion of white adipose tissue, thereby reducing the risk of chronic inflammation, tissue damage, and insulin resistance caused by ectopic lipid accumulation in organs such as the liver, skeletal muscles, heart, and pancreas.

The Role of GIP on the Gastrointestinal Tract

It is well established that GLP-1 can delay gastric emptying, but current experiments have shown that physiological doses of GIP have no significant effect on gastric emptying.⁹ In addition, GIP has been shown to enhance glucose absorption in intestinal epithelial cells and reduce the absorption of Na, K, and HCO3–.^40,41 At present, there remains a limited body of research on the gastrointestinal effects of GIP, and further studies are warranted to elucidate its mechanisms and functional roles.

The Regulatory Role of GIP in Bone Remodeling

GIPR is expressed in bone tissue and involved in regulating bone remodeling.^9,42 In healthy individuals, GIP inhibits bone resorption, with a more pronounced effect observed under conditions of elevated blood glucose levels.⁴³ Although infusion of GIP leads to a short-term increase in insulin secretion, studies by Clowes et al⁴⁴ suggest that hyperinsulinemia does not result in acute suppression of bone resorption. This indicates that the observed effect is due to the action of GIP rather than the elevated insulin levels. In another study of type 1 diabetic patients, short-term GIP infusion still inhibited bone resorption, independent of changes in plasma glucose levels.⁴⁵ However, there remains no consensus on whether the inhibitory effects of GIP on bone resorption are affected by blood glucose levels. GIPR knockout mice showed increased osteoclasts, increased bone resorption, unchanged bone formation, decreased bone mass, and diminished bone strength.^46,47 In vitro studies of mouse osteoblast cultures have confirmed that GIP directly acts on osteoblasts to improve collagen maturation and increase collagen fiber diameter.⁴⁸ The mechanisms by which GIP influences osteoclasts and osteoblasts require further investigation. In summary, current research shows that GIP inhibits bone resorption in the human body and promotes bone formation while also inhibiting bone resorption in mice.

The Effects of GIP on the Cardiovascular System

The effects of GIP on the cardiovascular system remain poorly understood, unlike GLP-1 receptor agonists which have a clear protective effect on the cardiovascular system. GIPR is expressed in the ventricles, while GLP-1R is mainly expressed in the atria.⁴⁹ Activation of GIPR in isolated mouse hearts can increase fatty acid oxidation in cardiomyocytes and reduce myocardial triglyceride storage, without affecting myocardial glucose metabolism. Furthermore, whole-body GIPR knockout mice exhibit improved outcomes after ischemia-induced cardiac injury, associated with reduced hormone-sensitive lipase (HSL) phosphorylation, decreased myocardial triglyceride metabolism, and reduced myocardial cell necrosis and adverse ventricular remodeling. Similarly, specific knockout of GIPR in cardiomyocytes leads to reduced HSL phosphorylation. However, the specific mechanism by which GIPR knockout affects lipid metabolism to benefit the ischemic heart remains to be further studied.⁴⁹ Besides, GIP is involved in regulating atherosclerosis and may exert protective effects on this process.⁵⁰ Animal experiments have shown that GIP can reduce the infiltration of macrophages in plaques, enhance collagen content, and increase plaque stability.⁵¹ Long-term infusion of GIP in ApoE (-/-) diabetic mice and db/db mouse models can reduce foam cell formation, thereby inhibiting the progression of atherosclerosis driven by macrophages.⁵² Interestingly, serum levels of GIP are elevated in patients with atherosclerosis,⁵¹ suggesting a potential compensatory response or involvement in the disease process. The net effect of GIP agonism on human cardiovascular disease requires further investigation.

GIP and Metabolic Disorders

Pathophysiological Changes Associated with GIP in Diabetes

In patients with T2DM, the secretion levels of glucose-dependent insulinotropic polypeptide (GIP) are normal or slightly elevated. A meta-analysis⁵³ showed that T2DM patients have no significant differences in GIP secretion peak concentration or area under the secretion curve compared to non-diabetic patients. However, the insulinotropic effect of GIP is reduced in T2DM patients. Studies⁵⁴ have shown that in healthy adults, GIP-mediated incretin effect contributes to approximately 70% of total postprandial insulin secretion. In contrast, this contribution is reduced to about 30% in patients with T2DM. Further studies⁸ have found that the weakening of the incretin effect of GIP in T2DM patients is mainly due to GIP dysfunction. Infusing T2DM patients with different doses of GIP and GLP-1 showed that both GIP and GLP-1 can dose-dependently promote insulin secretion, but the degree of insulinotropic effect of GIP is lower, even at high doses. Especially, the insulinotropic effect of GIP in the late phase is weakened, while that of GLP-1 is relatively normal.⁵³ Research by Xu G et al⁵⁵ has showed that hyperglycemia can reduce the expression of GIPR, suggesting that the diminished incretin effect of GIP may be associated with reduced receptor expression or alterations in downstream signaling pathways. Beyond simple receptor downregulation, chronic hyperglycemia and lipotoxicity are now recognized as key drivers of GIP resistance. In vitro and rodent studies indicate that sustained high glucose levels can impair GIPR signaling at multiple levels. For instance, hyperglycemia has been linked to reduced GIPR mRNA and protein expression in β-cells, contributing to the blunted insulin response.⁵⁵ More importantly, defects extend to post-receptor signaling. Key effector pathways such as cAMP production, protein kinase A (PKA) activation, and calcium influx in response to GIP stimulation are attenuated under diabetic conditions. This dysfunction may involve oxidative stress and the activation of stress-sensitive kinases that interfere with normal GIPR coupling to G-proteins.⁵⁶ The reduction of the incretin effect of GIP in T2DM patients exacerbates the abnormal glucose metabolism, forming a vicious cycle, which in turn further leads to a decrease in the mass and functional insulin secretion of pancreatic β-cells, promoting the pathological progression of T2DM.⁵⁶

The Therapeutic Effects of GIP-Related Formulations on T2DM

In clinical trials involving patients with T2DM, infusion of GIP beyond physiological levels induced an early increase in insulin levels after meals, but also led to an increase in glucagon levels, exacerbating postprandial hyperglycemia.⁵⁷ Moreover, in T2DM patients with impaired GIPR pathways, infusion of GIP had weaker stimulatory effects on insulin and C-peptide compared to infusion of GLP-1 alone.⁵⁸ These findings have somewhat discouraged further research on GIP. However, there are also corresponding positive results that high physiological levels of GIP can promote the secretion of glucagon in T2DM patients who experience insulin-induced hypoglycemia, thereby raising blood glucose levels.⁵⁹ Due to the limited sample sizes in these clinical studies, the results lack representativeness and warrant larger-scale clinical trials. Relevant animal experiments have also been conducted. In obese diabetic rat models, the GIP analogue D-Ala(2)GIP has demonstrated the capacity to counteract β-cell apoptosis, enhance β-cell function, and consequently reduce blood glucose levels.⁶⁰ Similarly, in obese mouse models, administering the GIP receptor agonist N-AcGIP in isolation, when compared to a placebo, has resulted in elevated insulin secretion, enhanced glucose tolerance, and significant reductions in blood glucose concentration and glycated hemoglobin levels.⁶¹ On the other hand, injection of muGIPR-Ab, a GIP receptor antagonist, decreased insulin levels and did not significantly improve glucose tolerance.¹⁸ Besides, infusion of the GIP receptor antagonist GIP 3–30NH2 can inhibit about 80% of GIP’s insulinotropic effect in T2DM patients.⁶² The role and mechanism of GIP receptor agonists or antagonists in T2DM is still inconclusive and require further research.

The Effects of GIP on Obesity and Insulin Resistance

Compared with lean subjects, the expression of GIPR in subcutaneous adipose tissue is significantly decreased in obese individuals with insulin resistance, and the regulatory effect of GIP on the metabolism of subcutaneous adipose tissue is weakened.⁶³ In vitro cell experiments also indicate that GIP can increase insulin sensitivity in adipocytes from lean individuals, but this effect is weakened in adipocytes from obese subjects.⁶⁴ After weight loss in obese individuals, the weakened effect of GIP on the regulation of blood flow and metabolism in subcutaneous adipose tissue, such as glucose uptake, is partially restored.⁶⁴ These findings indicate that there is a weakened effect of the GIP pathway in adipose tissue of obese and insulin-resistant individuals. Currently, a series of animal experiments indicate that supplementation with GIP can improve insulin resistance in obese animals. In a diet-induced obese mouse model, the application of a long-acting GIP analog can significantly increase the expression of pAkt, a key mediator of insulin signaling, in both adipose tissue and liver.⁶⁵ Secondly, this treatment can increase the volume of adipocytes, improve lipid storage capacity in adipose tissue, reduce expression of inflammatory cytokines and T cell infiltration in adipose tissue, and increase secretion of adipokines such as adiponectin that enhance insulin sensitivity, thus ultimately improving insulin resistance by alleviating inflammation.⁶⁵ GIP overexpressing transgenic mice also show reduced macrophage infiltration and adipocyte degeneration in adipose tissue, increased insulin secretion, improved glucose tolerance and insulin sensitivity when fed a high-fat diet.⁶⁶ In vitro culture of mesenteric adipose tissue cells from obese patients shows that application of GIP analogs can reduce the expression of the adipokine progranulin, which mediates the expression of inflammatory cytokine IL-6.⁶⁵ However, conflicting results have been observed in other animal experiments, where GIP administration was associated with increased expression of inflammatory factors and macrophage infiltration in adipose tissue of obese mice, resulting in higher blood glucose levels.⁶⁷ These discrepant findings may be attributable to several experimental variables, including the specific GIP analog or dose employed, the genetic background and severity of the obese animal model (eg, diet-induced vs genetic, degree of metabolic dysfunction), the duration of treatment, and the specific inflammatory markers or macrophage subsets assessed. Such heterogeneity underscores the complexity of GIP’s actions in the context of established obesity and adipose tissue inflammation. In summary, these findings suggest that GIP plays an important regulatory role in adipose tissue metabolism and insulin sensitivity, indicating its potential as a therapeutic target for improving insulin sensitivity in obese individuals.

Synergistic Effects of GLP-1/GIP/GCG Receptor Agonists

GLP-1 and GIP exhibit synergistic effects. In healthy individuals, injection of dual agonist GIP and GLP-1 receptor augments the insulin secretion of β cell compared to injection of either single agonist alone.^61,68 In obese mouse model, dual GIP and GLP-1 receptor agonists superior efficacy in reducing blood glucose and glycosylated hemoglobin levels compared to monotherapy. Tirzepatide, a dual GIP and GLP-1 receptor agonist, is more effective in reducing weight by reducing fat mass in diet-induced obese mice than single GLP-1 receptor agonist.⁶⁸ In clinical trials, Tirzepatide has a better effect in reducing weight and hemoglobin A1c levels.⁶⁹ Compared to the selective GLP-1 receptor agonist semaglutide (1 mg), the highest dose (15 mg) of tirzepatide achieved a greater reduction in glycated hemoglobin (−2.30 vs −1.86 percentage points) and body weight (an additional 5.5 kg reduction) over 40 weeks.⁶⁹ In summary, Tirzepatide, which activates both GIPR and GLP-1R, significantly improves insulin secretion and insulin resistance. It provides a stronger hypoglycemic effect and is not affected by the weakened GIP-mediated insulin secretion in T2DM. Moreover, the introduction of GIP can reduce intake by affecting appetite and more effectively reduce weight than single GLP-1 receptor agonist.⁶⁹ From a clinical safety perspective, available data on GIP-based therapies, particularly from trials with dual GIP/GLP-1 receptor agonists like Tirzepatide, indicate a generally manageable safety profile. The most common adverse events are gastrointestinal (eg, nausea, diarrhea, vomiting), typically mild to moderate in severity and often transient.¹¹ Notably, the addition of GIP agonism appears to potentially mitigate the severity of nausea induced by GLP-1 receptor agonism in preclinical models, which may translate to improved tolerability.³⁴

While isolated activation of the glucagon receptor (GCGR) can increase energy expenditure and reduce hepatic fat, its promotion of gluconeogenesis concurrently raises the risk of hyperglycemia. The introduction of GLP-1 agonism mitigates this risk. Dual GLP-1/GCGR receptor agonists, such as Cotadutide, have demonstrated efficacy not only in lowering blood glucose compared to placebo but also in reducing body weight and improving hepatic fat metabolism. In animal studies, these agents have shown potential in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis.^70,71 Furthermore, triple agonists targeting the GCG, GIP, and GLP-1 receptors—exemplified by SAR441255—have been developed. The inclusion of both GIP and GLP-1 agonism in this design not only counteracts the diabetogenic risk associated with standalone GCGR activation but also yields superior effects in glycemic control and weight management.⁷²

Heterogeneity in Patient Response to GIP-Based Therapies

Individual responses to GIP-based therapies can vary significantly, underscoring the necessity for a personalized medicine approach. Key factors influencing therapeutic efficacy include: genetic background (where functional variants in the GIP receptor gene can alter signaling efficacy—some variants associated with a leaner BMI enhance receptor sensitivity,⁷³ while others like E354Q are linked to an increased risk of type 2 diabetes and exhibit enhanced receptor desensitization⁷⁴); baseline metabolic status (obesity is often associated with blunted GIP receptor expression and signaling in adipose tissue,⁶³ and chronic hyperglycemia may downregulate receptor expression, whereas improving glycemic control can restore the insulinotropic effect of GIP in patients with T2DM^55,56); and drug mechanism (the concept of ligand-biased signaling suggests that different analogs may preferentially activate specific downstream pathways, leading to distinct metabolic outcomes⁷⁵). Notably, the glucose-lowering efficacy of the dual GIP/GLP-1 receptor agonist tirzepatide appears consistent regardless of the baseline duration of diabetes. Future research should focus on elucidating how these factors interact to determine treatment outcomes, paving the way for tailored patient selection and optimized therapeutic strategies.

The Therapeutic Effects of GIP on AD

GIP based medication holds potential therapeutic effects in degenerative central nervous system disorders, including Alzheimer’s disease (AD). AD has been described as type 3 diabetes, reflecting insulin resistance and impaired glucose regulation in the brain. In AD, the concept of brain insulin resistance was first proposed by Hoyer et al. Through postmortem pathological analysis of brain tissues from AD patients, they identified reduced mRNA levels of insulin receptor substrates (IRS) and downstream IRS-related phosphatidylinositol 3-kinase activity.⁷⁶ Clinical studies have also shown a reduction in insulin and insulin receptor levels in AD patients, as well as reduced tyrosine kinase activity, which plays a critical role in insulin receptor signaling.^77,78 Subsequently, animal and clinical trials have demonstrated that intranasal insulin administration can improve AD pathology.^79–81 Moreover, GLP-1 receptor agonists can exert therapeutic effects on AD by reducing β-amyloid protein deposition, p-Tau protein levels, and improving central insulin signaling pathways, among other mechanisms.^82,83 Animal experiments have also shown that GIP may have therapeutic effects on AD. The proposed neuroprotective mechanisms of GIP in AD models extend beyond peripheral metabolic effects and involve direct actions within the brain. These may include: Enhancing brain insulin signaling by increasing insulin receptor sensitivity and downstream pathways (eg, Akt/CREB), thereby counteracting brain insulin resistance;⁸⁴ Reducing Alzheimer’s pathology by decreasing β-amyloid production/aggregation and tau hyperphosphorylation;^85,86 Exerting anti-inflammatory effects by modulating glial cell activation and reducing pro-inflammatory cytokine release;⁸⁷ Promoting synaptic plasticity and neuronal survival through increased expression of neurotrophic factors and reduction of oxidative stress.^87,88

In the APP/PS1 mouse model, injection of D-Ala (2) GIP, a GIPR agonist, reduced β-amyloid protein deposition and attenuated synaptic loss, improving cognitive impairment in both young and old AD mice.^85,86 Subsequently, the modification of D-Ala2GIP to D-Ala2-GIP-Glu-PAL, a more stable GIP analog, further proved that it improved cognitive impairment in transgenic AD mice by activating the cAMP/PKA/CREB signaling pathway in the hippocampus after GIPR activation.⁸⁴ When GIP was used in combination with GLP-1, the GLP-1/GIP dual receptor agonist DA-JC1 reduced glial cell reactivity and alleviated hippocampal inflammation and oxidative stress damage in AD mice.⁸⁷ Another dual GLP-1/GIP receptor agonist, DA4-JC, reduced β-amyloid protein deposition and inflammatory cytokines, enhanced hippocampal synaptic plasticity, and improved central insulin signaling in AD mice by downregulating inhibitory phosphorylation of IRS1ser1101 and upregulating promoting phosphorylation of Aktser473 levels, demonstrating greater efficacy compared to single receptor agonists.^87,88 Although clinical evidence regarding the role of GIP in AD patients remains limited, with no large-scale human trials completed to date, its therapeutic potential for AD is increasingly recognized, primarily based on robust preclinical evidence from animal models.

Conclusion

In this review, we have elaborated on the multifaceted physiological functions of GIP, spanning its roles in pancreatic islets, adipose tissue, the central nervous system, cardiovascular system, gastrointestinal tract, and bone. We summarized the pathophysiological changes in GIP signaling in T2DM and obesity, and the therapeutic potential of GIP-based strategies, particularly dual receptor agonists like tirzepatide, for these metabolic disorders (Figure 3). Furthermore, we explored the emerging and compelling evidence from preclinical studies supporting the neuroprotective effects of GIP in neurodegenerative diseases such as AD, highlighting its potential to improve brain insulin signaling, reduce pathology, and enhance cognition.

Figure 3 GIP-related pathophysiological changes and therapeutic effects in diseases. There is still a lack of experience with long-acting GIP receptor agonists in human use. Animal experiments show that GIP can reduce β cell apoptosis, increase insulin secretion, etc. The regulatory effect of GIP on the metabolism of subcutaneous adipose tissue is weakened in obese individuals with insulin resistance, and weight loss can improve the effect. GIP can through improving lipid storage capacity in adipose tissue, reducing expression of inflammatory cytokines and increasing secretion of adipokines such as adiponectin that enhance insulin sensitivity, eventually improves insulin resistance of obese individuals. Mainly degenerative diseases of central nervous system are AD and PD, which have brain insulin resistance. A series of animal experiments have shown that GIP can alleviate their pathological changes and symptoms, but the specific mechanism needs further exploration. Abbreviations: IR, insulin resistance; AT, insulin resistance; HbA1c, glycated hemoglobin A1c; AD, Alzheimer’s disease; PD, Parkinson’s disease.

The revival of GIP research, fueled by the success of dual agonists, underscores its importance beyond a mere adjunct to GLP-1. Future research should focus on: 1) Elucidating the precise mechanisms of GIP action in different tissues, especially in the human CNS; 2) Conducting large-scale, long-term clinical trials to establish the efficacy and safety profile of GIP-based monotherapies and combination therapies, particularly regarding cardiovascular and neurodegenerative outcomes; 3) Investigating the causes and consequences of GIP resistance in metabolic diseases; 4) Exploring the therapeutic potential of GIP in other conditions linked to metabolism and inflammation. Addressing these questions will be crucial for fully harnessing the therapeutic potential of this versatile incretin hormone.