GIPR has garnered significant attention lately. According to Pharmsnap clinical database, a GIPR target drug (Tirzepatide) has already entered the market in China for treating type 2 diabetes, obesity, and cardiovascular disease, etc. GIPR belongs to the G protein-coupled receptor (GPCR) family. GPCRs have been widely reported to regulate various diseases (see early articles on GPRC5D, CXCR4, and GCGR).
As for GIPR, current studies mainly focus on its functions in glucose and lipid metabolism. Furthermore, latest research shows GIPRs contribute to gastrointestinal neuroendocrine tumors (NETs). Today, we'll learn how GIPR, a type of GPCR, helps regulate metabolism. Also, its potential in the fight against diabetes and obesity!
2. What is the Ligand for GIPR?
Gastric inhibitory polypeptide receptor (GIPR) is a receptor for GIP and a G protein-coupled receptor with seven transmembrane domains (click the feature article: Transmembrane Protein Series III: G Protein-Coupled Receptors) [1]. The human GIPR gene is located on Chromosome 19q13.3 and has a molecular weight of 50 KD. The N-terminal region of GIPR contains a glycosylation sequence (N-X-S/T) and a cytoplasmic loop, while the C-terminal region is enriched in threonine and serine, making it a potential site for phosphorylation (Figure 1) [2-4].
GIPR is expressed in a variety of tissues including pancreatic cells, stomach, small intestine, adipose tissue, adrenal cortex, heart, pituitary gland, bone, lung, and spleen. Within pancreatic islets, GIPR expression is exclusive to alpha and beta cells. GIPR administration activates G proteins, leading to increased intracellular cAMP and Ca2+ levels through PI3K, PAK, PKB, and other signaling pathways. This in turn regulates the expression of downstream genes [2-4].
Consumption of food triggers GIPR to promote insulin secretion, leading to a decrease in blood glucose levels. Simultaneously, GIPR influences adipocyte metabolism and storage, as well as glucose synthesis and release in the liver. Multiple studies have demonstrated the significant role of GIPR in regulating insulin secretion, glucose and lipid metabolism, and maintaining normal metabolic function [5].
Figure 1. GIPR Structure [4]
GIP is the ligand for GIPR, which is secreted by K-cells in the small intestine. GIP and glucagon-like-peptide-1 (GLP-1) are the main intestinal insulin peptides. GIP and GLP-1 act on the corresponding receptors of beta cells, GIPR and GLP-1R, respectively, to regulate β-cell differentiation and proliferation, insulin synthesis and secretion (Figure 2) [6]. GIP also promotes insulin secretion, sensitivity, islet cell proliferation, and neural repair, while regulating transcription factors such as RFX6, PDX1, GATA-4, ISL1, and others [6-10].
GIP binds to GIPR, leading to a change in the conformation of G proteins. This activates adenylate cyclase (AC), which releases cAMP into the cell, thereby elevating intracellular cAMP concentration. As a result, the PAK signaling pathway is activated, ultimately increasing the concentration of critical proteins that regulate insulin synthesis and secretion, including CREB. It's crucial for GIP to bind to the corresponding GIPR on the cell surface to exert biological effects, making GIPR the key factor for GIP's function [10].
Figure 2. GIP and GLP-1 act on the corresponding receptors GIPR and GLP-1R in pancreatic β cells [6]
The GIPR-GIP pathway is important for processes like islet proliferation, energy metabolism regulation, and intestinal function. It's also closely related to lipid accumulation and insulin resistance in adipose tissue. However, more research is needed to fully understand the downstream signaling pathways it triggers.
Studies on adipose isocytes have shown that GIPR-GIP activates CREB, TORC2 or insulin, synergistically promoting pathways such as PKB phosphorylation and LPL, thereby promoting fat accumulation (Figure 3) [11-12]. GIP also promotes IL-6 expression of adipose tissue. Plus, GIPR-GIP induces insulin resistance through MAPK, Akt and FoxO1 to reduce caspase3 and bax activity, exerting pro-proliferative and anti-apoptotic effects [11-13].
GIPR-GIP signaling pathway can cause leptin resistance in obesity by inhibiting the leptin receptor signaling pathway, like Epac/Rapl. This results in an increase in the expression of negative regulators within the leptin signaling pathway, leading to the inhibition of leptin-induced neuronal activation of proopiomelanocortin (POMC). Therefore, inhibition of the GIPR-GIP signaling pathway could be a new target for weight loss [14-15].
In addition, GIPR-GIP increases TCF4 via the Akt signaling pathway, which boosts GIPR expression and creates a positive feedback loop, enhancing GIP signaling pathway. This improves β-cell proliferation, insulin secretion, and glucose homeostasis. Thus, targeting GIPR could be a potential solution for pancreatic β-cell dysfunction caused by blocked Akt and upstream signaling pathways due to insulin resistance [16-17].
Figure 3. GIPR-GIP related signaling pathways [12]
GIPR is vital for glucose and energy metabolism and can affect appetite and weight control, much like GLP-1R. The widely targeted GLP-1R reduces appetite and helps with weight loss and blood glucose control in diabetic patients. Therefore, GIPR, a close relative of GLP-1R, is an important therapeutic target for controlling metabolic diseases such as obesity and diabetes.
Diabetes is a metabolic disease with four types: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), atopic, and gestational diabetes mellitus. Over 90% of patients have type 2 diabetes. Studies found higher GIP levels in obese mice and individuals with glucose intolerance. Additionally, plasma GEP levels were linked to BMI and insulin resistance in healthy individuals. Blocking the GIR-GIPR resulted in significant improvements in metabolism-related abnormalities, such as insulin resistance in diet-induced obesity mice [18-20].
Emerging research suggests that the GIPR-GIP axis may not function optimally in individuals with obesity. Furthermore, studies indicate that this axis can trigger the expression of the SOCS3 gene in both human subcutaneous adipocytes and mouse adipocytes, as well as stimulate the synthesis and secretion of cytokines IL-6 and IL-1beta [21-23].
Conversely, impeding the GIPR-GIP signaling pathway—whether through the injection of GIPR inhibitors into the lateral ventricles of mice or by employing GIPR knockout mice—led to decreased food consumption, body weight, adiposity, and levels of inflammatory markers, such as leptin and IL-6, in both serum and adipose tissue. Additionally, lipid oxidation was augmented in adipose tissue [21-23].
The GIPR-GIP pathway is frequently abnormally activated in conditions like food addiction, acromegaly, and gastrointestinal neuroendocrine neoplasms (GINEN). This abnormal activation is associated with unusual growth hormone (GH) activity during glucose tolerance testing. In some cases of GINEN, GIPR overexpression occurs in the absence of negative growth inhibitor receptors, leading to increased hormone secretion and cell proliferation [24-27].
Furthermore, in tumor tissues of GINEN patients, the expression ratio of GIPR to SSTR2 was observed to be prominently elevated compared to normal tissues. Specifically, the relative expression of GIPR was significantly higher than that of SSTR2. These results indicate that GIPR could serve as a potential diagnostic marker for GINEN [24-27].
There are over 40 GIPR-targeted drugs in clinical studies worldwide, developed by companies such as Eli Lilly, Amgen, Carmot Therapeutics, Zhejiang Doer Biologics, Huadong Medicine, and Gmax Biopharm (Hangzhou). These drugs come in different forms, including monoclonal antibodies, dual antibodies, peptide-coupled drugs, and fusion proteins. Most of them work by either activating or inhibiting GIPR. Some of them have additional effects, such as GLP-1R agonism, GCGR agonism, and NPY receptor modulation.
Aforementioned, one GIPR-targeted drug has already been approved for marketing. Now, GIPR as key regulator in glucose and lipid metabolism, as well as neuroendocrine tumors, more drugs targeting GIPR are expected to emerge in the future.
Drugs | Target | Mechanism of action | Indications | Status | Drug Type | Institutes |
---|---|---|---|---|---|---|
Tirzepatide | GIPR+GLP-1R | GIPR agonist; GLP-1R agonist | Type 2 diabetes; overweight; obstructive sleep apnea syndrome; cardiovascular disease; Obesity | Approval for listing | Synthetic peptides | Ei Lilly & Co; Ei Lily Japan KK; Eli Lilly Suzhou Pharmaceutical Co. |
Retatrutide | GCGR +GIPR | GCGR agonist; GLP-1R agonist | Cardiovascular disease; obesity; overweight; type 2 diabetes | Clinical Phase 3 | Synthetic peptides | Ei Lilly & Co; Lilly Suzhou Pharmaceutical Co. |
Maridebart Cafraglutide | GIPR+GLP-1R | GIPR antagonist; GLP-1R agonist | Type 2 diabetes; obesity; overweight | Clinical Phase 2 | Peptide-coupled drugs (PDC) | Amgen, Inc. |
LY-3537031 | GIPR+GlP-1R | GIPR agonist, GLP-1R agonist | / | Clinical Phase 1 | Synthetic peptides | Ei Lilly & Co |
CT-388 | GIPR+GlP-1R | GIPR agonist, GLP-1R modulator | Diabetes mellitus; type 2 diabetes; obesity; non-alcoholic steatohepatitis | Clinical Phase 1 | Synthetic peptides | Carmot Therapeutics, Inc. |
DR10627 | GIPR+GlP-1R | GIPR agonist, GLP-1R modulator | Diabetes mellitus; non-alcoholic steatohepatitis | Clinical Phase 1 | Synthetic peptides | Zhejiang Doer Biologics Co. |
GMA-106 | GIPR+GlP-1R | GIPR antagonist, GLP-1R antagonist | Pulmonary sedation; type 2 diabetes; nonalcoholic steatohepatitis; obesity; overweight | Clinical Phase 1 | Bispecific antibodies | Gmax Biopharm (Hangzhou) Co. |
Maridebart | GIPR | GIPR antagonists | Tumors | Clinical phase no | Monoclonal antibodies | / |
Efocipegtrutide | GIPR+GlP-1R | GIPR agonist, GLP-1R agonist | / | Clinical phase no | Fusion proteins | / |
DR10628 | GIPR+GlP-1R | GIPR agonist, GLP-1R agonist | Diabetes mellitus; non-alcoholic steatohepatitis | Preclinical | Fusion proteins | Zhejiang Doer Biologics Co. |
HDM-1005 | GIPR+GlP-1R | GIPR agonist, GLP-1R agonist | Diabetes; obesity | Preclinical | Bispecific antibodies | Huadong Medicine Co. |
111In-3BP tracer | GIPR | GIPR antagonists | Neuroendocrine tumors | Preclinical | Synthetic peptides | 3B Pharmaceuticals GmbH |
DR10625 | FGF21 + GIPR + GLP-1R | FGF21 modulator, GIPR agonist, GLP-1R agonist | Obesity; type 2 diabetes mellitus; nonalcoholic steatohepatitis | Preclinical | Fusion proteins | Zhejiang Doer Biologics Co. |
XW-017 | GIPR | GIPR agonist | Obesity; type 2 diabetes mellitus; nonalcoholic steatohepatitis | Preclinical | Synthetic peptides | Hangzhou Sciwind Biosciences Co. |
LBT-6030 | GIPR+GlP-1R | GIPR agonist, GLP-1R agonist | Diabetes | Preclinical | Biologics | Longevity Biotech, Inc. |
3B-402 | GIPR | GIPR modulators | Neuroendocrine tumors | Drug Discovery | Synthetic peptides | 3B Pharmaceuticals GmbH |
3B-401 | GIPR | GIPR modulators | Neuroendocrine tumors | Drug Discovery | Synthetic peptides | 3B Pharmaceuticals GmbH |
ZP-3022 (Zealand Pharma A/S) | GCGR + GIPR + GLP-1R + NPY | GCGR modulators, GIPR agonists, GLP-1R agonists | / | Preclinical | Biologics | / |
ZP-1-98 (Zealand Pharma A/S) | GIPR | GIPR agonist | / | Preclinical | Biologics | / |
CYT-014-GIPQb | GIPR | GIPR modulators | / | Drug Discovery | Biologics | / |
Table 1: Drugs in clinical development for GIPR (partial)
To fully support researchers and pharmaceutical companies in their research on GIPR in diabetes, obesity, and cancers, CUSABIO presents GIPR active protein to support your research on the mechanism of GIPR or its potential clinical value (click for the full list of GIPR products: GIPR Proteins; GIPR antibodies).
High specificity was validated by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Mouse Gipr at 2μg/mL can bind Anti-Mouse Gipr recombinant antibody (CSB-RA009438MA1MO), the EC50 is 8.622-11.36 ng/mL.
High specificity was validated by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Rat Gipr at 2μg/mL can bind Anti-Mouse Gipr recombinant antibody (CSB-RA009438MA1MO), the EC50 is 6.946-8.740 ng/mL.
References
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