GLP-1R: An Energy Metabolism Regulator of GPCR Family, an Effective Drug Target for Type 2 Diabetes Therapy!

1. What is GLP-1R?

1.1 GLP-1R Structure

GLP-1R is a G protein-coupled receptor located on human chromosome 6p21. Its structure includes a large extracellular domain and a seven-times-transmembrane core domain with α-helix bundles. The N-terminal extracellular segment with 116 amino acid residues has three pairs of disulfide bonds for ligand recognition. The transmembrane domain (117-381 amino acid residues) contains the ligand's N-terminal binding site, while the C-terminal intracellular sequence (59 amino acid residues) recruits downstream G proteins (Figure 1) ^[1-3].

Figure 1. GLP-1R structure ^[1]

1.2 GLP-1R Expression and Function

GLP-1R is extensively distributed throughout the body in various tissues, including pancreatic islets, stomach, small intestine, heart, kidneys, lungs, and brain. In the gastrointestinal tract, it contributes to gastric emptying delay, increased satiety, and controlled food intake, aiding in weight reduction. In nervous tissue, GLP-1R provides neuroprotection and enhances learning and memory. In the cardiovascular system, GLP-1R regulates heart rate, ventricular diastolic pressure, and prevents cardiomyocyte apoptosis ^[4-8].

Notably, GLP-1R's significant role in pancreatic β-cells leads to insulin release promotion and glucagon release inhibition, thereby helping to regulate blood glucose levels. This makes GLP-1R an essential target for diabetes treatment ^[4-8].

2. What are the Ligands for GLP-1R?

GLP-1Rs endogenous ligands are glucagon-like polypeptide-1 (GLP-1) and oxyntomodulin (OXM). L-cells in the gut, mainly located in the epithelial layer of the small intestine and colon, secrete GLP-1 and OXM when food enters the digestive system, especially the small intestine ^[9-13].

GLP-1 serves as the primary agonist for GLP-1R in vivo and activates the receptor through a "two-domain model." Firstly, the C-terminal domain of GLP-1 (cGLP-1) binds to the "affinity trap" formed by GLP-1R's extracellular domain (ECD), positioning the N-terminal domain of GLP-1 (nGLP-1) in the "pocket" created by the receptor's core domain (TMD). This interaction effectively triggers downstream signaling pathways, including PKA, PI3K, and MAPK, leading to essential physiological processes like insulin release, β-cell proliferation, reduced glucagon release, and delayed gastric emptying ^[9-13].

Figure 2. The "two-domain model" of receptor-ligand interaction for GPCR ^[12]

3. What is the Mechanism of Action of GLP-1 R?

GLP-1R is a versatile coupled receptor. When it binds to ligand GLP-1, the G protein α subunit dissociates from the β and γ subunits, triggering receptor modification and activation of multiple downstream signaling pathways. These pathways encompass various G protein signaling routes, such as Gαs, Gαi, Gαo, Gαq/11, and the non-G protein-dependent β-arrestin pathway ^{[12, 14-16]}.

In pancreatic islet β-cells, activated GLP-1R couples to Gs proteins, leading to adenylyl cyclase activation, increased cAMP content, and elevated PKA and Epac2 levels. These changes alter ion channel activity, closing potassium channels while opening voltage-dependent calcium channels (VDCCs). Consequently, calcium influx rises, promoting insulinogen gene transcription and insulin secretory vesicle release. GLP-1 enhances glucose sensitivity and stimulates glucose-dependent insulin secretion via the cAMP-PKA pathway. Furthermore, GLP-1R activation through PI3K and MAPK pathways induces β-cell growth and differentiation ^{[12, 14-16]}.

Additionally, cAMP interacts with cAMP-regulated guanylate exchange factors (cAMP-GEFs) in β-cells, independently of PKA, activating the Ras/MAPK pathway to foster β-cell growth and differentiation. GLP-1R also modulates the cAMP-responsive element binding protein (CREB) and protein resurrection factors like Bcl-2 and Bcl-XL to inhibit apoptosis and promote β-cell growth and differentiation. Recently, β-arrestin recruitment has been implicated in GLP-1R function ^{[12, 14-16]}. For instance, knockout of β-arrestin1 in β-cells reduces cAMP and insulin release, while β-arrestin2 knockout in mice results in postprandial hyperglycemia, reduced glucose tolerance, and insulin resistance ^[15].

Figure 3. GLP-1R related signaling pathways in pancreatic β-cells ^[12]

4. The Roles of GLP-1R in Type 2 Diabetes and Other Diseases

GLP-1R is a highly successful drug target for treating type 2 diabetes (T2DM). Apart from lowering glucose levels with low hypoglycemia risk, it also aids in weight loss, blood pressure reduction, and improved blood lipids. Additionally, GLP-1R holds potential for addressing obesity and cardiovascular disease. Further research into its function may unveil new therapeutic approaches for various related conditions.

4.1 GLP-1R and Type 2 Diabetes

GLP-1R agonists are a novel class of anti-type 2 diabetes (T2DM) drugs. Unlike many current hypoglycemic agents that cause weight gain, such as biguanides, TZDs, and DPP-4 inhibitors, GLP-1R agonists offer a pharmacologic therapy urgently needed by T2DM patients, effectively lowering blood glucose levels and improving obesity simultaneously ^[17-20].

Exenatide was the first FDA-approved GLP-1R agonist for T2DM treatment. In recent years, several other GLP-1R-targeted drugs have been successfully developed, including Lixisenatide, PEG-Loxenatide, Semaglutide, Beinaglutide, and Liraglutide ^[17-22]. These medications promote insulin release, regulate blood glucose levels, and enhance insulin resistance and β-cell function.

4.2 GLP-1R and Obesity

Obese patients may develop insulin resistance under certain pathologies, prompting their pancreatic beta cells to increase insulin secretion as a compensatory mechanism. However, this compensatory response may eventually diminish or fail over time, leading to disruptions in glucose metabolism and the onset of diabetes. Therefore, risk factors for diabetes, such as obesity and overweight, are closely related ^[23-26].

Numerous studies have revealed that diabetic obese and diabetic patients show a gradual decrease in pancreatic GLP-1R protein expression, suggesting that reduced Therefoere, the expression of GLP-1R is a crucial pathological mechanism that contributes to the higher probability of diabetes development in obese patients ^[23-26].

4.3 GLP-1R and Other Diseases

GLP-1R is implicated in various complications of diabetes, particularly atherosclerotic cardiovascular disease. Studies demonstrate that GLP-1R agonists (GLP-1RA) not only lower blood glucose but also independently protect the cardiovascular system. GLP-1RA may offer a protective effect in the coronary atherosclerotic process by modulating macrophage polarization towards the M2 type ^[27-28].

Moreover, in spinal cord injury studies, GLP-1RA, like Liraglutide, has shown potential in promoting motor function recovery and safeguarding spinal cord tissue ^[29]. In investigations related to polycystic ovary syndrome (PCOS), GLP-1RA combined with metformin treatment has been observed to reduce luteinizing hormone (LH) levels in overweight or obese PCOS patients ^[30]. Further research has indicated that GLP-1RA, such as Exenatide, regulates the hypothalamus by modulating SIRT1 and kisspeptin expression in PCOS ^[31-32].

5. GLP-1R Clinical Trials for Drug Development

According to Pharmsnap, more than 200 drugs based on GLP-1R targets are currently in clinical studies. These drugs are primarily GLP-1R agonists, which include many small molecule lead compounds based on GLP-1R for the treatment of diabetes. As mentioned earlier, several GLP-1R drugs are already on the market, primarily for type 2 diabetes treatment. In recent years, GLP-1R-based mono- and bi-antagonists and other biologics have also emerged, such as the GCGR x GLP-1R, GDF-15 x GIP-1R, FGF21 x GIP-1R dual agonists (Table 1).

These GLP-1R-based targeted drugs are expected to be more effective in managing blood glucose and regulating lipids, improving the quality of life of patients, while delaying the complications associated with type 2 diabetes. These explorations have important clinical applications for the development of next-generation diabetes drugs!

Table 1. Part GLP-1R clinical trials for drug development

To fully support researchers and pharmaceutical companies in their research on GLP-1R in type 2 diabetes or other diseases, CUSABIO presents GLP-1R active protein to support your research on the mechanism of GLP-1R or its potential clinical value (click for the full list of GLP-1R products: GLP-1R proteins; GLP-1R antibodies; GLP-1R kits).

GLP-1R protein

Recombinant Human Glucagon-like peptide 1 receptor (GLP1R), partial (Active) (Code: CSB-MP009514HUb1)

High Specificity Validated by SDS-PAGE

High purity was greater than 95% as determined by SDS-PAGE. SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Human GLP1R at 2 μg/mL can bind Anti-GLP1R recombinant antibody (CSB-RA009514MA1HU), the EC₅₀ is 54.54-94.23 ng/mL.