Explore GLP-1R New Prospects for Treating Diabetes and Obesity

Diabetes is a chronic disease. When the pancreas cannot produce sufficient insulin or when the body cannot effectively use the produced insulin, diabetes occurs. According to statistics, about 537 million adults (20-79 years old) worldwide in 2021 have diabetes; it is expected that by 2030, the number will rise to 643 million; by 2045, it will rise to 783 million. Diabetes has become one of the main hazards that threaten human life.

What is GLP-1R?

GLP-1 is a peptide hormone derived from pancreatic hypoglycemia, which is mainly produced by the intestine and brain stems. The main source of GLP-1 in the blood circulation is the intestine, and the intestinal endocrine L cells scattered in the entire epithelium can feel the increase in nutritional levels in the intestine, so that the release speed of the GLP-1 release and the absorption speed of nutrients are phase phase. match. GLP-1 is mainly used for metabolism, participating in the adjustment and control of nutrition intake after meals.

GLP-has only one known receptor, namely GLP-1R. GLP-1R is manifested in many tissues of the human body, including pancreatic (α cells, β cells), central nervous system, gastrointestinal and cardiovascular system. When insulin β is activated when GLP-1R is activated, the GLP-1R in the cells will stimulate insulin secretion, inhibit insulin alpha through central appetite inhibitory, the cell releases pancreatic hyperglycetes, and can delay stomach emptiness, thereby reducing blood sugar, weight loss, etc. effect.

The Structure of GLP-1R

GLP-1R (Volcanic Hypoglobin-1 receptor) is a GL Protein-Coupled Receptor (GPCR), which is located on the cyt membrane and is used to perceive and transmit GLP- 1 (pancreatic high glucose-1) signal of hormones. The following are some of the main characteristics of the GLP-1R structure:

1. Seven membrane leaping structure: GLP-1R is a seven-membrane leap protein. It includes a cross-membrane consisting of seven alpha spirals. These spirals form a complex receptor on the cell membrane.
2. The external structure of the N-end: The N-end part of the GLP-1R is located outside the cells, which contains the binding site of the GLP-1. When the GLP-1 is combined with the GLP-1R, the external structure changes in structure, which triggers the startup of downstream signal transmission.
3. Internal structure of the C end: The C-end part of the GLP-1R is located on the inside of the cell. It interacts with G protein and other signal conductive molecules to pass the signal and regulate the physiological response in the cell.
4. Logic binding: GLP-1R is combined with GLP-1 hormone through the external structure of its N-terminal, which is the starting point of signal conduction. After the combination of GLP-1 and GLP-1R, the internal signal conduction path of the receptor is activated, causing the physiological effects in the cells, such as promoting insulin secretion and slowing gastric emptying.
5. Activated Constitution: When the GLP-1 is combined to the GLP-1R, the receptor experience changes in conformity. This change enables the receptor to interact with G protein, thereby activating the downstream signal transmission pathway.

Although the structure of the GLP-1R has been understood to a certain extent, there are still many details that need to be further studied due to their complexity and difficulty in researching.

Function of GLP-1R

When the gut is exposed to nutrients, it triggers the secretion of substantial amounts of GLP-1. The effectiveness of GLP-1 hinges on the presence and function of its receptor, GLP-1R. Importantly, GLP-1R is not confined to pancreatic tissue; it is widely distributed throughout various tissues in the body. In pancreatic alpha cells, GLP-1 plays a pivotal role in reducing glucagon secretion—an essential process within the pancreas. In β cells, GLP-1 acts as a dual agent, promoting both insulin secretion and the reduction of blood sugar levels, thus establishing GLP-1R as a key target in the treatment of diabetes.

Moreover, GLP-1 stimulates the proliferation of β cells while safeguarding them against death caused by ER stress. In the intestinal tract, GLP-1 fosters the division and growth of crypt cells, facilitating intestinal development. Under the influence of GLP-1, intestinal epithelial lymphocytes also dampen inflammatory responses, offering protection to intestinal tissue. In the realm of the brain, GLP-1 has the ability to curb appetite and reduce cravings for specific foods, making it a potential treatment option for obesity.

Notably, GLP-1R expression extends to the cardiovascular system, where GLP-1 serves a cardioprotective role. This includes the augmentation of heart rate and cardiac output.

GLP-1R-related diseases

GLP-1R and its Crucial Role in Diabetes

There exists a crucial connection between GLP-1R and diabetes, particularly type 2 diabetes. GLP-1R is primarily found on the surface of islet β cells. When GLP-1 binds to GLP-1R, it has the remarkable ability to stimulate insulin secretion while concurrently lowering blood sugar levels. This is achieved by amplifying the secretion of islet β cells and suppressing the release of glucagon.

Due to its pivotal role in insulin secretion, GLP-1R agonists are employed in the treatment of type 2 diabetes. These medications encompass GLP-1 receptor agonists (GLP-1ra) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which either mimic or enhance the actions of GLP-1 to enhance blood sugar regulation. Notably, GLP-1R agonists not only improve blood sugar control but also contribute to weight reduction. This aspect is particularly significant for diabetes patients since effective weight management is integral to diabetes care.

Stimulation of GLP-1R and Parkinson’s Disease

Current treatments for Parkinson's Disease (PD) primarily address the resulting motor dysfunction arising from dopamine deficiency. In the MPTP-induced PD mouse model, EX-4 treatment emerged as a guardian of dopaminergic neurons, preserving dopamine levels and enhancing motor function. Notably, research has documented that EX-4 administration led to increased cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN), alongside a substantial elevation in striatal dopamine concentration within the 6-hydroxydopamine (6-OHDA)-induced PD animal model. These findings strongly indicate that EX-4 can shield neurons from metabolic and oxidative stress, offering compelling preclinical support for its therapeutic potential in PD.

Furthermore, vildagliptin, a DPP-4 inhibitor, demonstrated its effectiveness by inhibiting the receptor for advanced glycation end products (RAGE)-activated NF-κB pro-inflammatory signaling cascade. This intervention not only prevented dopaminergic neuron demise but also ameliorated motor impairment in the rat rotenone model of PD.

The first open-label clinical study unveiled that the administration of exenatide, a long-acting GLP-1R agonist, yielded enduring improvements in both motor and cognitive function among PD patients. However, it's worth noting that liraglutide, another GLP-1R agonist, failed to exhibit neuroprotective effects when confronted with moderate or substantial midbrain dopaminergic neuronal loss and the associated functional motor deficits observed in the rat 6-OHDA lesion model of PD. The underlying cause for the discrepancy in the protective effect in PD models needs to be further clarified.

Stimulation of GLP-1R and Alzheimer’s Disease

Beginning in the late 1990s, GLP-1R garnered attention as a potential therapeutic target for Alzheimer's Disease (AD). This interest stemmed from the recognition that diabetes and AD share similar pathological characteristics, including chronic oxidative stress and inflammatory responses. Notably, GLP-1 exhibited the ability to shield murine hippocampal HT22 cells from cell death caused by H2O2, Aβ1–42, and other toxic agents through AKT- and ERK1/2-mediated signaling pathways. Moreover, the enduring GLP-1 analogue, EX-4, not only markedly ameliorated learning and memory deficits but also stimulated long-term potentiation (LTP) via the cAMP-CREB signaling axis, while regulating intracellular Ca2+ homeostasis in an Aβ fragment-induced rat hippocampal injury model.

Liraglutide, a long-acting GLP-1R agonist, has been extensively explored as a therapeutic agent for AD. Previous studies involving AD animal models showcased liraglutide's ability to significantly reduce neuronal hyperphosphorylated tau, prevent declines in learning and memory, increase protein O-glycosylation, halt the loss of hippocampal neurons, decrease Aβ plaque load, and prevent synaptic loss. Additionally, an in vitro study revealed that liraglutide's neuroprotective function is mediated through the PI3K-AKT signaling pathway.

Lixisenatide, another GLP-1R agonist initially developed for type 2 diabetes treatment, has demonstrated neuroprotective effects similar to liraglutide. These effects encompass improved working memory, increased LTP, reduced Aβ deposition, and decreased inflammatory responses in an AD mouse model. The neuroprotective attributes of lixisenatide were attributed to induced AKT and MEK signaling pathways.

Furthermore, the DPP-4 inhibitor linagliptin has been reported to possess neuroprotective functions that include attenuating Aβ plaque formation, preventing GSK3β and tau hyperphosphorylation, alleviating inflammation, and increasing brain incretin levels. Additionally, linagliptin mitigates Aβ-induced mitochondrial dysfunction and intracellular ROS production by stimulating the 5' AMP-activated protein kinase (AMPK)-Sirt1 signaling pathway.

The Role of GLP-1/GLP-R Axis in Related Signal Pathways

GLP-1 is known to increase insulin secretion by β cells under hyperglycemic conditions. Although the GLP-1R agonists are used to treat type 2 diabetes in clinic, there are direct evidences about the therapeutic actions of GLP-1-based therapies in different healthy conditions in humans, including adipogenesis, osteogenesis, and nociception, with many signaling pathways are involved.

PKA/STAT3 pathway

GLP-1 and its analogues exert their functions, such as M2 polarization, by triggering the activation of the signal transducer and activator of transcription 3 (STAT3). Upon GLP-1 treatment, the phosphorylation of JNK and its subsequent signal transduction through the cyclic adenosine monophosphate/protein kinase A (PKA) signaling pathway are diminished. Conversely, the phosphorylation of STAT3 is enhanced, further promoting the polarization of macrophages toward the M2 phenotype.

To investigate the effects of Exendin-4 on macrophages and bone formation, an ovariectomized model and a macrophage-depleted model were employed. The results demonstrated that Exendin-4 facilitated the polarization of bone marrow-derived macrophages toward the M2 phenotype and stimulated TGF-β1 secretion via the PKA-STAT3 signaling pathway.

In the context of non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet, Kupffer cell M2 polarization in the liver was studied. These investigations revealed that liraglutide could counteract the detrimental effects of NAFLD by modulating Kupffer cell M2 polarization through the cAMP-PKA-STAT3 signaling pathway.

MAPK and NF-κB pathway

The Mitogen-Activated Protein Kinase (MAPK) pathway plays a significant role in GLP-1R signaling. In a study involving male ob/ob mice, liraglutide was administered subcutaneously for 4 weeks, resulting in the down-regulation of fatty acid synthase (FASN) through the MAPK/ERK and PKA signaling pathways.

In vitro research using peripheral blood mononuclear cells demonstrated that exendin-4 effectively suppressed inflammatory responses and reduced oxidative stress, with these effects mediated by the suppression of the MAPK signaling pathway. Moreover, the protective impact of GLP-1 on IL-6 production and the dysfunction of high glucose-induced endothelial progenitor cells (EPCs) was also attributed to the MAPK signaling pathway.

In a behavioral study involving male Sprague-Dawley rats subjected to partial hepatectomy, surgical trauma led to exacerbated spatial learning and memory impairment. However, treatment with exendin-4 suppressed the activation of nuclear factor kappa-B (NF-κB) and IL-1β, thereby ameliorating hepatectomy-induced behavioral deficits and inflammation. Similarly, GLP-1R-mediated suppression of NF-κB p65 was found to modulate neuroinflammation induced by neuropathic pain and improve recognition memory dysfunction.

PI3K/Akt pathway

GLP-1 receptor agonists (GLP-1RAs) can also exert their effects through the Phosphoinositide 3-kinases (PI3K)/AKT pathway. To induce hypoxia/reoxygenation (H/R) injury, microvascular endothelial cells (CMECs) were isolated from neonatal Sprague–Dawley (SD) rat hearts using enzyme dissociation. In this context, the GLP-1 analogue liraglutide played a protective role by activating the PI3K/Akt/survivin pathways, safeguarding cardial microvascular endothelium from H/R injury.

Liraglutide-induced PI3K activation was also found to enhance keratinocyte migration and facilitate wound healing in mice. Furthermore, incubating MC3T3-E1 cells with liraglutide, which directly acts on osteoblasts, resulted in the activation of the PI3K/AKT signaling pathway, ultimately promoting bone formation.

However, it's worth noting that there are some reports suggesting that the PI3K/Akt pathway can be inhibited by GLP-1 and its analogues. For instance, in studies involving pancreatic cancer cell lines and mouse xenograft models of human pancreatic cancer, the GLP-1R agonist liraglutide was evaluated both in vitro and in vivo. The results indicated that GLP-1R activation with liraglutide dose-dependently suppressed Akt activation and inhibited tumorigenicity/metastasis in human pancreatic cancer cells under both in vitro and in vivo conditions.

GLP-1R Protein

Recombinant Human Glucagon-Like Peptide 1 Receptor (GLP1R) Protein (His&Myc), Active

Click here for more GLP-1R

Synonym : GLP GLP 1 R GLP 1 receptor GLP 1R GLP-1 receptor GLP-1-R GLP-1R GLP1R GLP1R_HUMAN Glucagon like peptide 1 receptor Glucagon-like peptide 1 receptor MGC138331 OTTHUMP00000016340

References:

 

[1] MacDonald, P. E. & Wheeler, M. B. Voltage-dependent K+ channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets. Diabetologia 46, 1046–1062.
[2] Kang, G. X. et al. A cAMP and Ca2+ coincidence detector in support of Ca2+ induced Ca2+ release in mouse pancreatic beta cells. J Physiol-London 566, 173–188.
[3] Meloni, A. R., DeYoung, M. B., Lowe, C. & Parkes, D. G. GLP-1 receptor activated insulin secretion from pancreatic ss-cells: mechanism and glucose dependence. Diabetes Obesity & Metabolism 15, 15–27.
[4] Van de Velde, S., Hogan, M. F. & Montminy, M. mTOR links incretin signaling to HIF induction in pancreatic beta cells. Proceedings of the National Academy of Sciences of the United States of America 108, 16876–16882.
[5] Faubert, B. et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1 alpha. Proceedings of the National Academy of Sciences of the United States of America 111, 2554–2559.
[6] Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional Regulation of Genes Encoding Glycolytic-Enzymes by Hypoxia-Inducible Factor-1. Journal of Biological Chemistry 269, 23757–23763 (1994).
[7] Ferrick, D. A., Neilson, A. & Beeson, C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Discov Today 13, 268–274.
[8] Buteau, J., Foisy, S., Joly, E. & Prentki, M. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52, 124–132 (2003).
[9] Xie, J. et al. Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1. Journal of molecular endocrinology 53, 105–115.
[10] Miao, X. Y. et al. The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway. Peptides 39, 71–79.
[11] Zhang Y, Zhou H, Wu W, Shi C, Hu S, Yin T, et al. Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways. Free Radical Biol Med (2016) 95:278–92.
[12] Graaf Cd, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, Ahn JM, Liao J, Fletcher MM, Yang D, Brown AJ, Zhou C, Deng J, Wang MW. Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol Rev. 2016 Oct;68(4):954-1013.
[13] Shioda, N.; Han, F.; Fukunaga, K. Role of Akt and ERK signaling in the neurogenesis following brain ischemia. Int. Rev. Neurobiol. 2009, 85, 375–387.
[14] Harkavyi, A.; Whitton, P.S. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br. J. Pharmacol. 2010, 159, 495–501.
[15] Teramoto, S.; Miyamoto, N.; Yatomi, K.; Tanaka, Y.; Oishi, H.; Arai, H.; Hattori, N.; Urabe, T. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2011, 31, 1696–1705.
[16] Chien, C.T.; Jou, M.J.; Cheng, T.Y.; Yang, C.H.; Yu, T.Y.; Li, P.C. Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats. J. Cereb. Blood Flow Metab. 2015, 35, 1790–1803.
[17] Jin, J.; Kang, H.M.; Jung, J.; Jeong, J.W.; Park, C. Related expressional change of HIF-1α to the neuroprotective activity of exendin-4 in transient global ischemia. Neuroreport 2014, 25, 65–70.
[18] Zhu, H.; Zhang, Y.; Shi, Z.; Lu, D.; Li, T.; Ding, Y.; Ruan, Y.; Xu, A. The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci. Rep. 2016, 6, 26859.
[19] Darsalia, V.; Olverling, A.; Larsson, M.; Mansouri, S.; Nathanson, D.; Nystrom, T.; Klein, T.; Sjoholm, A.; Patrone, C. Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice. Regul. Pept. 2014, 190, 25–31.
[20] Goreth, M.B. Pediatric Mild Traumatic Brain Injury and Population Health: An Introduction for Nursing Care Providers. Crit. Care Nurs. Clin. North Am. 2017, 29, 157–165.
[21] Wan W, Qin Q, Xie L, Zhang H, Wu F, Stevens RC, Liu Y. GLP-1R Signaling and Functional Molecules in Incretin Therapy. Molecules. 2023 Jan 11;28(2):751.