The glucagon-like peptide-1 receptor (GLP1R) is a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

(GPCR) found on

beta cell Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...

s of the pancreas and on

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

of the brain. It is involved in the control of

blood sugar level The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (1 ...

by enhancing insulin secretion. In humans it is synthesised by the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

''GLP1R'', which is present on

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...

. It is a member of the

glucagon receptor family The glucagon receptor family is a group of closely related G-protein coupled receptors which include: * Glucagon receptor * Glucagon-like peptide 1 receptor * Glucagon-like peptide 2 receptor * Gastric inhibitory polypeptide receptor The fir ...

of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane domain (TMD) that binds the N-terminal region of GLP-1. In the TMD domain a fulcrum of polar residues regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

Ligands

GLP1R binds

glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cer ...

(GLP1) and

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...

as its natural endogenous agonists.

Agonists An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...

: *

GLP-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...

– endogenous in humans *

oxyntomodulin Oxyntomodulin (often abbreviated OXM) is a naturally occurring 37-amino acid peptide hormone found in the colon, produced by the oxyntic ( fundic) cells of the oxyntic (fundic) mucosa. It has been found to suppress appetite. The mechanism of a ...

* exendin-4, *

exenatide Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulf ...

* lixisenatide * albiglutide * beinaglutide *

dulaglutide Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardio ...

* efpeglenatide * langlenatide *

liraglutide Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects ...

* PEG- Loxenatide *

semaglutide Semaglutide is an anti-diabetic medication used for the treatment of type2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a ...

* taspoglutide * Ecnoglutide * Utreglutide * Glepaglutide * Apraglutide * Maridebart Cafraglutide/ AMG133 *

Tirzepatide Tirzepatide is an antidiabetic medication used to treat type2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections (under the skin). In the United States, it is sold under the brand name Mounjaro for diabetes ...

* pegapamodutide * Mazdutide *

Survodutide Survodutide (BI 456906) is an experimental peptide that works as a dual glucagon/ GLP-1 receptor agonist. Unlike other dual GLP-1/glucagon dual agonists, it is a glucagon analog rather than an analog of oxyntomodulin. It is developed by Boehring ...

* Bamadutide * Pemvidutide * Cotadutide * Retatrutide *

lithium chloride Lithium chloride is a chemical compound with the formula Li Cl. The salt is a typical ionic compound (with certain covalent characteristics), although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorid ...

* Grutalumab * DA1726 * GX-G6 * GZR18 * HRS9531 * BGMO504 * PB718 * RAY1225 * VCT220 * VK2735 * BLX7006 * Supaglutide/ Efsubaglutide: approved in China for treatment of Diabetes mellitus. * ASC30 * Danuglipron * Aleniglipron( GSBR-1290) * Lotiglipron * Orforglipron * CT-996 * CT-388 * HS-10535 * UBT251 :

, GIP &

Glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...

receptor triple agonist. * Efinopegdutide : HM12525A/ MK-6024/ JNJ-64565111/ LAPS- GLP-1R/

GCGR The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors (secretin receptor family), coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of ...

agonist * Efocipegtrutide/ HM15211

Antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.-39GLP-1 * T-0632 * GLP1R0017 * Avexitide/ exendin 9-39

Allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...

s * Positive: ** BETP * Negative: ** HTL26119 ** ** **

Structure

The GLP-1 receptor is a transmembrane protein composed of seven alpha-helical transmembrane domains (TM1-TM7), an extracellular N-terminus, and an intracellular C-terminus. It belongs to the class B family of G protein-coupled receptors, also known as secretin-like receptors. The N-terminus of the receptor is responsible for binding glucagon-like peptide-1 (GLP-1) ligands, while the intracellular C-terminus interacts with intracellular signaling proteins to initiate downstream signaling pathways. The extracellular N-terminus contains key regions involved in ligand recognition and binding. It undergoes conformational changes upon ligand binding, leading to activation of intracellular signaling cascades. The intracellular C-terminus interacts with

G proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...

and other signaling molecules to initiate cellular responses. GLP-1R complex

Function

Glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cer ...

(GLP-1) is a hormone consisting of 30 amino acids. It is released by intestinal L cells when nutrients are consumed. GLP-1 has multiple effects, including enhancing

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

secretion from pancreatic beta cells in response to

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

, increasing insulin expression, preventing beta-cell apoptosis, promoting the formation of new beta cells, reducing glucagon secretion, slowing down stomach emptying, promoting satiety, and improving glucose disposal in peripheral tissues. Due to these diverse effects, there has been significant interest in developing long-lasting agonists of the GLP-1 receptor (GLP-1R) for the treatment of type 2 diabetes (T2D). GLP1R is also expressed in the brain where it is involved in the control of

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

. Furthermore, mice that over express GLP1R display improved memory and learning. Stretch responsive vagal neurons in the stomach and intestines also express GLP1R. GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation.

Mechanism of action

Upon binding to its ligand GLP-1, the GLP-1 receptor activates intracellular signaling pathways that regulate insulin secretion, glucose metabolism, and satiety. In pancreatic beta cells, GLP-1 receptor activation enhances glucose-stimulated insulin secretion. This occurs through the activation of

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, leading to increased intracellular levels of

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triph ...

(cAMP). The rise in cAMP activates

protein kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

(PKA), which promotes insulin exocytosis and enhances beta cell survival and proliferation. GLP-1 receptor signaling in pancreatic alpha cells reduces glucagon secretion, further contributing to glucose lowering. By inhibiting glucagon release, GLP-1 receptor activation helps to maintain glucose homeostasis. Another important function of the GLP-1 receptor is the regulation of gastric emptying. Activation of the receptor delays the rate at which the stomach empties, leading to increased satiety and reduced food intake. This effect contributes to weight management and appetite control. 'Appetite regulation and satiety': GLP-1 receptor signaling influences the central nervous system, particularly regions involved in appetite regulation. Activation of the GLP-1 receptor promotes feelings of satiety, leading to a reduction in food intake and improved weight management. Gastric emptying': GLP-1 receptor activation slows down the rate at which the stomach empties its contents into the small intestine. This delay in gastric emptying contributes to the feeling of fullness and aids in controlling postprandial blood glucose levels.

Clinical significance

Glucose Control: GLP-1 and its agonists enhance glucose control by promoting insulin secretion from pancreatic beta cells in a glucose-dependent manner. This means that they stimulate insulin release when blood glucose levels are elevated, helping to maintain normal blood sugar levels. By mimicking the physiological actions of GLP-1, GLP-1 receptor agonists effectively lower blood glucose levels, particularly after meals. Weight Management: GLP-1 and its agonists have demonstrated the ability to promote weight loss or weight stabilization. These agents help reduce appetite, delay gastric emptying, and enhance satiety, leading to reduced food intake. The weight loss effect is particularly beneficial for individuals with type 2 diabetes who often struggle with obesity or overweight conditions. Cardiovascular Protection: GLP-1 receptor agonists have shown potential cardiovascular benefits beyond glucose control. Some studies suggest that these agents may reduce the risk of cardiovascular events, such as heart attacks, strokes, and cardiovascular-related mortality. The cardiovascular protective effects may be related to their favorable effects on blood pressure, lipid profiles, inflammation, and endothelial function. Beta Cell Preservation: GLP-1 and its agonists have been found to exert protective effects on pancreatic beta cells, which are responsible for producing insulin. They can enhance beta cell survival, promote beta cell proliferation, and inhibit beta cell apoptosis, thus preserving beta cell function over time. Combination Therapy: GLP-1 receptor agonists are often used as part of combination therapy in the treatment of type 2 diabetes. They can be prescribed alongside other oral antidiabetic medications, such as metformin or sulfonylureas, to provide additional glycemic control and improve overall treatment outcomes. Different GLP-1 receptor agonists go through inactivation by

dipeptidyl peptidase-4 Dipeptidyl peptidase-4 (DPP4 or DPPIV), also known as adenosine deaminase complexing protein 2 or CD26 (cluster of differentiation 26) is a protein that, in humans, is encoded by the ''DPP4'' gene. DPP4 is related to FAP, DPP8, and DPP9. The en ...

(DPP-4) enzymes (The clinical use of GLP-1 is hampered by its short

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

in the circulation (1-2 min), because of its proteolytic degradation by the enzymes DPP-4 and

neutral endopeptidase Neprilysin (; also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10) and common acute lymphoblastic leukemia antigen (CALLA)) is an enzyme that in humans is encoded by the ''MME'' ge ...

). One strategy used for overcoming this problem is by synthesising new GLP-1 receptor agonists with a prolonged circulating half-life that will display a reduced degradation by DPP-4 enzymes. Another strategy is to inihibit DPP-4 enzymes. The debate about which treatment in combatting T2D still wages. Some studies suggest GLP1 Receptor Agonists (GLP1RAs) which have shown significant results compared to treatment with DPP-4 inhibitors. Some studies provided an insight into the reduction in limb incidents when treated with GLP1RAs. Other studies showed that GLP1RAs provide superior glycaemic control and weight loss when compared with DPP-4 inhibitors in patients with T2D.

Semaglutide

Commercially known as Ozempic or Wegovy,

is one of a class of drugs called glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It is primarily used for the treatment of type 2 diabetes. Semaglutide has an experimented half-life of 165–184 hours compared with

Liraglutide Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects ...

(13 hours) and GLP-1 (2 minutes). Semaglutide has also shown effectiveness in treating

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. In doses higher than those used for diabetes management, it can help reduce appetite and body weight. The precise mechanism of action is not fully understood, but it is believed to involve multiple factors. Semaglutide decreases appetite by acting on the brain. It also slows down stomach emptying, which further reduces appetite. The medication is administered as a once-weekly subcutaneous injection. The starting dose is usually low and gradually increased over several weeks to help minimize potential gastrointestinal side effects, such as nausea. The optimal dose for an individual is determined by their healthcare provider based on factors such as blood sugar levels, response to treatment, and tolerance. Clinical trials reported the efficacy of semaglutide in improving

glycemic control Diabetes mellitus is a metabolic disease that is characterized by chronic elevated blood glucose levels (hyperglycemia). Therefore, the main goal of diabetes management is to keep blood glucose levels within normal limits or a target range as ...

, in terms of reductions in

HbA1c Glycated hemoglobin, also called glycohemoglobin, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose, and fructose, spontaneously (that is, non-enzymatically) bond with hemoglob ...

(a measure of long-term blood sugar control) as well as fasting and postprandial (after-meal) glucose levels.

Possible side effects

Common side effects include nausea, vomiting, diarrhea, and constipation. These are usually temporary and tend to diminish over time. Rare but more serious side effects may include

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

gallbladder disease Gallbladder diseases are diseases involving the gallbladder and is closely linked to biliary disease, with the most common cause being gallstones (cholelithiasis). The gallbladder is designed to aid in the digestion of fats by concentrating and ...

, and allergic reactions. It is essential to consider potential side effects and risks before starting treatment.

Huntington's disease

The diabetic, pancreatic, and neuroprotection implications of GLP1R are also thought to be potential therapies for treating the diabetes and energy metabolism abnormalities associated with

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

affecting the brain and periphery. Exendin-4, an FDA-approved antidiabetic glucagon-like peptide 1 (GLP-1) receptor agonist, has been tested in mice with the mutated human huntingtin protein showing neurodegenerative changes, motor dysfunction, poor energy metabolism, and high blood glucose levels. Exendin-4 (Ex-4) treatment reduced the accumulation of mutated human

huntingtin Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutation, Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role an ...

(htt) protein aggregates, improved motor function, extended the survival time, improved glucose regulation, and decreased brain and pancreas pathology. Exendin-4 increases beta cell mass in the pancreatic islets to improve the release of insulin to ultimately increase glucose uptake. The mechanism regarding this insulin increase involves Ex-4 and GLP-1. When the islets in the pancreas are exposed to GLP-1, there is an increased expression of the anti-apoptotic gene

bcl-2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...

and decreased expression of pro-apoptotic genes bax and

caspase-3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also ...

, which leads to greater cell survival. GLP-1 binding to its

activates various different pathways including the growth factor receptor and is coupled to pathways stimulating

mitogenesis A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The cell cycle Mitogens ac ...

. Some of these pathways include

Rap Rapping (also rhyming, flowing, spitting, emceeing, or MCing) is an artistic form of vocal delivery and emotive expression that incorporates " rhyme, rhythmic speech, and ommonlystreet vernacular". It is usually performed over a backin ...

, Erk1/2,

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...

, B-RAF, PI3-K,

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

PKA In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...

, and TORC2 that are activated to initiate

exocytosis Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...

, proinsulin gene expression and translation, increase insulin biosynthesis, and genetically increase beta cell proliferation and neogenesis. The GLP-1R is a G protein-coupled receptor that is dependent on glucose and GLP-1 is a peptide hormone that acts directly on the beta cell to stimulate insulin secretion by activating signal transduction when glucose is present. When glucose is not present, this receptor no longer couples to stimulate insulin secretion in order to prevent hypoglycemia. Relating glucose metabolism and insulin sensitivity back to Huntington's disease, increased insulin release and beta cell proliferation by a GLP-1 agonist, Ex-4, helps combat the damage done by mutant htt in peripheral tissues. Htt aggregation decreases beta cell mass and thus impairs insulin release and increases blood glucose levels. Disruption of glycemic homeostasis then affects nutrient availability to neurons and alters neuron function contributing to neurodegeneration and motor problems seen in Huntington's disease. The health of the nervous system is related to metabolic health, thus a diabetes medication as a Huntington's disease treatment is a potential treatment. Ex-4 easily crosses the blood-brain barrier and GLP-1 and Ex-4 have been shown to act on neurons in the brain by exerting neuroprotective actions. In studies with Huntington's disease mice, daily treatments of Ex-4 significantly reduced glucose levels compared to those mice treated with saline. It also increased insulin sensitivity by about 50%, improved insulin-stimulated glucose uptake, and protect pancreatic beta cell function. Huntington's disease has also been linked to imbalances in

leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

and

ghrelin Ghrelin (; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrel ...

levels. Ex-4 restored ghrelin levels and also lowered leptin levels allowing Huntington's disease mice to eat more and counteract symptomatic weight loss. This treatment restored beta cell and islet structure, reduced mutated human huntingtin aggregates in the brain and pancreas, and also improved motor function seen by the increased activity level of the mice. Improvements were found in the areas of the body that expressed GLP-1R. In addition to its other effects on the Huntington's disease mouse model, daily treatment of Ex-4, the GLP-1R agonist, significantly delayed the onset of mortality and extended the lifespan by approximately one month.

References

External links

* * * {{G protein-coupled receptors G protein-coupled receptors