Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long

peptide hormone Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...

deriving from the tissue-specific posttranslational processing of the

proglucagon Proglucagon is a protein that is cleaved from preproglucagon. Preproglucagon in humans is encoded by the ''GCG'' gene. Proglucagon is a precursor of glucagon, and several other components. It is generated in the alpha cells of the pancreas and i ...

peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and

proteolytic cleavage Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...

, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1

protein secondary structure Protein secondary structure is the three dimensional form of ''local segments'' of proteins. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary structu ...

includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region. Alongside

glucose-dependent insulinotropic peptide Glucose-dependent insulinotropic polypeptide (GIP), also known as Gastric inhibitory polypeptide or gastric inhibitory peptide (also abbreviated as GIP), is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor o ...

(GIP), GLP-1 is an incretin; thus, it has the ability to decrease

blood sugar levels Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the b ...

in a glucose-dependent manner by enhancing the

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...

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

. Beside the insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. Unlike GIP, the action of GLP-1 is preserved in patients with

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

and substantial pharmaceutical research has therefore been directed towards the development of GLP-1-based treatment. Endogenous GLP-1 is rapidly degraded primarily by dipeptidyl peptidase-4 (DPP-4), as well as neutral endopeptidase 24.11 (NEP 24.11) and

renal clearance In pharmacology, clearance is a pharmacokinetic measurement of the volume of plasma from which a substance is completely removed per unit time. Usually, clearance is measured in L/h or mL/min. The quantity reflects the rate of drug elimination div ...

, resulting in a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

of approximately 2 minutes. Consequently, only 10–15 % of GLP-1 reaches circulation intact, leading to fasting plasma levels of only 0–15 pmol/L. To overcome this, GLP-1 receptor agonists and DPP-4 inhibitors have been developed to increase GLP-1 activity. As opposed to common treatment agents such as

and sulphonylurea, GLP-1-based treatment has been associated with

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...

and a lower risk of

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

, two important considerations for patients with type 2 diabetes.

Gene expression

The proglucagon gene is expressed in several organs including the

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...

( α-cells of the

islets of Langerhans The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...

), gut (intestinal enteroendocrine L-cells) and

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

(caudal

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

and

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

). Pancreatic proglucagon gene expression is promoted upon fasting and hypoglycaemia induction and inhibited by insulin. Conversely, intestinal proglucagon gene expression is reduced during fasting and stimulated upon food consumption. In mammals, the transcription gives rise to identical

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

in all three cell types, which is further translated to the 180 amino acid precursor called

. However, as a result of tissue-specific posttranslational processing mechanisms, different peptides are produced in the different cells. In the

( α-cells of the

is cleaved by prohormone convertase (PC) 2 producing glicentin-related pancreatic peptide (GRPP),

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises 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 medication to tre ...

, intervening peptide-1 (IP-1) and major proglucagon fragment (MPGF). In the gut and brain,

is catalysed by PC 1/3 giving rise to glicentin, which may be further processed to GRPP and oxyntomodulin, GLP-1, intervening peptide-2 (IP-2) and glucagon-like peptide-2 ( GLP-2). Initially, GLP-1 was thought to correspond to proglucagon (72–108) suitable with the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

of the MGPF, but sequencing experiments of endogenous GLP-1 revealed a structure corresponding to proglucagon (78–107) from which two discoveries were found. Firstly, the full-length GLP-1 (1–37) was found to be catalysed by

endopeptidase Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this ...

to the biologically active GLP-1 (7–37). Secondly, the

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...

corresponding to proglucagon(108) was found to serve as a substrate for amidation of the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

resulting in the equally potent GLP-1 (7–36) amide. In humans, almost all (>80%) secreted GLP-1 is amidated, whereas a considerable part remains GLP-1 (7–37) in other species.

Secretion

GLP-1 is packaged in secretory granules and secreted into the

hepatic portal system In human anatomy, the hepatic portal system is the system of veins comprising the hepatic portal vein and its tributaries. It is also called the portal venous system (although it is not the only example of a portal venous system) and splanchnic ...

by the intestinal L-cells located primarily in the distal

ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...

and colon, but also found in the

jejunum The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialised for the absorption by enterocytes of small nutrient molecules which have been previou ...

and

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

. The L-cells are open-type triangular

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...

directly in contact with the lumen and neuro-vascular tissue and are accordingly stimulated by various

nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excre ...

neural In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

and

endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...

factors. GLP-1 is released in a biphasic pattern with an early phase after 10–15 minutes followed by a longer second phase after 30–60 minutes upon meal ingestion. As the majority of L-cells are located in the distal

and colon, the early phase is likely explained by neural signalling, gut peptides or

neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neurot ...

. Other evidence suggest that the amount of L-cells located in the proximal

is sufficient to account for the early phase secretion through direct contact with luminal nutrients. Less controversially, the second phase is likely caused by direct stimulation of L-cells by digested

nutrients A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excr ...

. The rate of

gastric emptying Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and ...

is therefore an important aspect to consider, as it regulates the entry of nutrients into the small intestines where the direct stimulation occurs. One of the actions of GLP-1 is to inhibit

, thus slowing down its own

upon postprandial activation. Fasting plasma concentration of biologically active GLP-1 range between 0 and 15 pmol/L in humans and is increased 2- to 3-fold upon food consumption depending on meal size and nutrient composition. Individual nutrients, such as

fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...

, essential amino acids and

dietary fibre Dietary fiber (in British English fibre) or roughage is the portion of plant-derived food that cannot be completely broken down by human digestive enzymes. Dietary fibers are diverse in chemical composition, and can be grouped generally by the ...

have also shown to stimulate GLP-1 secretion.

Sugars Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...

have been associated with various

signalling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...

, which initiate

depolarisation In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...

of the L-cell membrane causing an elevated concentration of

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

Ca²⁺ which in turn induce GLP-1 secretion.

Fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...

have been associated with the mobilisation of

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

Ca²⁺ stores and subsequently release of Ca²⁺ into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. The mechanisms of protein-triggered GLP-1 secretion are less clear, but the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

proportion and composition appear important to the stimulatory effect.

Degradation

Once secreted, GLP-1 is extremely susceptible to the catalytic activity of the proteolytic enzyme dipeptidyl peptidase-4 (

DPP-4 Dipeptidyl peptidase-4 (DPP4), 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 enzyme was ...

). Specifically,

cleaves the

peptide bond In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein cha ...

between Ala⁸-Glu⁹ resulting in the abundant GLP-1 (9–36) amide constituting 60–80 % of total GLP-1 in circulation.

is widely expressed in multiple tissues and cell types and exists in both a membrane-anchored and soluble circulating form. Notably,

is expressed on the surface of

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

, including those located directly adjacent to GLP-1 secretion sites. Consequently, less than 25% of secreted GLP-1 is estimated to leave the gut intact. Additionally, presumably due to the high concentration of

found on

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

, 40–50% of the remaining active GLP-1 is degraded across the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

. Thus, due to the activity of

only 10–15 % of secreted GLP-1 reaches circulation intact.

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 ...

24.11 (NEP 24.11) is a membrane-bound zinc metallopeptidase widely expressed in several tissues, but found in particularly high concentrations in the

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

, which is also identified accountable for the rapid degradation of GLP-1. It primarily cleaves peptides at the

side of

aromatic amino acids An aromatic amino acid is an amino acid that includes an aromatic ring. Among the 20 standard amino acids, the following are classically considered aromatic: phenylalanine, tryptophan and tyrosine. Although histidine contains an aromatic ring, ...

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

and is estimated to contribute by up to 50% of the GLP-1 degradation. However, the activity only becomes apparent once the degradation of

has been prevented, as the majority of GLP-1 reaching the

have already been processed by

. Similarly,

appear more significant for the elimination of already inactivated GLP-1. The resulting

of active GLP-1 is approximately 2 minutes, which is however sufficient to activate GLP-1 receptors.

Physiological functions

GLP-1 possesses several physiological properties making it (and its functional analogs) a subject of intensive investigation as a potential treatment of

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, as these actions induce long-term improvements along with the immediate effects. Although reduced GLP-1 secretion has previously been associated with attenuated incretin effect in patients with

, it is now granted that GLP-1 secretion in patients with type 2 diabetes does not differ from healthy subjects. The most noteworthy effect of GLP-1 is its ability to promote insulin secretion in a glucose-dependent manner. As GLP-1 binds to GLP-1 receptors expressed on the pancreatic β cells, the receptors couples to G-protein subunits and activates adenylate cyclase that increases the production of

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

from ATP. Subsequently, activation of secondary pathways, including PKA and Epac2, alters the ion channel activity causing elevated levels of cytosolic Ca²⁺ that enhances exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect. Additionally, GLP-1 ensures the β cell insulin stores are replenished to prevent exhaustion during secretion by promoting insulin gene transcription,

stability and biosynthesis. GLP-1 evidently also increases β cell mass by promoting proliferation and neogenesis while inhibiting

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

. As both type 1 and 2 diabetes are associated with reduction of functional β cells, this effect is highly interesting regarding diabetes treatment. Considered almost as important as the effect of enhancing insulin secretion, GLP-1 has been shown to inhibit glucagon secretion at glucose levels above fasting levels. Critically, this does not affect the glucagon response to

as this effect is also glucose-dependent. The inhibitory effect is presumably mediated indirectly through

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-cou ...

secretion, but a direct effect cannot be completely excluded. In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NEC ...

and

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

effects including reduced necrotic and apoptotic signaling,

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as d ...

, and dysfunctions. In the diseased brain, GLP-1 receptor agonist treatment is associated with protection against a range of experimental disease models such as

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

, stroke,

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic br ...

, and

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...

. In accordance with the expression of GLP-1 receptor on brainstem and hypothalamus, GLP-1 has been shown to promote satiety and thereby reduce food and water intake. Consequently, diabetic subjects treated with GLP-1 receptor agonists often experience weight loss as opposed to the weight gain commonly induced with other treatment agents. In the stomach, GLP-1 inhibits gastric emptying, acid secretion and motility, which collectively decrease appetite. By decelerating gastric emptying GLP-1 reduces postprandial glucose excursion which is another attractive property regarding diabetes treatment. However, these gastrointestinal activities are also the reason why subjects treated with GLP-1-based agents occasionally experience

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

. GLP-1 has also shown signs of carrying out protective and regulatory effects in numerous other tissues, including heart, tongue, adipose, muscles, bones, kidneys, liver and lungs.

References

External links