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

Alongside glucose-dependent insulinotropic peptide (GIP), GLP-1 is an incretin; thus, it has the ability to decrease blood sugar levels in a glucose-dependent manner by enhancing the secretion of insulin. 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. Glucagon-like peptide-1 receptor agonists gained approval as drugs to treat diabetes and obesity starting in the 2000s.

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, resulting in a half-life 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 insulin and sulphonylureas, GLP-1-based treatment has been associated with weight loss and a lower risk of hypoglycemia, two important considerations for patients with type 2 diabetes.

The proglucagon gene is expressed in several organs including the pancreas (α-cells of the islets of Langerhans), gut (intestinal enteroendocrine L-cells) and brain (caudal brainstem and 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 all three cell types, which is further translated to the 180 amino acid precursor called proglucagon. However, as a result of tissue-specific posttranslational processing mechanisms, different peptides are produced in the different cells.^[1][2]

In the pancreas (α-cells of the islets of Langerhans), proglucagon is cleaved by prohormone convertase (PC) 2 producing glicentin-related pancreatic peptide (GRPP), glucagon, intervening peptide-1 (IP-1) and major proglucagon fragment (MPGF).^[3]

In the gut and brain, proglucagon 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 of the MPGF, 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 to the biologically active GLP-1 (7–37). Secondly, the glycine corresponding to proglucagon (108) was found to serve as a substrate for amidation of the C-terminal arginine 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.^[3][4]

GLP-1 is packaged in secretory granules and secreted into the hepatic portal system by the intestinal L-cells located primarily in the distal ileum and colon, but also found in the jejunum and duodenum. The L-cells are open-type triangular epithelial cells directly in contact with the lumen and neuro-vascular tissue and are accordingly stimulated by various nutrient, neural and endocrine factors.^[2]

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 ileum and colon, the early phase is likely explained by neural signalling, gut peptides or neurotransmitters. Other evidence suggests the L-cells located in the proximal jejunum are 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. The rate of gastric emptying is therefore an important aspect to consider, as it regulates the entry of nutrients into the small intestine where the direct stimulation occurs. One of the actions of GLP-1 is to inhibit gastric emptying, thus slowing down its own secretion (negative feedback) upon postprandial activation.^[1][2]

Fasting plasma concentrations of biologically active GLP-1 range between 0 and 15 pmol/L in humans and are increased 2- to 3-fold upon food consumption depending on meal size and nutrient composition. Individual nutrients, such as fatty acids, essential amino acids and dietary fibre have also been shown to stimulate GLP-1 secretion.

Sugars have been associated with various signalling pathways, which initiate depolarisation of the L-cell membrane causing an elevated concentration of cytosolic Ca²⁺, which in turn induces GLP-1 secretion. Fatty acids have been associated with the mobilisation of intracellular Ca²⁺ stores and subsequently release of Ca²⁺ into the cytosol. The mechanisms of protein-triggered GLP-1 secretion are less clear, but the amino acid proportion and composition appear important to the stimulatory effect.^[5]

Once secreted, GLP-1 is extremely susceptible to the catalytic activity of the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4). Specifically, DPP-4 cleaves the peptide bond between Ala⁸-Glu⁹ resulting in the abundant GLP-1 (9–36) amide constituting 60–80% of total GLP-1 in circulation. DPP-4 is widely expressed in multiple tissues and cell types and exists in both a membrane-anchored and soluble circulating form. Notably, DPP-4 is expressed on the surface of endothelial cells, including those located directly adjacent to GLP-1 secretion sites.^[2] Consequently, less than 25% of secreted GLP-1 is estimated to leave the gut intact. Additionally, presumably due to the high concentration of DPP-4 found on hepatocytes, 40–50% of the remaining active GLP-1 is degraded across the liver. Thus, due to the activity of DPP-4 only 10–15% of secreted GLP-1 reaches circulation intact.^[3]

Neutral endopeptidase 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, which is also identified accountable for the rapid degradation of GLP-1. It primarily cleaves peptides at the N-terminal side of aromatic or hydrophobic amino acids and is estimated to contribute by up to 50% to GLP-1 degradation. However, the activity only becomes apparent once the degradation of DPP-4 has been prevented, as the majority of GLP-1 reaching the kidneys has already been processed by DPP-4. Similarly, renal clearance appear more significant for the elimination of already inactivated GLP-1.^[6]

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

GLP-1 possesses several physiological properties making it (and its functional analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus, as these actions induce long-term improvements along with the immediate effects.^{[need quotation to verify][7][8][9][10]} Although reduced GLP-1 secretion has previously been associated with attenuated incretin effect in patients with type 2 diabetes, further research indicates that GLP-1 secretion in patients with type 2 diabetes does not differ from healthy subjects.^[11]

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 pancreatic β cells, the receptors couple to G-protein subunits and activate adenylate cyclase, which increases the production of cAMP from ATP.^[3] Subsequently, activation of secondary pathways, including protein kinase A (PKA) and Epac2, alters cell ion channel activity, causing elevated levels of cytosolic Ca²⁺ that enhance exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect.^[3]

Additionally, GLP-1 ensures the β cell insulin stores are replenished to prevent exhaustion during secretion by promoting insulin gene transcription, mRNA stability and biosynthesis.^[2][12] GLP-1 also increases^[13] β cell mass by promoting proliferation and neogenesis while inhibiting apoptosis. As both type 1 and 2 diabetes are associated with reduction of functional β cells, this effect is desirable in diabetes treatment.^[12] An additional important effect of GLP-1, is inhibition of glucagon secretion at glucose levels above fasting levels. Critically, this does not affect the glucagon response to hypoglycemia as this effect is also glucose-dependent. The inhibitory effect is presumably mediated indirectly through somatostatin secretion, but a direct effect cannot be completely excluded.^[14][15]

In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis^[16][17] and neuroprotective effects including reduced necrotic^[18] and apoptotic^[19][18] signaling, cell death,^[20][21] and dysfunctions.^[22] 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,^[23][17] Alzheimer's disease,^[24][25] stroke,^[23] traumatic brain injury,^[13][18] and multiple sclerosis.^[26] 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.^[2][15]

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.^[14]

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.^{[citation needed]}

In the early 1980s, Richard Goodman and P. Kay Lund were postdoctoral researchers working in Joel Habener's laboratory at Massachusetts General Hospital.^[27] Starting in 1979, Goodman harvested DNA from American anglerfish islet cells and spliced the DNA into bacteria to find the gene for somatostatin; Lund then joined the Habener laboratory and used Goodman's bacteria to identify the gene for glucagon.^[27] In 1982, they published their discovery that the gene for proglucagon actually codes for three peptides, namely glucagon and two novel peptides.^[27] Those two novel peptides were later isolated, identified, and investigated by other researchers, and are now known as glucagon-like peptide-1 and glucagon-like peptide-2.^[27]

In the 1980s, Svetlana Mojsov worked on the identification of GLP-1 at Massachusetts General Hospital, where she was head of a peptide synthesis facility.^[28] To try to identify whether a specific fragment of GLP-q was an incretin, Mojsov created an incretin-antibody and developed ways to track its presence. She identified that a stretch of 31 amino acids in the GLP-1 was an incretin.^[29][30] Mojsov and her collaborators Daniel J. Drucker and Habener showed that small quantities of laboratory-synthesized GLP-1 could trigger insulin.^[31][32][33]

Mojsov fought to have her name included in patents, with Mass General eventually agreeing to amend four patents to include her name. She received her one-third of drug royalties for one year.^[28]

The discovery of GLP-1's extremely short half-life meant that it was impossible to develop into a drug.^[34][35] This caused diabetes research to shift towards other therapeutic options such as targeting the GLP-1 receptor, which then led to the development of GLP-1 receptor agonists.^[34][35]

• Glucagon
• Glucagon-like peptide-1 receptor
• Glucagon-like peptide-2
• Type 2 diabetes
• GLP-1 receptor agonists — albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, tirzepatide and semaglutide, the latter of which is marketed under the brands Ozempic, Rybelsus and Wegovy.
• Dipeptidyl peptidase-4
• Gastric inhibitory polypeptide

• Banting and Best Diabetes Centre at UT glp1
• Glucagon-Like+Peptide+1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Insulin release pathways

This article needs more reliable medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Juvéderm" – news · newspapers · books · scholar · JSTOR (May 2015)

Juvéderm (/ˈdÊ’uːvɪdɜːrm/), an injectable filler (injectable facial filler), is used by cosmetic, dermatological, and plastic surgeons to soften deep folds and reduce wrinkles in the faces of patients. The substance is largely hyaluronic acid, a substance normally found in the skin, muscles, and tendons of mammals. Approved in June 2006 by the U.S. Food and Drug Administration, Juvéderm’s prime use is removing nasolabial folds, or “smile lines,” creases of skin which run from the corners of the nose to the corners of the mouth. It is also used as a lip augmentation agent, and to fill in hollow places and scars on the face. However, all hyaluronic acid facial filler products are eventually absorbed by the body, usually within six to nine months, requiring the patient to undergo repeat injections to maintain the younger look. Juvéderm is also used by physicians to plump lips, which also lose fat and internal shape with normal aging.

Before being released onto the U.S. market, Juvéderm was compared with Zyplast dermal filler, a bovine-based injectable facial filler made from collagen. In clinical studies conducted at several U.S. medical centers to evaluate safety and efficacy, or effectiveness, 146 subjects were followed for 24 weeks. The subjects had Juvéderm injected into one nasolabial fold and Zyplast in the other. Using scientific measuring scales, Juvéderm was deemed to provide a more persistent correction in the subjects’ facial folds. At the end of the study, the researchers asked subjects to judge which fold looked better to them. Eighty-eight percent chose the area treated with Juvéderm.^[1] Before FDA approval, two other clinical studies on Juvéderm were done on a total of 293 subjects in the United States. The safety profile and effectiveness was found to be similar to the first test.

In 1934, medical researchers Karl Meyer and John Palmer, scientists at Columbia University in New York, found that one of the chief functions of hyaluronic acid is maintaining skin volume and hydration, along with other body maintenance functions and tasks.

Meyer and Palmer first isolated the substance from the eye of a cow and named hyaluronic acid by combining the Greek word for glass—hyalos—and the uronic sugar contained in hyaluronic acid.

Hyaluronic acid later found uses in the baking and food industry in the 1940s and, by the 1990s, found its way into the medical field for use in joint pain, treating wounds, eye surgery and, finally, in 1996, for facial tissue augmentation in Europe.

Juvéderm’s current competitive edge in cosmetic surgery is possible because, according to the manufacturers, Juvéderm is “cross linked.” In hyaluronic acid’s natural form, the substance is a liquid which the body metabolizes in about half a day. Cross linking is a process which chemically binds the individual chains of the acid so it is changed into a gel which lasts much longer once injected inside the face.

Several other facial fillers used in Europe and the U.S. — such as Restylane, Belotero and Hylaform —are also cross-linked, with competition driving the other fillers toward even more highly cross linked compounds, according to Professor Berthold Rzany, professor of dermatology at the Charité Universitätsmedizin Berlin Germany.

Juvéderm works well for cosmetic and plastic surgery applications because hyaluronic acid can absorb up to 1,000 times its own weight in water, thereby adding new volume under the surface of sagging skin. Older faces take on more youthful aspects because hyaluronic acid is known to bind with collagen—the material that supports human facial skin—and elastin to move more basic nutrients into the skin. Juvederm hydrates the skin and increases the capacity of skin to hold water therefore skin holds more moisture and looks fresher than before.

Patients, physicians and researchers say usual, expected side effects include; temporary redness, pain and tenderness during injections and swelling and bruising at the injection sites. The more serious side effects include: immune system reactions which result in facial lumps and bumps known as granulomas, bothersome reactions which are very difficult for physicians to treat.^[2] According to Allergan, Juvéderm should not be used in patients with severe allergies, particularly those who have allergies to bacterial proteins or patients with a history of anaphylaxis, which is a potentially life-threatening hypersensitivity to some drugs and proteins.

• FDA Summary of Juvéderm’s effectiveness and safety
• FDA: Physician’s instructions (intended use, contraindications, warnings and dosage) for using Juvéderm
• Raspaldo, Hervé; Gassia, Véronique; Niforos, François-Rene; Michaud, Thierry (2012). "Global, 3-dimensional approach to natural rejuvenation: Part 1 - recommendations for volume restoration and the periocular area". Journal of Cosmetic Dermatology. 11 (4): 279–289. doi:10.1111/jocd.12003. PMID 23174051.