View source for Glucagon-like peptide-1/ja

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[[Image:Incretins and DPP 4 inhibitors.svg|thumb|350px|right|GLP-1と糖尿病]]

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'''Glucagon-like peptide-1''' ('''GLP-1''') is a 30- or 31-amino-acid-long [[peptide hormone]] deriving from the tissue-specific posttranslational processing of the [[proglucagon]] peptide. It is produced and secreted by intestinal [[Enteroendocrine cell|enteroendocrine L-cells]] and certain neurons within the [[Solitary nucleus|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.
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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 agonist]]s gained approval as drugs to treat diabetes and obesity starting in the 2000s.
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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 agonist]]s and [[DPP-4 inhibitors]] have been developed to increase GLP-1 activity. As opposed to common treatment agents such as [[insulin]] and [[sulphonylurea]], 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.
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==Gene expression==
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The proglucagon gene is expressed in several organs including the [[pancreas]] ([[α-cell]]s 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.
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In the [[pancreas]] ([[α-cell]]s 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).
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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 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]] 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.
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==Secretion==
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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 (anatomy)|lumen]] and neuro-vascular tissue and are accordingly stimulated by various [[nutrient]], [[neural]] and [[endocrine]] factors.
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GLP-1 is released in a [[phase (pharmacology)|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 suggest that the amount of L-cells located in the proximal [[jejunum]] 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]]. The rate of [[gastric emptying]] 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 [[gastric emptying]], thus slowing down its own [[secretion]] upon [[postprandial]] activation.
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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]], [[essential amino acids]] and [[dietary fibre]] have also shown to stimulate GLP-1 secretion.
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[[Sugars]] have been associated with various [[signalling pathways]], which initiate [[depolarisation]] of the L-cell membrane causing an elevated concentration of [[cytosolic]] Ca<sup>2+</sup> which in turn induce GLP-1 secretion. [[Fatty acids]] have been associated with the mobilisation of [[intracellular]] Ca<sup>2+</sup> stores and subsequently release of Ca<sup>2+</sup> 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.
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==Degradation==
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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 [[alanine|Ala]]<sup>8</sup>-[[glutamic acid|Glu]]<sup>9</sup> 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. 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.
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[[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 amino acids]] or [[hydrophobic]] [[amino acids]] and is estimated to contribute by up to 50% of the 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]] have already been processed by [[DPP-4]]. Similarly, [[renal clearance]] appear more significant for the elimination of already inactivated GLP-1.
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The resulting [[half-life]] of active GLP-1 is approximately 2 minutes, which is however sufficient to activate [[GLP-1 receptor]]s.
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==Physiological functions==
GLP-1 possesses several physiological properties making it (and its [[Functional analog (chemistry)|functional analog]]s) a subject of intensive investigation as a potential treatment of [[diabetes mellitus]], 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 [[type 2 diabetes]], it is now granted that GLP-1 secretion in patients with type 2 diabetes does not differ from healthy subjects.
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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 receptor]]s expressed on the [[Beta cell|pancreatic β cells]], the receptors couples to [[Heterotrimeric G protein|G-protein]] subunits and activates [[adenylate cyclase]] that increases the production of [[Cyclic adenosine monophosphate|cAMP]] from [[Adenosine triphosphate|ATP]]. Subsequently, activation of secondary pathways, including PKA and [[RAPGEF4|Epac2]], alters the ion channel activity causing elevated levels of cytosolic Ca<sup>2+</sup> that enhances exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect.<
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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. GLP-1 evidently also increases 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 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 [[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.
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In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including [[neurogenesis]] and [[Neuroprotection|neuroprotective]] effects including reduced necrotic and apoptotic signaling, [[cell death]], 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]], [[Alzheimer's disease]], stroke, [[traumatic brain injury]], and [[multiple sclerosis]]. 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.
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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]].
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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.
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== Research history ==
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. 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. Mosjov and her collaborators [[Daniel J. Drucker]] and Habener showed that small quantities of lab-synthesized GLP-1 could trigger insulin.
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Mojsov fought to have her name included in patents, with the Massachusetts General Hospital eventually agreeing to amend four patents to include her name. She received her one-third of drug royalties for one year.
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== See also ==
* [[Glucagon-like peptide 1 receptor]]
* [[Glucagon-like peptide-2]]
* [[Type 2 diabetes]]
* [[GLP-1 receptor agonist]]s : [[albiglutide]], [[dulaglutide]], [[exenatide]], [[liraglutide]], [[lixisenatide]], [[semaglutide]], [[tirzepatide]]
* [[Dipeptidyl peptidase-4]]
* [[Glucose-dependent insulinotropic peptide]]
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== References ==
{{reflist|32em}}
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== External links ==
* {{UTGlucagon|glp1}}
* {{MeshName|Glucagon-Like+Peptide+1}}
* [http://www.genome.jp/kegg-bin/show_pathway?ko04911+K04581 Insulin release pathways]
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{{Proglucagon}}
{{Oral hypoglycemics and insulin analogs}}
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American diabetes association:link-http://diabetes.diabetesjournals.org/content/56/1/8.full
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{{二次利用|date=20 January 2024}}
{{DEFAULTSORT:Glucagon-Like Peptide-1}}
[[Category:Anti-diabetic drugs]]
[[Category:Peptide hormones]]
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