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]]

'''グルカゴン様ペプチド-1'''（'''GLP-1'''）は、[[proglucagon/ja|プログルカゴン]]ペプチドの組織特異的翻訳後プロセシングに由来する30または31アミノ酸長の[[peptide hormone/ja|ペプチドホルモン]]である。GLP-1は、[[Enteroendocrine cell/ja|腸内分泌L細胞]]および食物摂取時に脳幹の[[Solitary nucleus/ja|孤束路核]]内の特定のニューロンによって産生および分泌される。初期生成物であるGLP-1 (1-37)は、[[amidation/ja|アミド化]]および[[proteolytic cleavage/ja|タンパク質分解切断]]を受けやすく、その結果、2つの切断された等価な生物学的活性型であるGLP-1 (7-36)アミドおよびGLP-1 (7-37)が生じる。活性型GLP-1の[[protein secondary structure/ja|タンパク質二次構造]]は、アミノ酸13-20位と24-35位の2つの[[α-helices/ja|α-ヘリックス]]をリンカー領域で隔てている。

[[glucose-dependent insulinotropic peptide/ja|グルコース依存性インスリン分泌促進ペプチド]]（GIP）と並んで、GLP-1は[[incretin/ja|インクレチン]]であり、[[insulin/ja|インスリン]]の[[secretion/ja|分泌]]を促進することにより、グルコース依存的に[[blood sugar levels/ja|血糖値]]を低下させる作用を持つ。インスリン分泌促進作用以外にも、GLP-1は多くの調節作用や保護作用と関連している。GIPとは異なり、GLP-1の作用は[[2型糖尿病]]の患者でも維持されている。[[Glucagon-like peptide-1 receptor agonist/ja|グルカゴン様ペプチド-1受容体作動薬]]は、2000年代から糖尿病と肥満の治療薬として認可されるようになった。

内因性GLP-1は主に[[dipeptidyl peptidase-4/ja|ジペプチジルペプチダーゼ-4]]（DPP-4）と中性エンドペプチダーゼ24.11（NEP24.11）および[[renal clearance/ja|腎クリアランス]]によって速やかに分解され、その結果、[[half-life/ja|半減期]]は約2分となる。その結果、GLP-1の10～15％しかそのまま循環に到達しないため、空腹時の血漿中濃度は0～15pmol/Lにしかならない。これを克服するために、GLP-1活性を高める[[GLP-1 receptor agonist/ja|GLP-1受容体作動薬]]や[[DPP-4 inhibitors/ja|DPP-4阻害薬]]が開発されてきた。[[insulin/ja|インスリン]]や[[sulphonylurea/ja|スルホニルウレア]]などの一般的な治療薬とは対照的に、GLP-1ベースの治療は[[weight loss/ja|体重減少]]と[[hypoglycemia/ja|低血糖]]のリスクの低下と関連しており、2型糖尿病患者にとって重要な2つの考慮事項である。

==遺伝子発現==
{{Anchor|Gene expression}}

プログルカゴン遺伝子は、[[pancreas/ja|膵臓]]（[[islets of Langerhans/ja|ランゲルハンス島]]の[[α-cell/ja|α細胞]]）、腸（腸内分泌L細胞）および[[brain/ja|脳]]（尾側[[brainstem/ja|脳幹]]および[[hypothalamus/ja|視床下部]]）を含むいくつかの臓器で発現している。膵プログルカゴン遺伝子の発現は、空腹時および低血糖誘導時に促進され、インスリンによって抑制される。逆に、腸のプログルカゴン遺伝子発現は空腹時には減少し、食物摂取により刺激される。哺乳類では、転写は3つの細胞型すべてで同一の[[mRNA/ja|mRNA]]を生じ、さらに[[proglucagon/ja|プログルカゴン]]と呼ばれる180アミノ酸の前駆体に翻訳される。しかし、組織特異的な翻訳後プロセシング機構の結果、異なる細胞では異なるペプチドが産生される。

[[pancreas/ja|膵臓]]（[[islets of Langerhans/ja|ランゲルハンス島]]の[[α-cell/ja|α細胞]]）では、[[proglucagon/ja|プログルカゴン]]は[[prohormone convertase/ja|プロホルモン変換酵素]]（PC）2によって切断され、グリセンチン関連膵ペプチド（GRPP）、[[glucagon/ja|グルカゴン]]、介在ペプチド-1（IP-1）、主要プログルカゴンフラグメント（MPGF）を産生する。

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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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