Peptide hormones are hormones whose molecules are peptides . Peptide hormones have shorter amino acid chain lengths than protein hormones . These hormones have an effect on the endocrine system of animals , including humans . Most hormones can be classified as either amino-acid-based hormones (amine, peptide, or protein) or steroid hormones . The former are water-soluble and act on the surface of target cells via second messengers ; the latter, being lipid-soluble, move through the plasma membranes of target cells (both cytoplasmic and nuclear ) to act within their nuclei .
31-458: 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 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
62-421: 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 sulphonylurea , GLP-1-based treatment has been associated with weight loss and
93-535: A direct effect cannot be completely excluded. In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis and 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
124-480: 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
155-595: A similar fashion to peptide hormones, and some " neuropeptides " may be used as neurotransmitters in the nervous system in addition to acting as hormones when released into the blood. When a peptide hormone binds to a receptor on the surface of the cell, a second messenger appears in the cytoplasm , which triggers signal transduction leading to the cellular responses. Some peptides ( angiotensin II , basic fibroblast growth factor -2, parathyroid hormone-related protein ) also interact with intracellular receptors located in
186-447: 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. The most noteworthy effect of GLP-1
217-516: 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,
248-699: 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 . 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. In the early 1980s, Richard Goodman and P. Kay Lund were postdoctoral researchers working in Joel Habener 's laboratory at Massachusetts General Hospital . Starting in 1979, Goodman harvested DNA from American anglerfish islet cells and spliced
279-507: 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. Neutral endopeptidase 24.11 (NEP 24.11)
310-431: Is extremely susceptible to the catalytic activity of the proteolytic enzyme dipeptidyl peptidase-4 ( DPP-4 ). Specifically, DPP-4 cleaves the peptide bond between Ala - Glu 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
341-428: 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
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#1732783644566372-490: 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 couple to G-protein subunits and activate adenylate cyclase that increases the production of cAMP from ATP . Subsequently, activation of secondary pathways, including PKA and Epac2 , alters the ion channel activity causing elevated levels of cytosolic Ca that enhances exocytosis of insulin-containing granules. During
403-402: 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. In the pancreas ( α-cells of
434-720: 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. 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. Sugars have been associated with various signalling pathways , which initiate depolarisation of
465-638: The cell nucleus . Preprohormones , peptide hormone precursors, are then processed in several stages, typically in the endoplasmic reticulum , including removal of the N-terminal signal sequence and sometimes glycosylation , resulting in prohormones . The prohormones are then packaged into membrane-bound secretory vesicles , which can be secreted from the cell by exocytosis in response to specific stimuli (e.g. an increase in Ca and cAMP concentration in cytoplasm). These prohormones often contain superfluous amino acid residues that were needed to direct folding of
496-502: The cytoplasm or nucleus by an intracrine mechanism. 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 reason, endopeptidases cannot break down peptides into monomers, while exopeptidases can break down proteins into monomers. A particular case of endopeptidase
527-463: 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). 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
558-437: 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. 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
589-515: 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
620-763: The 1980s, Svetlana Mojsov worked on the identification of GLP-1 at Mass General, 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. Mojsov and her collaborators Daniel J. Drucker and Habener showed that small quantities of lab-synthesized GLP-1 could trigger insulin. 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. The discovery of GLP-1's extremely short half-life meant that it
651-576: The DNA into bacteria to find the gene for somatostatin , then Lund joined the Habener lab and used Goodman's bacteria to search for the gene for glucagon. In 1982, they published their discovery that the gene for proglucagon actually codes for three peptides: glucagon and two novel peptides. 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. In
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#1732783644566682-482: The L-cell membrane causing an elevated concentration of cytosolic Ca which in turn induce GLP-1 secretion. Fatty acids have been associated with the mobilisation of intracellular Ca stores and subsequently release of Ca 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. Once secreted, GLP-1
713-500: 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. 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 )
744-454: 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
775-521: 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
806-488: The hormone molecule into its active configuration but have no function once the hormone folds. Specific endopeptidases in the cell cleave the prohormone just before it is released into the bloodstream , generating the mature hormone form of the molecule. Mature peptide hormones then travel through the blood to all of the cells of the body, where they interact with specific receptors on the surfaces of their target cells. Some neurotransmitters are secreted and released in
837-485: 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, 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
868-422: 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
899-500: 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. 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
930-504: Was impossible to develop into a drug. 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. American diabetes association:link- http://diabetes.diabetesjournals.org/content/56/1/8.full Peptide hormone Like all peptides, peptide hormones are synthesized in cells from amino acids according to mRNA transcripts, which are synthesized from DNA templates inside
961-471: 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)