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These are some of the weight loss medicines that have made headlines. These are brand names and they are not all the same. The active ingredients that cause weight loss differ in the different preparations. The active drug in Saxenda is called liraglutide, while the drug in both Ozempic and Wegovy is semaglutide. The drug in Mounjaro and Zepbound is tirzepatide. The drugs all have a similar mechanism of action in that they act as mimetics of the natural hormone, GLP-1, which stands for glucagon-like peptide-1. Tirzepatide is a bit different, in that while it mimics GLP-1, its main action is to mimic another hormone, GIP, standing for gastric inhibitory peptide. The first drugs of this type were originally developed as a treatment for diabetes, but when patients treated with the drugs developed significant weight loss, it was recognised that the drugs could be effective in the treatment of obesity and metabolic syndrome. So, what are the hormones glucagon-like peptide-1and gastric inhibitory peptide?
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GLP-1 is made in cells from a 160 amino acid long precursor peptide called proglucagon It is expressed in α islet cells of the pancreas, endocrine L-cells in the small and large intestines and some neurones of the solitary tract in the brain. The proglucagon structure contains the sequences for several smaller peptides, including glucagon and GLP-1, which can be cleaved out of the precursor by cutting at different sites. This is the job of prohormone convertase enzymes, which cleave the peptide at specific sites. The prohormone convertase enzyme expressed in pancreatic cells differs from that the intestines and brain, and they splice proglucagon in different places. This results in the cells secreting a different complement of short peptides. The pancreatic α cells make the hormone, glucagon, along with peptides comprising amino acids 1 to 30 and 64-158 of the prohormone. The L-cells in the intestine and some brain neurones make GLP-1 and GLP-2, along with a peptide comprising amino acids 1-69 of the prohormone. The actions of GLP-2 are mainly on the gastrointestinal tract. GIP or gastric inhibitory peptide is also known as glucose-dependent insulinotropic polypeptide. It is made in much the same way as glucagon-like peptide, but it is synthesised in K cells of the duodenum and jejunum. GIP is made from a 153 amino acid preprohormone precursor that is distinct from proglucagon. It is called proGIP and contains the amino acid sequence of GIP between residues 51 and 93. A prohormone convertase cleaves either side of the GIP sequence to release the mature GIP peptide from its precursor.. GLP-1 and GIP are known as incretin hormones, meaning that they are secreted in response to food ingestion and act to lower blood glucose. They have complementary effects, mainly on the pancreas, brain, stomach and adipose, or fat tissue. GLP-1 stimulates postprandial insulin secretion by the pancreas, while inhibiting glucagon secretion. It also increases satiety through both an effect on the brain and on the gastrointestinal tract, where it slows gastric emptying. Together, these effects help to improve glucose control in type 2 diabetes and promote weight loss. GIP also stimulates postprandial insulin, but it has the opposite effect to GLP-1 on glucagon secretion, causing it to increase. In adipose tissue, GIP stimulates the storage of fat which improves insulin sensitivity. GIP also reduces gastric acid secretion, which slows digestion, improves glucose control and enhances satiety. Both hormones also increase beta cell survival by stimulating cell proliferation and inhibiting cell death. As the main effects are on the pancreas, before explaining how these the hormones control insulin and glucagon secretion, I will give a brief overview of how the pancreas works.
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The pancreas is a lobular gland situated just behind the stomach. The lobules contain the structures that synthesise the substances that are key to the function of the pancreas. Around the outer circumference of each lobule are the acini, which synthesise digestive enzymes. The acinar cells making up each acini secrete the enzymes into a central duct. It connects to the main pancreatic duct, which delivers the enzymes to the inside of the small intestine, where they work to break down carbohydrates, proteins and fats in food. This is an example of an exocrine gland, which secretes directly into a ductal system. The central core of the lobule is known as the endocrine pancreas. It is comprised of clusters of secretory cells, known as an islet of Langerhans. There are several cell types, each specialised for secreting a particular hormone. The majority secrete insulin and are known as beta cells. They account for 40 -50% of islet cells in humans. Glucagon secreting cells are called alpha cells and make up about 20% of the islet cell population. The other hormones secreted are somatostatin from delta cells, pancreatic polypeptide from gamma cells and ghrelin from epsilon cells. They respectively make up less than 10%, 5% and 1% of the total cell population. The cells in the islet secrete their hormones out of the cell and into the interstitial space. There is an extensive capillary network supplying the islets with blood, so the secreted hormones are taken up into the circulation which transports them to their site of action.
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The hormones insulin and glucagon play key and complementary roles in the regulation of blood glucose. They form negative feedback loops to maintain the blood glucose concentration in its optimal range of 4 to 5.9 mM. When blood glucose levels rise following a meal, the increase is detected in the beta islet cells of the pancreas as blood flows through the organ. The beta cells respond by releasing insulin into the circulation. Insulin acts on several sites in the body to remove glucose from the blood. It stimulates adipocytes in adipose tissue to take up and store excess glucose as fat. In the liver and skeletal muscle, insulin stimulates cells to take up and store excess glucose as glycogen. These effects lower the blood glucose and restore it back to the normal level. When blood glucose is too low, alpha cells in the pancreas release the hormone glucagon. It acts on the liver to stimulate the breakdown of glycogen into glucose, which enters the circulation and restores the glucose level to normal. So how do GLP-1 and GIP exert their effects on insulin and glucagon secretion?
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GLP-1and GIP both act as receptor agonists. That means that they bind to specific receptors sites on the cell membrane and activate the receptor to bring about a cellular response. The receptors for each hormone are different proteins, but both are G-protein coupled receptors. These are membrane-spanning proteins that interact on the cytoplasmic side with a GTP-binding protein, made up of 3 subunits alpha, beta and gamma. When the receptor is inactive, the GTP-binding protein is bound to GDP. When an agonist binds to its receptor site on the extracellular side, it induces a conformational change in the receptor protein. That causes GTP to replace GDP on the G-protein. And when that happens, the alpha subunit dissociates from beta and gamma and is now free to interact with other proteins. There are several different alpha subunits, but both the GLP-1 and GIP receptors couple to the S isoform, which stimulates the enzyme adenylyl cyclase. That increases the conversion of ATP to cyclic AMP, which in turn stimulates the activity of protein kinase A. In pancreatic beta cells, protein kinase A phosphorylates the transcription factor CREB, which promotes the production of insulin. It also phosphorylates phosphatidylinositol 3-kinase, leading to activation of the kinase Akt, which increases the sensitivity of the beta cell to glucose and supports the survival of beta cells. In this way, GLP-1 and GIP act on different receptors, but bring about essentially the same effects on beta cells, resulting in enhanced secretion of insulin. In pancreatic alpha cells, GLP-1 and GIP act at the same G-protein coupled receptors, but the downstream signalling pathways are a bit different. As in beta cells, cAMP generated in these cells activates protein kinase A. However, it also activates Epac, short for exchange protein directly activated by cAMP. Both protein kinase A and Epac enhance glucagon release.
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Observant viewers will have noticed a discrepancy . I have just told you that GLP-1 receptors on alpha cells stimulate glucagon release. But earlier I told you that GLP-1 inhibits glucagon release. How can we reconcile these two facts? The reasons are not yet fully understood, but two factors can explain it. Firstly, GLP-1 receptors are expressed at a very low level on alpha cells, so any stimulatory effect would be small. Secondly, GLP-1 has an indirect paracrine effect in the pancreas that results in inhibition of glucagon release. It involves GLP-1 receptors on pancreatic delta cells, which stimulate the secretion of somatostatin. Somatostatin then acts on alpha cells to inhibit glucagon secretion. So, the overall effect of GLP-1 is to inhibit glucagon release. This is the string of amino acids that make up the peptide structure of GLP-1. The first few amino terminal resides are critical for GLP-1 to bind to and activate its receptor. So, the peptide is inactivated by the enzyme, dipeptidyl peptidase-4, which cleaves it between the first alanine and glutamate. This limits the plasma half life of GLP-1 to only a few minutes. This property renders the native hormone useless as a therapeutic drug, because it would have to be administered multiple times a day. GLP-1 mimetics were developed by modifying the peptide in ways that would prolong the plasma half life and allow the blood concentration to remain high enough for long enough to minimise the dosing frequency. Liraglutide was created from GLP-1 by replacing the lysine residue at position 34 with arginine and attaching a 16-carbon chain fatty acid to the lysine at position 26 via a glutamate linker. The arginine residue made it easier to attach the fatty acid. The idea behind the fatty acid extension was that it would increase binding of the drug to plasma albumin, thus shielding it from dipeptidyl peptidase, slowing its degradation and prolonging its circulation time. The plasma half time of liraglutide is 13 hours, meaning that it can be injected once a day. The development of semaglutide built on the structure of liraglutide. The fatty acid was extended to an 18-carbon chain, to improve plasma albumin binding. In addition, the first alanine was replaced with alpha-aminobutyric acid, which makes it highly resistant to cleavage by dipeptidyl peptidase-4, while retaining hormone activity. Semaglutide has a plasma half life of around a week, so it can be delivered by weekly injections.
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This is the amino acid sequence of the hormone GIP, which was the starting point for the development of agonists that mimic the actions of both GIP and GLP-1. This type of drug has been called a dual agonist or co-agonist. Like GLP-1, GIP is cleaved at the amino end by dipeptidy peptidase-4 and degraded, so it has a short half life in plasma of only a few minutes. To be useful as a drug, it had to be modified to limit this degradation and prolong its life in plasma. This was achieved in tirzepatide, the first co-agonist at GIP and GLP-1 receptors. You can see that, similarly to the GLP-1 agonists, the alanine at position 2 of GIP, as well as an alanine at position 13, has been swapped for the peptidase-resistant alpha-amino butyric acid. This protects the peptide from enzymatic breakdown. The addition of a 20-carbon chain fatty acid, linked by glutamate to the lysine at position 20, enhances binding to albumin and prolongs its plasma half-life to around 5 days. Stable therapeutic plasma levels of tirzepatide can therefore be achieved with once weekly injection. The amino acids in tirzepatide are not entirely homologous with those in GIP. As indicated by the pink shading, there are only 18 amino acids in common and complete divergence at the carboxyl ends of the peptides. That is because some amino acids were modified to enable tirzepatide to interact with GLP-1 receptors. So, comparing the tirzepatide sequence with GLP-1 You can see substantial homology between the two peptides, as highlighted by the green shading. This makes tirzepatide a groundbreaking therapeutic, combining the effects of two incretin hormones into one molecule. In clinical trials, its dual action has demonstrated superior control of blood glucose and weight loss compared to GLP-1 agonists.
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Most people would prefer to take a weight loss drug in an oral formulation. Unfortunately, GLP-1 and GIP agonists are peptides and peptides face several major challenges when taken orally. They may be broken down by digestive enzymes in the gastrointestinal tract before they can be absorbed. Their structures can be denatured in the low pH of the stomach. Since the 3-dimensional structure is key to their interaction with receptors, that could render them ineffective. Acid pH can also affect the stability of peptides. Drugs must be absorbed across the mucosal wall of the intestines and into the blood stream before they can be effective. The large size and hydrophilicity of peptides makes this very difficult. All of these problems can be bypassed when a drug is given by subcutaneous injection. The peptide can cross directly into local capillaries from the site of the injection, thereby reaching the bloodstream, which circulates it to its sites of action.
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