CBAD 15 Lecture Notes PDF

Lecture 15 Wednesday 18 December 2024 22:02 E 50% 18.12.24 H 75% 19.12.24 Regulation - Glucose Homeostasis: - Glucose is absorbed from the gastrointestinal tract and into the circulation. - Glucose is then transported to different tissues that require glucose for metabolism. - The b...

Lecture 15 Wednesday 18 December 2024 22:02 E 50% 18.12.24 H 75% 19.12.24 Regulation - Glucose Homeostasis: - Glucose is absorbed from the gastrointestinal tract and into the circulation. - Glucose is then transported to different tissues that require glucose for metabolism. - The brain can only use glucose as a metabolic fuel. - Glucose is mostly stored in the muscles and liver. Glucose During and Following Eating: - Once a meal has been consumed, there is an elevated rate of glucose absorbed into the body’s blood circulation. - There is an increased demand for oxygen and metabolic reactions may be activated. - The plentiful glucose is converted to and stored as glycogen. between meals, glucose levels are low. - In order to replenish glucose to their normal levels, glycogen is broken down and glucose is released into the blood. - Circulating (blood) glucose levels are usually 5mM, regardless of hunger intensity. The pancreas is an organ that is part of the endocrine system. - Involved in digestion. - The Islets of Langerhans are collections of different types of pancreatic cells. - The islets are part of the endocrine pancreas, which release hormones directly into the bloodstream. - There are approx. 3 million islets in the pancreas, each with an approx. 0.1mm diameter. - The islets consist of: ❖15-20% α cells, which produce glucagon. ❖65-80% cells, which produce insulin and amylin. ❖3-10% cells, which produce Ɣ somatostatin. - They are vital for the regulation of blood glucose, and treatment of diabetes when the disease is caught early. - Insulin is shown as green in the islet, and glucagon is shown as red. Insulin - Insulin Structure: - Polypeptide hormone. - Synthesised as an 84 amino acid-long hormone inside the beta cells of the Islets of Langerhans. - Proinsulin is the biologically inactive precursor to insulin and is processed in the Golgi Apparatus. - Prohormone convertase 1 and 2 activate pro-insulin. They both take 33 amino acids (aka the C chain) from the main proinsulin, forming a C peptide. - Insulin consists of 2 polypeptide chains. Disulphide bridges link them together. The alpha chain is 21 amino acids long, whilst the beta chain is 30 amino acids long. - These insulin molecules are stored inside of secretory granules alongside pro-insulin and C peptides inside of pancreatic beta cells. - Although C peptides have some biological activity, their role is undecided by researchers. Insulin Transport and Breakdown: - Resting insulin levels are not high enough to cause any changes to cell function. - Glucose infusions are used to maintain high glucose levels, which triggers the secretion of insulin from beta cells/ - First phase: Insulin is released from secretory granules. - Second phase: New insulin is synthesised and released. - Insulin travels in the blood freely, and there is little to no binding with blood plasma proteins. - Insulinase is an enzyme that is mostly found in the liver, but can also be found in muscle cells and the kidney. The function of insulinase is to break down insulin. - The effects of insulin on cell function is quickly reversible because the half life of insulin is approx. 6 minutes in plasma. - C chain is assayed to provide a measure of the rate of insulin secretion in the body. Measuring Insulin Levels: - Experiments involving the continuous infusion of glucose are used to pinpoint what the concentration of insulin in the blood is when blood glucose concentration is greater than 9mM. - This constant synthesis of insulin means that the concentration of insulin in the blood remains high. - The molecular process that explains why insulin secretion is triggered with high glucose concentrations is poorly understood by scientists. Entry of Glucose into Pancreatic Beta Cell - - GLUT2 transporter proteins are expressed in pancreatic beta cells. They are a Type 2 glucose transport system. - These transporters are constantly active, as their activity is hormone-insensitive. - Due to this hormone insensitivity, the glucose concentration within cells is influenced by the concentration of circulation glucose. - Glucose undergoes phosphorylation and is converted to glucose 6-P via glucokinase within pancreatic beta cells. Glycolysis and mitochondrial oxidation metabolise glucose 6-P, resulting in ATP/ADP generation. - The concentration of ATP is regulated by circulating glucose levels. ATP-Sensitive K+ Channels - - Pancreatic beta cells express ATP-sensitive K+ channels, which remain open when the ATP concentration is normal. - These channels close when high concentrations of ATP are present. - The channels control the membrane potential (Vm) of the cells, so when they close and prevent the exit of K+ ions, depolarisation occurs. - ATP levels are highly dependent on the glucose levels outside of the cell. Consequently, external glucose levels determine the Vm of the cell. - Targeted by drugs used to treat diabetes. Voltage-Gated Ca 2+ Channels - - At normal/resting potential, the ion channels are closed. Therefore, the cell membranes are impermeable to calcium ions. - During depolarisation, the ion channels open, increasing the cell membrane’s permeability to calcium ions. - GLUT2, ATP-sensitive K+ channels and voltage-gated Ca2+ channels all play a role in controlling glucose-evoked insulin secretion. Low Glucose Concentration: - Normal glucose concentration/levels means that the concentration of ATP is also within a normal range. - ATP-dependent K+ channels remain open, allowing K+ to leave, causing the membrane potential to become hyperpolarised. - Voltage-gated Ca2+ channels are closed. - Beta cells do not release insulin. High Glucose Concentration: - High glucose levels cause the intracellular ATP levels to rise as well. - ATP-dependent K+ channels close, causing the cell membrane to depolarise. - Voltage-gated Ca2+ channels open, allowing calcium ions to flood into the cell. - Secretory vesicles containing insulin fuse to the cell membrane and release insulin via exocytosis. - When physiological conditions are stable, the consumption of food triggers insulin secretion. - Peaks on the graph represent food ingestion periods. - Insulin levels are usually monitored over a 24-hour period. nsulin Secretion into Blood - - Insulin enters into the hepatic portal vein after being secreted from the pancreas. - Portal circulation transports blood, which contains glucose, from the gut to the liver. - Blood flowing through the pancreas drains into the hepatic portal vein. - The liver is the first organ to be exposed to newly secreted insulin. - The liver is the major site of glucose storage. Insulin Receptors - - Dimer present on the surface of receptor cells. - One receptor is made up of 2 alpha and 2 beta subunits. - Dimerisation and activation are triggered by the binding of insulin to the receptor. - Once dimerisation has occurred and the receptor becomes activated, the two subunits phosphorylate one another. This occurs at the site of many tyrosine residues. Insulin Binding - - The binding of insulin to its complementary receptor stimulates the uptake of glucose by the liver. - The activation of PI3K is nearly wholly responsible for the effects insulin has on a cell. - Nearly every type of cell in the human body is affected by insulin binding to it. - The liver, skeletal muscle and white adipocytes produce the most vital effects needed for survival. - IRS-1 initiates the MAPK cascade, which is responsible for cell growth stimulation and cell survival. - Serine phosphorylation of IRS-1 may impede their action. The liver is one of the main and most important insulin targets, and promotes glucose uptake by the liver. - This uptake is reliant on the Type 4 Glucose Transport System (GLUT-4). - GLUT4 is primarily located (when the cell is not stimulated by insulin) in the membrane of vesicles within cells instead of the plasma membrane. - This leads to the plasma membrane having poor glucose permeability. - PI3K is activated by insulin, which in turn stimulates the activity of protein kinase B (PKB). - PKB promotes the GLUT4 translocation to the plasma cell membrane, which permits glucose entry into liver cells. Glucose uptake and storage is promoted by insulin. - PI3K/PKB moderates (mediates) this process, which mainly takes place in the liver and the skeletal muscle, but occurs in all cells to a certain degree. - If glycogen stores reach their maximum capacity, any additional glucose is converted to fatty acids. - This is done via the inactivation of glycogen synthase. - GLUT4 transporters continue to allow glucose to enter cells. - Fatty acids enter the circulation and are stored as fat. Insulin encourages the use of glucose as a metabolic fuel. - When insulin is not present, cells are poorly permeable to glucose. - Fatty acid oxidation tends to be used to meet metabolic needs. - High levels of insulin leads to high glucose permeability, and the choice of metabolic fuel switches from fatty acids to glucose. - Insulin prevents the usage of free fatty acids as a metabolic fuel, which are instead stored as fat. - However, this does not happen in the brain. The cells of the central nervous system can take up glucose regardless of the influence of insulin. - Fatty acids are not used as metabolic fuel in the brain. Fat Release - - Occurs from adipocytes. - Insulin stimulates fat deposition within adipocytes. Protein Synthesis - - Insulin promotes protein synthesis. - The levels of amino acids in the circulation are elevated. This encourages the secretion of insulin from pancreatic beta cells. - TORC1 (Target of Rapamycin Complex 1) is a kinase which is activated by insulin receptors. TORC1 is dependent on PI3K. - TORC1 is one of the main regulators in protein synthesis across all cells. - When amino acids are plentiful, they enter the process of protein synthesis after being stimulated by insulin Glucagon - - When the glucose concentration in the body is low, alpha cells of the pancreas release glucagon. Glucagon Structure and Function: - 29 amino acids long. - Single polypeptide chain. - Stored in secretory granules in alpha cells, which is similar to how insulin is stored in beta cells. - Hypoglycaemia is the main trigger for glucagon secretion. - Hyperglycemia is the main suppressor for glucagon secretion. - The rate of glucagon and insulin secretion are mirror images of one another when graphically displayed, and their functions counter one another. - Glucagon stimulates glucose release from hepatocytes. - Strong hyperglycaemic effects. - An injection of 1 microgram of glucagon per kg of body mass raises blood glucose by approx. 20% in a 20 minute window. Exercise and Glucagon: - The high demand for glucose during exercise triggers the secretion of glucagon. - There are no glucagon receptors found on the surface of skeletal muscle cells. - Exercise, however, stimulates the translocation of GLUT4 transporters to the skeletal muscle cell surfaces. Indirectly, glucagon is responsible for glucose metabolism within skeletal muscle cells during exercise. - The mechanism which involves low glucose promoting glucagon release from pancreatic alpha cells remains unknown. Glycogenolysis - - Glucagon triggers glycogenolysis using a mechanism involving a G protein-coupled receptor. - The glucagon receptor is a G protein coupled receptor, involving 7 transmembrane domains. - The receptor couples to Gs and activates the cAMP/PKA-dependent signalling pathway. -This pathway can also be activated via adrenaline and adrenoreceptors. Fat Storage and Glucagon - - High levels of glucagon cause the release of fatty acids from adipocytes, which is the antithesis to the effect insulin has on fat storage. Glucagon and insulin levels alter in accordance with the presence of amino acids in the blood plasma. - If high amounts of proteins but low amounts of carbohydrates are consumed, glucose levels remain the same but amino acid levels in the plasma increase. - This change in amino acid levels triggers the secretion of insulin, which stimulates cells to increase the amount of amino acids they are taking in. - Plasma glucose levels also decrease to inappropriate levels. - The increase of amino acid levels in the plasma promotes the release of glucagon from cells, which will cause glucose to be released into the blood. - The rise in plasma glucose levels neutralises the effects of the inappropriate response to insulin. - Glucagon has no effect on the uptake of amino acids. Glucagon and Starvation - - Even during times of starvation, blood glucose concentration must remain stable, as the brain is reliant upon the glucose in the blood to function. - Hypoglycemia triggers glucagon secretion. - Glucagon triggers the synthesis of glucose from amino acids and lipids when glycogen stores become exhausted. - Gluconeogenesis occurs in the kidneys and liver. - Due to the activity of glucagon, protein and lipid breakdown takes place to ensure that the metabolism of the brain remains stable