Diabetes_ type 1 and type 2_ part 1.pdf

07/11/23 Diabetes: type 1 and type 2: part 1 Learning objective: the importance of glucose as an energy source: how do cells use glucose for energy? Learning objective: the main glucose transporters. Learning objective: the roles of insulin and glucagon in glucose level regulation, protein and fat m...

07/11/23 Diabetes: type 1 and type 2: part 1 Learning objective: the importance of glucose as an energy source: how do cells use glucose for energy? Learning objective: the main glucose transporters. Learning objective: the roles of insulin and glucagon in glucose level regulation, protein and fat metabolism and the normal physiology of feeding and fasting. Learning objective: describe the physiological response to hypoglycaemia. Learning objective: describe and de ne type 1 diabetes as a simple de ciency state. Learning objective: type 2 diabetes- relation to obesity, insulin resistance and relative insulin de ciency. Glycolysis: Stage 1: Trap glucose in the cell ( glucose-6-phosphate cannot leave the cell ) Stage 2: Cleavage fructose 1,6-bisphosphate into t wo three-carbon fragments. These resulting fragments are readily interconvertible. Stage 3: Generate ATP from phosphorylated three-carbon metabolites of glucose. Glycolysis produces Pyruvate. Once produced it can produce lactate under anaerobic conditions, or it can be transported into the mitochondria where it is oxidatively decarboxylated by Pyruvate dehydrogenase complex to form acetyl Co-A which is the fuel for krebs. Krebs: Each cycle produces 3NADH, ATP, FADH2. Building up a supply of reduced NADH and FADH2. NADH and FADH2, produced by the cycle, relay electrons extracted from food to the ETC. ETC: In the cristae of the mitochondria, most of the chain’s components are protein, which exist in multi protein complexes. The carriers alternate reduced and oxidised states as they accept and or donate electrons. Electrons drop in free energy as they down the chain and are nally passed to O2 forming water. Each of the reactions is Exergonic and thus releases free energy. This free energy is used to translocate protons across the inner mitochondrial membrane, which will generate ATP. The elections have nally ended up in water are of low energy. During the coupled oxidation reduction reactions iron ions that are complexed with the proteins become oxidised and reduced. That is the Fe ions, participate in catalysis. How does glucose enter our cells ? Glucose uptake from the gut: This is almost completely achieved by Na dependent glucose transporters ( SGLT1/2 ), not the GLUT family transporters that other cells to take up glucose from the bloodstream. 1. As the name suggests, a sodium gradient from the lumen to the cell is needed for glucose uptake. 2. The transporter is saturable, if the glucose in the lumen rises above a certain level not all glucose is absorbed. Anatomy of the pancreas: Elliptical organ which is retroperitoneal 3 parts- head, body and tail. Function of the pancreas: Endocrine: pertaining to hormones and the glands that make them and secrete them into the bloodstream, through which they travel to affect distant organs. Endocrine function of the pancreas: Somatostatin: a hormone many different tissues produce, but it is found primarily in the nervous and digestive systems. In the pancreas, somatostatin inhibits the secretion of pancreatic hormones, including glucagon and insulin. Pancreatic polypeptide: produced and secreted by the PP cells of the pancreas, decreases food intake and increases energy expenditure. What is insulin: Insulin is produced by beta cells. Release is stimulated by high blood glucose levels and the parasympathetic ner vous system. Increases the uptake and storage of glucose, fatty acids and amino acids in cells and tissues. Gastric inhibitory polypeptide ( GOP ) and glucagon-like peptide-1 ( GLP-1 ) are the t wo primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from the pancreatic beta cells. How beta cells work: Two main ion channels are presents. The rst being an ATP sensitive potassium ion channel which is normally open and a voltage gated calcium ion channel which is normally closed. At rest, potassium ions diffuse out of the cell; this creates a potential difference across the cell membrane with the inside being more negative. When we eat, the GLUT2 transporter will mediate the uptake of glucose into the beta cell. Then glycolysis happens, and we get ATP generated. ATP sensitive potassium ion channel closes, and the potential difference across the cell becomes positive. This positive potential difference leads to the opening of the calcium voltage gated ion channels. This stimulates vesicles containing insulin to move to the cell surface membrane and release insulin. When we eat, the stomach releases GLP-1 which stimulates the release of insulin. Role of insulin in glucose regulation: after a meal: the fed state Insulin is an anabolic hormone. In many tissues, for example muscle the major transporter used for uptake of glucose, called GLUT4, is made available in the plasma membrane through the action of insulin. Insulin binds to its tyrosine kinase receptor and initiates the recruitment of GLUT4 to the cell surface. GLUT4 muscle proteins are integrated into the cell membrane allowing glucose to be transported into the cell. Role of insulin after a meal continued: liver 1. accelerates the uptake of blood glucose into liver by GLUT2. 2. The catalytic sites of glucokinase become lled with glucose. 3. The level of glucose-6-phosphate in the liver rises. 4. The increase in glucose-6-phosphate coupled with insulin action leads to a buildup of glycogen stores. 5. The liver helps to limit the amount of glucose in the blood during times of plenty by storing it as glycogen, so as to be able to release glucose in times of scarcity. Effect of feeding: What is glucagon: Glucagon is produced in alpha cells in response to a decrease in blood glucose levels. It mobilisers glucose, fatty acids and amino acids from stores into the blood. The main target organ of glucagon is the liver. Stimulates glycogen breakdown and inhibits glycogen synthesis Inhibits fatty acid synthesis by diminishing the production of pyruvate. Stimulates gluconeogenesis in the liver and blocks glycolysis. Incretins and glucose homeostasis: Effects of fasting: