[MUSIC] Welcome back to my Coursera class, Biochemical Principles of Energy Metabolism. We are in the very middle of Week 6. Week 6 is about two major hormones of pancreatic tissues, and we are going to talk about diabetes in more details in the later. So this Week 3 is about how insulin hormones can act upon peripheral tissues. So in the previous session, we talked about glucose stimulated insulin secretion in pancreatic beta cells. In response to high blood glucose levels, pancreatic beta cells can readily release stored insulin throughout the calcium activated vesicle exocytosis. And then further, more insulin can be synthesized, right? And today's session is about how those insulin can affect target tissues to remove, to stimulate the glucose uptake. So obviously, insulin, the major function for insulin is to stimulate skeletal muscle and other peripheral tissues to drive the glucose uptake. And moreover, our insulin can further trigger the glycogen synthesis and stimulate fat biosynthesis, those anabolic reactions, right? And you're looking at the pancreatic better cells secrete insulin hormones. So, Okay, so secreted insulin from pancreatic beta cells, they arrive at the specific target cells. So let's say this is skeletal muscle. Skeletal muscle cells. Right? And there are a lot of glucose. because right now, maybe this is situation of after meal, right? You are very full now. So Insulin binds to specific insulin receptor. And throughout a defined signaling cascade, activate the transport molecules, glut, so glucose transporter membrane proteins. This is facilitated diffusion. This glucose transporter membrane proteins, under the resting condition, this protein is just staying inside the cells in the form of vesicle. So insulin action trigger diffusion of this vesicle to the membrane, and this glucose transporter can finally localize in the plasma membrane. And they are doing their own jobs, right? To facilitate glucose uptake from the outside to the inside. So glucose transporter, once they are correctly localized to the plasma membrane of target cells can stimulate glucose uptake. So glucose level and insulin level, they're very, very tightly correlated. So as you can see this diagram, the y-axis, the red line is blood glucose level, and on blue line is serum insulin level. So this is meal. So breakfast, lunch, and dinner. Right after meal, the huge blood glucose, right? And immediately, that blood glucose is sensed by pancreatic beta cells and insulin levels. And then followed, there is beautiful correlation in healthy individuals. So the key theme of this session is to understand how insulin signaling can be transmitted inside a target cell. So insulin binds to insulin receptor, and this insulin receptor is kind of enzyme receptor, tyrosine kinase. Once insulin binds to insulin receptor, and when insulin receptor becomes activated, and they put phosphate group as a receptor tyrosine kinase, phosphorylate their own receptor structure, autophosphorylation. And then a series of signaling adapter, IRS1, recruited. And phosphorylated by the receptor tyrosine kinase, insulin receptor, and IRS phosphorylated. And very interesting, lipid kinase, PI3 kinase activated, and lipid molecule phosphorylated, and other kinase may be, in this case PKB or so-called ATP kinase, this kinase is further activated. So ultimately, PKB or called Akt kinase can be fully activated. Again, the key concept of this signal transduction is phosphorylation cascade. The very beginning, tyrosine depend on protein phosphorylation and series of signaling relay, and the lipid molecule can be phosphorylated. But ultimately, PKB Akt kinase can be phosphorylated and become activated. And further, the phosphorylation cascade and target protein modification, glucose uptake can be stimulated. And fat synthesis can be stimulated, and glycogen synthesis stimulated, even protein synthesis can be triggered. See, the biological outcome is very clear. So anabolic reactions, because high insulin reflects high blood glucose. That means excess energy, and those energy ultimately signals through insulin to stimulate those anabolic reactions, not just the glucose polymer glycogen or biosynthesis. Other macromolecules, like lipids or protein synthesis, can be unregulated throughout these signaling cascades. This is another diagram to help you to understand this insulin signalling. Again, insulin binds to receptor. This is receptor tyrosine kinase. Throughout those phosphorylation signalling cascade, you don't need to remember those details, like PI3K and Akt. But ultimately, those signalling cascade inside a target cell drives the localization of glucose transporter from the cytosome to the plasma membrane and drives the huge amount of glucose uptake. And those glucose, once they are getting into the cells, they can store the form of glycogen, and those energy and this high blood glucose condition, insulin signaling pathway activate the synthesis of macromolecules. Lipids, protein, and glycogen, and further, they increase the chance of cellular survival. That means the proliferation depend on biochemical events. And those signalling pathways are tightly regulated by the key hormone, insulin. This is the mode of action of insulin hormones in the target cell.