Welcome back to my Cousera class, Biochemical Principles of Energy Metabolism. This is the second session of week six. In the previous session, we studied about molecular pathways of how glucagon hormone can be released in response to low blood sugar conditions like fasting. And glucagons affect many biochemical reactions like the breakdown of glycogen and gluconeogenesis as well as glycolysis. So, in this session and the following session, we are going to talk about insulin, one of the major hormones produced from pancreas and which is very, very critical for the regulation of energy homeostasis. So, insulin molecule is really important in the field of biology, just fundamental biology, as well as the medicinal science. So, well, one example is the insulin and Nobel Prize. So in 1923, almost a century ago, insulin hormones, for the first time, has been extracted and discovered as the key hormone for reducing blood sugar and the key cause of the diabetic medical conditions. And this research has been done by a group of scientists at the University of Toronto and Banting and Macleod got Nobel Prizes. And the primary structure of insulin, that means the sequence of amino acid of this hormone, has been identified by Frederick Sanger. And this is still another area for insulin and Nobel Prize. The other one is three dimensional, 3D structure of insulin hormones, the peptide, done by Dorothy Hodgkins. And the more recently in 1977, Dr. Yalow identified a very unique assay called the radioimmunoassay to detect low level ligands in this case. This assay has been used to detect insulin levels. So, obviously the insulin is now is the key topic for investigation. So, this is the historical experiment done by Banting and Best, the Nobel prize topic, how they discovered the insulin for the major hormones to regulate blood glucose homeostasis. Well, you have experimental dog. They removed the pancreas, obviously the insulin is secreted from the pancreas, and it is pancreatectomy, the dog develop diabetes. I'm going to explain diabetes many times throughout our sessions. And Banting and Best isolated the islets of Langerhans. At least those days at least people clearly recognize the importance of islets of Langerhans, but they didn't know which factor actually is the key. And they tried to isolate the materials secreted from Langerhans, islets of Langerhans, and then throughout those purification, pancreas purification, and they injected that solution back into the diabetic dog. And then the dog's diabetic symptoms can be attained in a quite striking fashion. This is like a first the successful experiment to demonstrate the importance of insulin produced from islets Langerhans in the regulation of blood glucose and then in the context of treating diabetic symptoms. And you're looking at those days. This was the real mega-hit in terms providing another key major breakthrough in treating diabetic patients. You're looking at Banting and Best, and then diabetic dogs. So, what is insulin? Insulin is, again is like glucagon, very short chain polypeptide. And you're looking at two polypeptide chain, one on your top and the other one is bottom. And these two chain has been linked by the isopeptide bond between specific system residues, and even intramolecular system interactions available. And you're looking at 3D structure of human insulin. So, as you just saw from the previous slide, insulin is a small peptide hormone and two chains like alpha chain and the other chain, beta chain, or Covelli linked throughout those S_S the isopeptide bonds. And the source of insulin is pancreatic beta cell. These beta cell produce and secrete insulin hormone, not all the times, in response to increased levels of circulating blood glucose. This is opposite situation compared to the glucagon, glucagon secreted in response to lower blood sugar. This is opposite. It's like after meals, after lunch, or after dinner. So, a lot of chemical carbohydrate and those nutrients coming in. And blood glucose level will be increased and that time-point beta cell is activated and starts secreting insulin. So, functions of insulin is obviously to drive the glucose uptake. So, major organ and tissue for glucose uptake, blood glucose uptake into peripheral tissue, skeletal muscle is the major organ. And liver and adipose tissue also contribute to the uptake of glucose. And also, insulin stimulate the liver cells hepatocyte again to take up glucose, and then further stimulate glycogen production. So, extra glucose can be stored in the form of glycogen. And those biochemical reactions like glycogenolysis and gluconeogenesis, those reactions stimulated by glucagon, actually antagonized by insulin. And rather insulin stimulate the uptake of glucose and furthermore importantly, drive the fat biosynthesis in adipose tissue. That makes sense because in response to high levels of blood glucose, the main action of insulin is to reduce blood glucose levels, and further stimulate anabolic reactions to store extra energy. In fat cells, the lipid biosynthesis actually activated by insulin. And lastly, insulin can regulate neurons in the hypothalamus of the brain and reduce appetite. So, in response to high blood glucose levels, insulin can act as anorexigenic hormone in the brain. So, on this slide indicates how insulin secretion can be stimulated by glucose. So, this phenomenon is called glucose-stimulated insulin secretion. And you're looking at the biochemical flow of this very tightly regulated physiologic event. So, high levels of blood glucose, just so you can imagine after lunch or after dinner, after a meal. And glucose getting into the cells in particular pancreatic beta cells. And glucose degraded into glycolysis, this is cycle and mitochondrial oxphos pathway, ATP production is increased. And there is very unique potential channel in the membrane of beta cell, pancreatic beta cell, when ATP level's getting in increased, this channel is sensitive to ATP: ADP ratio, intracellular ATP: ADP ratio. So, when ATP: ADP ratio increased upon the glucose degradation and that channel actually closed. So, that means the beta cell membrane potential becomes depolarised. And this membrane potential changes can be transmitted on other channel of the pancreatic beta cell, voltage-gated calcium channel. So, the changes of membrane potential can actually stimulate the specific calcium channel. So, many calcium ions can get into the cytosol of pancreatic beta cell, and this increased calcium levels can trigger very, very regulated vesicle fusion. So, normally insulin hormones in the very beginning, once they are produced, they are encapsulated specific vesicles. And this vesicle fusion to plasma membrane can be triggered by calcium ions. So, insulin captured in this vesicle can be released out of pancreatic beta cell, and they can travel to other peripheral tissues. So, this vesicle fusion is exocytosis, and this event is stored insulin, exocytosis of stored insulin, can be triggered by the rapid rise of calcium ions. And also this increased calcium can activate a series of molecular events in particular, throughout those transcription factors insulin gene expression also can be activated. And more insulin can be synthesized and then released from the pancreatic beta cell. This is the Macleod's mobile, how pancreatic beta cells can sense high levels of blood glucose and then respond to those glucose levels, and finally trigger the release of insulin hormones from beta cells to peripheral tissues. So, we are going to study more about the biochemical actions of insulin in the following session.
