BISC 307L 2nd Edition Lecture 16 Current LectureControl of Insulin Secretion in Pancreatic Beta CellsInsulin has special significance because it was the first well studied endocrine hormone – structure was understood, gene identified, and it was successfully synthesized through recombinant DNA technology. The impetus for this was the therapeutic value of insulin in combatting diabetes.The rectangle is a beta cell, and at the bottom is insulin being released into the blood through exocytosis. How does a cell know when it is time to secrete insulin? Primary control, shown in the center of the figure, is exerted by glucose itself and by amino acids in the plasma, which are high intracellularly during the absorptive state when these nutrients are being absorbed. Glucose enters the beta cell by glut2 facilitated diffusion transporter in upper right corner. It stimulates energy metabolism inside the cell, which increases intracellular ATP - ATP binds to the inside of the ATP sensitive K channel on the right, in the membrane, which is normally open at low levels of ATP (when glucose is low in the blood). When blood glucose and intracellular ATP both rise, the formerly open channel is blocked and no longer hyperpolarizes the cell. Blocking of this channel therefore depolarizes the cell, causing vg Ca channels near the releasesites to open. Free Ca entering the beta cell triggers exocytosis of insulin carrying vesicles. This isthe main mechanism of control.On the bottom left – things that modulate/modify this primary level of control. The main mechanism to inhibit glucose dependent insulin secretion is sympathetic nerve activity. And the two mechanisms that stimulate insulin release:1. parasympathetic activity 2. the secretion of hormones that are collectively called incretins – they are small intestine hormones that stimulates glucose dependent insulin secretion from beta cells. The two main ones are GLP1 (glucagon-like peptide) and GIP(was called gastric inhibitory peptide, but now it stands for glucose-dependent insulinotropic peptide). How do they work? Both of these incretins are part of a feed forward mechanism that anticipates a rise in nutrients in the blood before it occurs. So GLP and GIP are released by the small intestine at the beginning of the meal or in anticipation of a meal, to prime the beta cells so they are more sensitive to the rises in glucose and amino acids that result when start eating. This way, they minimize the surge in blood glucose that would otherwise occur if this feed forward mechanism was not operative. Insulin Stimulates Glucose Uptake in Resting Skeletal Muscle and adipocytesThe action of insulin on cells – it affects most cells in the body, but we will be focusing on three types: cells of the skeletal muscle, adipose tissue/fat, and liver. This diagram focuses on insulin’s effect on glucose transporters in the membrane of resting skeletal muscles and adipose fat cells.Purple = plasma membrane of cell. Above = glucose molecules. Insulin binds to the tyrosine kinase insulin receptor and stimulates insertion of freeform Glut 4 facilitated diffusion glucose transporters into the membrane. They were previously in the membrane, but in the absence of insulin binding to its receptor, these glut 4 receptors are internalized by endocytosis and stored in vesicles just underneath the plasma membrane, where they do not participate. When insulin binds to its receptor, a reaction cascade occurs that ends up in the fusion of these vesicles and their Glut transporters into the membrane, where they allow glucose to come into the cell. As a result of this, plasma glucose is lowered. If you remember the 4 types of Glut transporters, there are some that are always in the membrane and some that are insulin dependent that get inserted into membranes. We are talking about resting skeletal muscle because active skeletal muscle can result in insertion of glut 4 transporters in the membrane independently of the action of the insulin receptors. Skeletal muscle activity itself can cause steps 3 and 4 shown above. This is why diabetics are strongly urged to exercise, because it will lower plasma glucose through this activity dependent insertion of Glut transporters in skeletal muscle cells. And skeletal muscle is a huge part of your body. Will effectively lower blood glucose levels. Effects of Insulin on Glucose Transport in LiverHow does insulin affect the uptake of glucose in liver cells(hepatocytes)?Insulin binding to its receptor initiates a signal transduction cascade, and the main target of this is the enzyme hexokinase, a cytoplasmic enzyme that is the first step of glycolysis. So when glucose gets into the cell it gets phosphorylated to form Glucose-6-Phosphate. As G-6-P it can continue through glycolysis and into the KREBS cycle. This prepares glucose for cellular metabolism, traps the glucose inside the cell because glucose can diffuse out of transporters (transporters that can’t transport G-6-P), and it lowers the concentration of glucose inside the cell and changes the concentration gradient (because it is no longer glucose). The transporter involved here is a glut 2 facilitated diffusion transporter – the type that is always in the membrane. It is important because the hepatocyte(liver cell) has to do two things:-In the absorptive state, it has to take up glucose (Above, on the left). Glucose is high, and it has to be taken up and processed.-In the post absorptive state, stores of glucose (stored by glycogen) in between meals have to bebroken down and released into blood to maintain normal levels. There have to be Glut transporters in the membrane for this to occur. That’s why you can’t have glut 4 transporters that depend on insulin(which depends on high glucose in the blood) to be active. These transporters have to be here all the time. Other Actions of InsulinSummary of what insulin does.A. Carbohydrates- Stimulates glycolysis- Stimulates glycogenesis (liver cells and skeletal muscles have this activity to the higher extent – they are massive organs and have the necessary enzymes for these mechanisms)B. Lipids- Stimulates formation of FFAs and lipogenesis. Digested fats and oils cannot just be absorbed as triglycerides and they can’t be transported either, because they are not water soluble. They have to be disassembled and complexed with proteins to create very small particles that are in suspension in the plasma, and are transported in