BISC 307L 1st Edition Lecture 15 Current Lecture Control of Insulin Secretion in Pancreatic B cells o o o o o Insulin the first endocrine hormone that was well studied Small protein The rectangle is beta cell How does the cell know when its time to secrete insulin Main mechanism is exerted by glucose itself and amino acids in the plasma Blood glucose and blood plasma Glucose enters through GLUT 2 which results in increase in ATP which binds to a ATP sensitive K channel which is usually open when there are low levels of ATP so when there is high level of ATP this channel is blocked This blocking of the formally open K channels depolarizes the membrane opens Ca2 channels trigger for exocytosis of vesicles containing insulin o Two methods that stimulate insulin release 1 Parasympathetic activity 2 Secretion of Incretins small intestinal hormones 1 GLP1 Glucagon like peptide 1 2 GIP Gastric inhibitory peptide now called glucose dependent insulinotropic peptide stimulates secretion of insulin due to glucose Both are part of a feed forward system that anticipate a rise in blood nutrient before the meal is taken in They prime the beta cell so that they are more sensitive to the rise in blood glucose when it actually happens o Main mechanism of inhibiting of insulin secretion Sympathetic activity Slide 5 Insulin Stimulates Glucose uptake in resting skeletal muscle and adipocytes o Three cell types 1 Skeletal muscle cells this slide resting when insulin binds to receptor this stimulates the insertion of preformed GLUT4 into membrane of resting skeletal muscle were previously in the membrane but in the absence of insulin binding to receptor these GLUT 4 receptors are internalized and stored in vesicles just under the membrane When insulin binds the GLUT 4 receptors emerge and become active as a result plasma glucose is lowered leaves ECF into cells Active skeletal muscle is not described will result in insertion of GLUT 4 transporters INDEPENDENT of insulin receptors why diabetic patients urged to exercise because don t need insulin in active skeletal muscle 2 Fat cells in adipose tissue this slide same mechanism 3 Liver cells next slide Effects of Insulin on Glucose Transport in Liver o o Liver cell Binding to receptor of insulin triggers signal transduction and main target activated is exokinase which is a cytoplasmic enzyme which is the first step of glycolysis Turns glucose into glucose 6 phosphate Does three things 1 Prepares glucose for cellular metabolism 2 Traps glucose inside the cell 3 Lowers concentration of glucose inside the cell Transporter involved is the GLUT 2 transporter doesn t depend on insulin to be in the membrane It takes up glucose in absorptive state but in fasted state stores of glucose glycogen are released through these GLUT 2 transporters back into the blood Other Actions of Insulin o A Carbohydrates Insulin Stimulates glycolysis glucose can be used Insulin Stimulates glycogenesis glycogen synthesis Liver cells and skeletal muscle mostly o B Lipids Insulin Stimulates formation of FFAs and lipogenesis disassembly of lipids lipoproteins appear in blood after meal and chylomicrons which transport lipids Insulin takes up these circulating molecules and convert them to free fatty acids FFAs which are esterified into triglycerides fats Every step is stimulated by insulin forms fat Insulin Inhibits lipolysis in adipose tissue Inhibits fat breakdown o C Protein Insulin has anabolic affect Insulin Stimulates Na dependent amino acid uptake Insulin Stimulates protein and RNA synthesis inhibits breakdown of protein proteolysis Amino acids taken up are synthesized into protein excess is converted to glucose or lipids Actions of Glucagon o o o o o o o Released in alpha cells Stimulated by a drop in plasma glucose Released by pancreas Also stimulated by a rise in certain amino acids Inhibited by insulin Glucagon binding to receptors on the liver cells initiates a cyclic A cascade which causes 1 Stimulation of glycogen breakdown glycogenolysis 2 Inhibition of glycolysis o Rise in plasma glucose will inhibit glucagon secretion o Has a weaker affect on stimulating gluconeogenesis conversion of amino acids to glucose o Liver can also take circulating fatty acids or pyruvate and convert to glucose also but not as often conversion of these things are stimulated by glucagon in liver cells o Insulin stimulates lipogenesis and protein synthesis in these cells o Under normal conditions this doesn t happen only happens during starvation cortisol is released o Under conditions of starvation This conversion of muscle and fat tissue to glucose and the resulting high levels of amino acids and pyruvate will cause problems Results in more acid production fatty acids enter citric acid cycle when Acetyl CoA is in excess it is converted to two types of keto acids acetoacetic acid and betahydroxybutric acid ketone bodies production of excess ketone bodies is the byproduct of excessive fat breakdown some peripheral tissues and brain can use ketone bodies but excess causes problems Diabetes Mellitus Type 1 o What goes wrong in type one When no insulin is released the things that liver does to store glucose and the things that skeletal muscle does to take up glucose aren t working result is increase in lipolysis Main problem is hyperglycemia high plasma glucose Brain is not getting signals that meal just occurred so the brain interprets this as starvation which leads to overeating or polyphagia Kidney plasma is filtered so what comes out I plasma without the cells Under normal conditions in the proximal tubule there are glucose uptake mechanisms so body can keep it With hyperglycemia the renal threshold for glucose uptake is saturated which leads to glucosuria which leads to osmotic diuresis too much water is being released due to so much glucose being released so excess volume of urine This leads to dehydration which stimulates excessive drinking and stimulates the release of ADH and leads to drop in blood pressure and blood volume and the cardiovascular system tries to compensate and this leads to death In the mean time fat is being broken down which results in excessive ketoacid metabolic acidosis death