Control of Insulin Secretion in Pancreatic B cellsInsulin the first endocrine hormone that was well studiedSmall proteinThe rectangle is beta cellHow does the cell know when its time to secrete insulin?Main mechanism is exerted by glucose itself and amino acids in the plasmaBlood glucose and blood plasmaGlucose 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 insulinTwo methods that stimulate insulin release:1. Parasympathetic activity2. Secretion of Incretins (small intestinal hormones)1. GLP1 Glucagon like peptide 12. 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*Main mechanism of inhibiting of insulin secretionSympathetic activitySlide 5- Insulin Stimulates Glucose uptake in resting skeletal muscle and adipocytesThree cell types1. Skeletal muscle cellsthis slide- restingwhen 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 membraneWhen 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 tissuethis slide- same mechanism3. Liver cells (next slide)Effects of Insulin on Glucose Transport in LiverLiver cellBinding 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 metabolism2. Traps glucose inside the cell3. Lowers concentration of glucose inside the cellTransporter 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 InsulinA. CarbohydratesInsulin Stimulates glycolysis (glucose can be used)Insulin Stimulates glycogenesis (glycogen synthesis)Liver cells and skeletal muscle mostlyB. LipidsInsulin 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 fatInsulin Inhibits lipolysis in adipose tissueInhibits fat breakdownC. Protein- Insulin has anabolic affectInsulin Stimulates Na+ dependent amino acid uptakeInsulin Stimulates protein and RNA synthesis, inhibits breakdown of protein (proteolysis)Amino acids taken up are synthesized into protein- excess is converted to glucose or lipidsActions of GlucagonReleased in alpha cellsStimulated by a drop in plasma glucoseReleased by pancreasAlso stimulated by a rise in certain amino acidsInhibited by insulinGlucagon binding to receptors on the liver cells initiates a cyclic A cascade which causes1. Stimulation of glycogen breakdown (glycogenolysis)2. Inhibition of glycolysisRise in plasma glucose will inhibit glucagon secretionHas a weaker affect on stimulating gluconeogenesis (conversion of amino acids to glucose)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)Insulin stimulates lipogenesis and protein synthesis in these cellsUnder normal conditions this doesn’t happen – only happens during starvation- cortisol is releasedUnder 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 problemsDiabetes Mellitus Type 1What goes wrong in type oneWhen 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 lipolysisMain 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deathBISC 307L 1st Edition Lecture 15 Current Lecture- Control of Insulin Secretion in Pancreatic B cellsoo Insulin the first endocrine hormone that was well studied o Small proteino The rectangle is beta cello How does the cell know when its time to secrete insulin? Main mechanism is exerted by glucose itself and amino acids