General Overview 1. What are the 3 endocrinologic functions of the pancreas?

Maintain constant blood glucose level, facilitate cellular storage of metabolic substrates following a meal, and provide mobilization of these substrates during periods of fasting 2. Which tissues use glucose as their primary source of energy? Brain, retina, and gonad germinal epithelium Anatomy of pancreas 1. What cell type is part of the exocrine pancreas? What is the function of these cells? Acini; secretes enzymes into duodenum of small intestine 2. Which cells of the islet of Langerhans produces insulin? Glucagon? Beta cells produce insulin; alpha cells produce glucagon 3. How does insulin affect glucagon secretion? Is this an autocrine or paracrine function? Insulin inhibits glucagon secretion. This is a paracrine function. Insulin 1. Structure/synthesis a. Explain the structure of insulin in detail. Include the type (steroid, protein, etc), names of chains, number of chains & how these chains are connected to one another. Insulin is a polypeptide consisting of an A and B chain. The two chains are linked by disulfide bonds. There are 2 chains. It is in a form called proinsulin (3 chains). C chain is cleaved and forms C peptide. b. Explain the synthesis of insulin including any precursors. Why is the C peptide important? Insulin is synthesized in beta cells as preproinsulin and then cleaved into proinsulin, which consists of 3 chains. The C peptide is important because it is a marker in blood that can be used to determine how much insulin-treated diabetic patient is making of their own natural insulin. c. How does insulin circulate in plasma (i.e. bound or unbound)? What is its half-life? How and where is it degraded? How long is it in circulation before it is cleared?

It is mostly unbound. The half-life is 6 minutes. It is cleared from circulation in 10-15 minutes. What doesnt bind with a receptor is degraded by insulinase in the liver and in the kidneys and muscles by cleaving A and B chains. 2. Release a. Explain the events involved in insulin release starting with glucose entering the beta cell and insulin being released via exocytosis. Include all intermediate steps and enzymes involved. Which step is considered to be rate limiting? (Slide 8 from 4/19) Glucose enters the beta cell through GLUT-2 receptor. Glucokinase then phosphorylates glucose to glucose-6-phosphate. This is the ratelimiting step. Next, oxidized G6P forms ATP by entering glycolysis and respiratory cycle. ATP inhibits ATP-sensitive K channel. This results in K remaining in the cell and depolarization occurring. Votage-gated Ca channels then open and induces exocytosis which releases insulin from the cell. b. Besides glucose, what other substances modulate insulin release? How does the PNS and SNS affect insulin release? Amino acids, gut hormones, and other hormones (GH, glucagon, cortisol) modulate insulin release. The PNS stimulates insulin secretion; whereas, the SNS inhibits insulin secretion. 3. Receptor a. What is the structure of the receptor? It is on the plasma membrane and has 2 alpha and 2 beta subunits. b. Explain the events that occur in the metabolic route starting with insulin binding to its receptor and ending with protein synthesis. (slide 11 & 12 from 4/19) Insulin binds to the alpha subunit and causes a conformational change of receptor. Then the beta subunits are autophosphorylated. Then, tyrosine kinase is activated. Then, insulin response substrates phosphorylate PI-3 kinase activating pathway leading to glycogen synthesis, Lipid metabolism, glucose transport, and protein synthesis. c. Explain the events that occur in the growth signal route starting with insulin binding to its receptor and ending with what the Ras-MAPK pathway stimulates. (slide 11 & 13 from 4/19) Insulin binds to alpha subunit of receptor, and activates beta subunits which are then autophosphorylated, and phosphorylation of Shc occurs, which activates the Ras-MAPK pathway. This pathway stimulates gene transcription, protein synthesis, and mitotic activity.

d. Explain the cascade of events that occurs involving glucose metabolism & uptake following insulin binding to its receptor (slide 14 from 4/19) Insulin binds to its receptor. Then there is a cascade of protein activations. These include translocation of Glut-4 transporter to plasma membrane resulting in influx of glucose, glycogen synthesis, glycolysis (produces pyruvate), fatty acid synthesis (from pyruvate). Pyruvate also produces amino acid alanine so can be used in protein production as well. 4. Carbohydrate Metabolism a. Muscles i. What source of food fuel do the muscles primarily use? Fatty acids ii. What 2 conditions do muscles use glucose? What happens with to the glucose the muscle doesnt need? Muscles use glucose during moderate/heavy exercise and after a meal. Excess glucose is stored as glycogen which can be used as energy later. iii. How does insulin affect glucose uptake in muscle cells? Insulin increases glucose uptake in muscle cells. iv. Be able to draw the graph on slide 17 from 4/19

b. Liver i. What effects does insulin have on glucose in the liver? Insulin causes glucose to be absorbed after a meal to be stored as glycogen. ii. What are the 3 mechanisms insulin uses to take up & store glucose? Explain each mechanism in detail. Inactivates liver phosphorylase-breakdown glycogen, increases glucokinase- traps glucose by phosphorylating it, increases glycogen synthase- makes glycogen

iii. What enzyme is glycogen production dependent upon? When is this enzyme active (i.e. what structural change happens to activate it)? Glycogen synthetase. It is active when it is dephosphorylated. iv. What 2 processes does insulin stimulate when glycogen stores have become saturated in the liver? 1. Promotes conversion of excess glucose into fatty acids Fatty acids are packaged as triglycerides in LDLs and transported in blood to adipose tissue where deposited as fat 2. Inhibits gluconeogensis Decreases quantity/activity of liver enzymes needed for gluconeogensis; decreases release of amino acids from muscles and other extra-hepatic tissues c. Brain i. Why does the brain not require insulin for glucose uptake into the cells? Most brain cells are permeable to glucose ii. What is the brains primary source of fuel? glucose iii. What is hypoglycemic shock? It is a nervous disruption leading to fainting, seizures, and/or coma due to blood glucose levels falling below normal. d. Adipose tissue i. How does insulin indirectly promote fat deposition (i.e. what is the function of glucose in fat production?)? Glucose is transported into adipose cells and is used as a substrate for glycerol portion of triglyceride. 5. Fat Metabolism a. What are the 2 ways insulin promotes fat storage in adipose tissue? 1. Increases utilization of glucose by bodys tissues which allows fat to be spared 2. promotes fatty acid synthesis Occurs when more carbohydrates are ingested than needed for immediate energy; occurs in liver; fatty acids transported from liver and stored in adipose tissue b. Explain in detail the 3 factors that increase fatty acid synthesis in the liver.

1. increase transport of glucose into liver cells via insulin. When liver glycogen concentration reaches 5-6%, glycogen synthesis is inhibited and all additional glucose becomes available to form fat. 2. excess of citrate and isocitrate ions formed by the citric acid cycle when excess amount of glucose are being used for energy. 3. most fatty acids are then synthesized within liver and used to form triglycerides. Triglycerides then released into blood in lipoproteins. c. Explain in detail the 3 functions of insulin in adipose cells (slide 24 fig from 4/19 you should know). 1. activates LPL in capillary walls of adipose tissue which breaks triglycerides down into fatty acids. It is required for them to be absorbed into adipose tissues and fatty acids are then converted into triglycerides and stored. 2. inhibits action of HSL, which hydrolyzes TG into FFA. 3. promotes glucose transport through adipocyte. Some are used to form FFA and most are used to produce a-glycerol phosphate which supplies glycerol portion of TG. 6. Protein Metabolism a. What are the 5 ways insulin promotes protein synthesis/storage? 1. Stimulates transport of amino acids into cells; 2. increases translation of mRNA (resulting in increase production of proteins), when insulin is absent ribosomes stop working; 3. increases rate of transcription of specific DNA for production of enzymes involved in carbohydrate, fat, and protein storage; 4. inhibits catabolism of proteins and decreases rate of amino acids leaving cells (especially in muscle); 5. decreases rate of gluconeogenesis by inhibiting enzymes involved in this process (especially in liver), also have decrease substrates to produce glucose because have decrease in amino acids available in plasma 7. Somatic Growth a. Be able to reproduce and explain the graph on slide 26 from 4/19

Insulin and growth hormone work together to promote growth. Both hormones stimulate cellular uptake of a different selection of amino acids. Growth requires both hormones.

8. Fuel Switching a. What is fuel switching? What happens when glucose levels are low? What happens when glucose levels are high? Fuel switching is utilizing the right fuel at the right time. When glucose levels are low, insulin is suppressed and fat is used exclusively for energy except in the brain. When glucose levels are high, insulin is stimulated and carbohydrates are used instead of fats. ** * Slide 28 from 4/19 is a great review of insulins effects ***

Glucagon

1. Compare and contrast insulin and glucagon. Include where they are produced, what type of hormone each is, their structure and how blood glucose levels affect the secretion of each. Insulin: beta cells in the Islets of Langerhans, polypeptide with 2 chains, secreted with high blood glucose levels Glucagon: alpha cells in the Islets of Langehans, 29 amino acid single chain, secreted with low blood glucose levels 2. What is another name for glucagon? Hyperglycemic hormone 3. What are the major target tissues of glucagon? Liver, adipose tissue, and cardiac muscle 4. What other hormone/neurotransmitter does glucagon have similar actions to? Epinephrine 5. Explain in detail the events of glycogenolysis starting with glucagon binding to its receptor on a hepatocyte. Glucagon binds to its receptor on a hepatocyte. Glucagon activates adenylyl cyclase and cAMP is produced, which activates protein kinase. Phosphorylase b kinase is then activated and phosphorylase kinase converts phosphorylase b into phosphorylase a. Phosphorylase a promotes degradation of glycogen into glucose-1-phosphate, and then becomes dephosphorylated to produce glucose which is released into the blood. 6. How does glucagon increase gluconeogenis in the liver? By increasing rate of amino acid uptake by liver cells and then conversion into glucose. 7. What effects does glucagon have on adipose tissue and liver triglycerides? It activates adipose cell lipase and results in increased fatty acids in circulation and thus available for energy. It inhibits triglyceride storage in the liver, preventing the liver from removing fatty acids from blood. 8. What 2 processes regulate glucagon secretion? Explain each in detail. 1. high circulating levels of glucose inhibits glucagon. In hypoglycemia, glucagon is secreted in large quantities resulting in increased amount of glucose released by liver cells. This is the exact opposite of insulin. 2. increased circulating amino acids stimulates glucagon secretion. This occurs after a meal high in protein. Same response seen in insulin. Glucagon promotes rapid conversion of amino acids into glucose, whereas insulin stimulates production of proteins.

9. Be able to reproduce 2 graphs on slide 1 from 4/21.

10. What happens during severe hypoglycemia? What happens during prolonged hypoglycemia? During severe hypoglycemia, the hypothalamus senses low glucose levels and stimulates adrenal glands to release epinephrine. During prolonged hypoglycemia, GH and cortisol are secreted which decrease glucose utilization by most cells and results in increased fat utilization. Type I Diabetes 1. What are 3 causes of the disease? Injury to beta cells of pancreas, disease that impairs insulin production by beta cells, hereditary (may increase beta cells vulnerability to being injured or impaired) 2. Why is it referred to as juvenile diabetes? Average onset is 14 years of age 3. What are the effects of high circulating glucose levels on the kidneys? The kidneys cant reabsorb all glucose so some is dumped in the urine. 4. How does high circulating glucose levels cause cellular dehydration? Renal dehydration? Cellular dehydration: Water leaves the cells and enters the ECF due to high glucose concentrations increasing osmotic pressure in ECF.

Renal dehydration: Loss of glucose in urine results in high osmotic pressure in tubular fluid, thus decreasing water reabsorption by the kidneys. 5. What are the 4 classic symptoms of type I diabetes? Polyuria, intracellular dehydration, extracellular dehydration, excessive thirst 6. What 3 types of tissue injuries do high levels of circulating glucose cause? What are the symptoms of these injuries? Abnormal function of blood vessels as well as structural changes. This results in inadequate blood flow to tissues and leads to stroke, heart attack, end-stage kidney disease, retinopathy and blindness, and ischemia and gangrene of limbs. There is also peripheral neuropathy and autonomic nervous system dysfunction. Both can result in impaired cardiovascular reflexes, bladder control, and decreased sensation in extremities. 7. How does high glucose levels affect fat utilization? How does this cause metabolic acidosis? How does this lead to arteriosclerosis? It increases fat utilization and metabolic acidosis. Diabetes increases shift from carbohydrate to fatty acid metabolism in liver and kidneys. Fatty acids are broken down and keto acids are released as a by-product. Excessive amounts of keto acids results in acidosis. Prolonged fat metabolism in liver causes an increase in circulating cholesterol, resulting in deposition of cholesterol in arterial walls leading to arteriosclerosis. 8. What happens to the bodys proteins when circulating levels of glucose are high? The bodys proteins are depleted. There is an increased metabolism and decreased storage of proteins (and fats). 9. What is the treatment for this type of diabetes? Regular administration of insulin Type II Diabetes 1. How does this type of diabetes differ from type I? What is the most common cause of type II? Type II diabetes is due to resistance of tissues to insulin, not decreased insulin production as in type I. Obesity is the most common cause. 2. What 3 factors precede type II diabetes? Obesity, insulin resistance, and metabolic syndrome i. How does obesity lead to insulin resistance? May be due to impaired insulin signaling due to toxic effects of lipid accumulation in tissues ii. How does insulin resistance lead to hyperinsulinemia? There is decreased carbohydrate utilization and storage resulting in increased circulating blood glucose and increased insulin secretion. Beta

cells try to compensate for this and release excessive amounts of insulin in the blood. iii. What 5 disorders comprise the metabolic syndrome seen in type II diabetes? Obesity, insulin resistance, fasting hyperglycemia, lipid abnormalities, hypertension 3. What are 5 other factors, besides obesity, that can cause type II diabetes? Pregnancy (gestational diabetes), mutations of insulin receptor, excess growth hormone, autoantibodies to the insulin receptor, lipodystrophy 4. What are the effects of prolonged insulin resistance? Pancreatic cells become exhausted/damaged resulting in decreased insulin production. Genetics play a major role in this. 5. What is the treatment for the disease in its early stage? In its late stage? Early stage: exercise, diet, and weight decrease; late stage: insulin adminstration i. What 3 drugs can be used to treat the disease in its early stage? What is the mechanism of action of these 3 drugs? Thiazolidinediones: increase insulin sensitivity Metformin: suppresses liver glucose production Sulfonylureas: increase release of insulin from pancreas Insulinomia/Hyperinsulinism 1. What is the primary cause of this disease? Excessive insulin production that occurs from adenoma of Islet of Langerhans 2. How is the CNS affected? Becomes excitable due to sensitized neuronal activity from lack of glucose 3. What is the difference between hypoglycemic coma & diabetic coma? Hypoglycemic coma: when blood glucose levels fall below 20-50 mg/100 ml, seizures and loss of consciousness occurs, seizures stop when patient enters coma Diabetic coma: deep increased breathing and acetone breath due to increased keto acids forming. Patient is trying to expire excess acid out of his/her system. 4. What is the treatment of this disorder? Large quantities of glucose intravenously, or glucagon and epinephrine