Metabolism Lectures Diabetes Dalay Olson Ph.D. Integrative Biology and Physiology Email: [email protected] Office: 3-120 Jackson Hall Learning Objectives 1. Compare and contrast type 1 and type 2 diabetes. Identify the major similarities and differences (insulin level, insulin signaling events, treatment options, glucose tolerance test responses etc.) 2. How is diabetes diagnosed in the clinic? What tests are available and commonly used? What information does a glucose tolerance give you? What information does a hemoglobin A1C tell you? What are the limitations of these tests? 3. Explain how chronic elevation of blood glucose levels can result in AGE formation and AGE receptor (RAGE) activation. Explain the downstream effects of RAGE activation. 4. Identify the role of PKC (Protein Kinase C) in arteriolar vasoconstriction in type 2 diabetics. 5. List the common symptoms you might see in the clinic for a patient suffering from type 2 diabetes. 6. Explain why the plasma becomes acidic in a patient with uncontrolled diabetes. 7. Explain the mechanism of action (what is the point of the drug?) of insulin sensitizers, insulin mimetics, insulin secretagogues and SGLT2 inhibitors. Natural Progression of Type-2-Diabetes Pre-diabetes Lean Obese Henry, Am J Med 1998; 105 (1A):20S-6S Think about what is happening with Type 1 diabetics…how does their response differ from that of a normal person? Glucose Insulin is not present, Insulin binds to receptor therefore the signal transduction pathway is not initiated and glucose Glucose transporters remain in enters cell Exocytosis intracellular vesicles. Signal transduction cascade Plasma glucose remains high! GLUT4 Think about what is happening with Type-2-diabetics…how does their response differ from that of a Type-1- diabetic? Glucose Insulin is present but is not Insulin binds to receptor functional, therefore the signal transduction pathway is not initiated and glucose Glucose transporters remain in Exocytosis enters cell intracellular vesicles. Signal transduction cascade Plasma glucose remains high! GLUT4 Insulin Mediated Glucose Uptake In the clinic, how can you tell if someone is diabetic? • Hemoglobin A1C test • Blood test that measures the total amount of Hemoglobin A1C present within the bloodstream • Marker of hemoglobin modification by glucose (glycation) • Higher levels of glucose in the bloodstream results in increased hemoglobin glycation. • Glucose Tolerance Test (GTT) • Fast overnight (don’t eat anything for at least 8 hrs) • Ingest a large amount of glucose (75g glucose) • 1-20oz bottle of mountain dew • 7 chocolate covered doughnuts • 14 teaspoons of sugar • Watch how quickly your body is able to remove glucose from the bloodstream over time. In the clinic, how can you tell if someone is diabetic? • Glucose Tolerance Test (GTT) • Fast overnight (don’t eat anything for at least 8 hrs) • Ingest a large amount of glucose (75g glucose) • 1-20oz bottle of mountain dew • 7 chocolate covered doughnuts • 14 teaspoons of sugar • Watch how quickly your body is able to remove glucose from the bloodstream over time. Fasting >126 mg/dL indicative of diabetes What would this look like? 200 ) dL 150 Starting glucose levels (before I drink the mountain dew) 100 50 Plasma [glucose]Plasma (mg/ 0 0 15 30 60 120 Time (minutes) In the name of science Here is what my data looks like 200 Time [Glucose] ) (minutes) mg/dL dL 150 0 70 15 143 100 30 140 60 102 50 120 67 Plasma [glucose]Plasma (mg/ Starting glucose levels 0 (before I drink the 0 15 30 60 120 mountain dew) Time (minutes) What does this test tell you? • Does this test tell you anything about my ability to remove glucose from the bloodstream? • Does this test tell you anything about how quickly I can remove 200 glucose from the bloodstream? ) dL 150 • Does this test tell me how effectively my insulin is working? 100 50 • Draw the same curve for a type-1-diabetic and a type-2- diabetic. Can this test distinguish between the two? 0 Plasma [glucose]Plasma (mg/ 0 15 30 60 120 Time (minutes) How would this graph change if you had type-1-diabetes? ***REMEMBER TYPE 1 DIABETICS DO NOT PRODUCE INSULIN!*** 200 ) dL 150 100 50 Plasma [glucose]Plasma (mg/ Starting glucose levels 0 (before a type 1 diabetic 0 15 30 60 120 were to drink a mountain dew) Time (minutes) How would this graph change if you gave them insulin? ***REMEMBER TYPE 1 DIABETICS DO NOT PRODUCE INSULIN!*** 250 ) dL 200 No insulin 150 100 Plasma [glucose]Plasma (mg/ Starting glucose levels 50 (before a type 1 diabetic 0 15 30 60 120 were to drink a mountain dew) Time (minutes) How would this graph change if you had type-2-diabetes? ***REMEMBER TYPE 2 DIABETICS DO NOT RESPOND WELL TO INSULIN!*** 250 ) dL ***Add a curve showing what 200 would happen if you gave these people insulin*** 150 100 Plasma [glucose]Plasma (mg/ Starting glucose levels 50 (before a type 2 diabetic 0 15 30 60 120 were to drink a mountain dew) Time (minutes) How would this graph change if you gave them insulin? ***REMEMBER TYPE 2 DIABETICS DO NOT RESPOND WELL TO INSULIN!*** 250 dL 200 Without insulin 150 100 Plasma [glucose]Plasma mg/ Starting glucose levels (before a type 2 diabetic were to drink a 50 mountain dew) 0 15 30 60 120 Can using this test you tell the difference between a type-1 or a type-2-diabetic? WHAT INFORMATION ARE YOU MISSING? Insulin! You need to know if they are producing insulin. Knowing more about insulin helps to diagnose type-2-diabetes Measure plasma insulin Insulin tolerance test + Insulin sensitive Insulin resistant + Insulin Why is elevated blood glucose actually bad? Glucose Protein + Vasoconstriction Advanced Glycation End (AGE) Products Acidic Diabetic ketoacidosis Elevated Ketone Bodies Elevated Plasma Glucose o Absence of functioning insulin releases o Absence of functioning insulin keeps inhibition on lipolysis, so fat begins dietary plasma glucose high. releasing fatty acids into the plasma. o Absence of functioning insulin is thought to stimulate gluconeogenesis (liver o Liver converts the fatty acids into production of sugar). ketones (just like it does in the post- absorptive state). o Inability to remove glucose from the plasma coupled to increased o Ketones are acidic and high levels can gluconeogenesis results in elevated decrease plasma pH. plasma glucose levels. o Glucose is acidic in high concentrations. Together elevated ketones and glucose significantly acidifies the blood, driving the acidosis seen in patients with diabetes! Advanced Glycation End (AGE) Products AGE Formation AGE Targets AGE Receptors (RAGE): + • Increased oxidative stress (NADPH oxidase) • Increased inflammation (NFkB signaling) Protein and Lipid Glycation Extracellular Proteins: • Extracellular matrix alterations damages endothelium and increases permeability. • AGEs reduce nitric oxide (NO)and eNOS production à limits vasodilation Hyperglycemia + H2O2 Protein and Lipid Glycation (AGE) Diacylglycerol Oxidative Stress Endothelial Cell PKC Smooth muscle Vasoconstriction Effects of prolonged elevated blood glucose levels: • blood vessel damage: cardiovascular disease and high blood pressure – heart attack, stroke, etc. • nerve damage: caused by the damage to capillaries which cuts off oxygen and nutrient supply to the nerves can also lead to infection leading to amputation • eye damage: damage blood vessels of the retina, could lead to blindness • kidney damage: damage to filtering system, kidney failure, kidney disease Current Treatments Insulin Insulin Insulin SGLT2 sensitizers mimetics secretagogues Inhibitors Thought Experiment: Symptoms of a diabetic patient Most diabetics will experience the following symptoms. Based the physiology you learned in this course, justify each symptom. o Hyperglycemia o Glucose in the urine (glucosuria) o Increased urination (polyurea) o Increased thirst (polydipsia) o Increased huger and eating (polyphagia) Complete the table to compare the groups. Symptom Justification (Why would a patient experience this symptom?) Hyperglycemia Glucose in the urine (glucosuria) Increased urination (polyurea) Increased thirst (polydipsia) Increased hunger and eating (polyphagia).