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Diabetes 1 Why is Diabetes Important? 2 Why is Diabetes Important? Source: 2004–2006 National Health Interview Survey estimates projected to year 2007 Why is Diabetes Important? • Diabetes is probably the most important endocrine disorder • A lot of people have diabetes and it causes a lot of healthcare issues • Type 2 diabetes is increasing among children, teens (10-19), and the elderly over 60 • Percent of people with diabetes, by age group – 20-39 – 2.6% – 40-59 – 10.8% – 60 and older – 23.8% 4 Type 2 Diabetes is Increasing in Children and Teens, Especially in Certain Groups 5 Type 2 Diabetes is Increasing in Children and Teens, Especially in Certain Groups Source: SEARCH for Diabetes in Youth Study. NHW=Non-Hispanic whites; AA=African Americans; H=Hispanics; API=Asians/Pacific Islanders; I=American Indians Chronic Complications of Diabetes Types 1 and 2 7 Chronic Complications of Diabetes Types 1 and 2 1. Frequent infections - The high level of blood glucose acts as a fuel for microorganisms 2. Diabetic retinopathy 3. Diabetic nephropathy 4. Arteriosclerosis/ vascular disease 5. Diabetic neuropathy • • One in four hospitalized patients has diabetes Problems two through five are the most responsible for health issues among diabetes Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 820 8 Diabetes Mellitus Types of Diabetes Mellitus 9 Diabetes Mellitus Types of Diabetes Mellitus A. Type 1: 1. Beta cells of the pancreas are destroyed by autoimmune attack. 2. No insulin is produced. 3. Must be treated with insulin injections in order to replace what is not present B. Type 2: 1. Insulin resistance 2. They have insulin but there is inadequate insulin secretion in order to control blood sugar 3. May be treated with diet and exercise, oral medications, and/or insulin injections 10 Lecture Outline 11 Lecture Outline I. Insulin Pathways in Liver, Muscle and Fat II. Pathophysiology of Diabetes Mellitus II. Symptomatology of Diabetes Types 1 and 2 III. Insulin Therapy: Focus on Type 1 IV. Adverse Effects of Insulin V. Pramlintide Therapy VI. Pregnancy in Type I Diabetes VII. Type 2 Diabetes: Pathophysiology and Presentation VIII. Drugs Primarily Targeting Type II Diabetes IX. Pregnancy in Type 2 Diabetes X. Gestational Diabetes 12 Diabetes and Insulin Therapy Diagram 13 Diabetes and Insulin Therapy Diagram 14 Insulin Pathways in the Liver Diagram 15 Insulin Pathways in the Liver Diagram 16 Insulin Pathways in the Liver Description 17 Insulin Pathways in the Liver Description • This is a liver cell • Liver takes up glucose – Can use it in the TCA cycle and make ATP – Can store it as glycogen (the storage form of glucose) • When we eat and blood sugar is high, insulin is high, the liver takes in glucose and stores it as glycogen • When we are fasting, blood sugar is getting low, insulin is low, and the pathway that is promoted by insulin is not going forward – Glycogen is being broken down and the liver can add glucose back to the blood stream to nourish the body • The liver, under the guidance of insulin, controls blood glucose in the body by breaking down glycogen or taking glucose out of the body – Insulin inhibits this pathway • Therefore, this pathway does not go forward unless insulin is low 18 Gluconeogenesis 19 Gluconeogenesis • The liver can make new glucose and add it to the bloodstream – Would want the liver to do this when glucose is low – The pathway is inhibited by insulin • The pathway is not activated after eating when insulin is high 20 Synthesis of Triglycerides 21 Synthesis of Triglycerides • Insulin also promotes the synthesis of triglycerides from fatty acids – Triglycerides are the storage form of fat • Want to store fats after you have just eaten – When fasting, triglyceride pathway is not being promoted, fats are broken down and made into acetyl-CoA – Can be used to form ketone bodies • Ketone bodies get into the circulation and go throughout the body and then are turned back into acetyl-CoA • The pathway for the synthesis of ketone bodies is inhibited by insulin – Insulin is high after eating - can use glucose to fuel the body so insulin is inhibitory for the production of glucose – The liver itself cannot use ketone bodies • After not eating for a while, blood sugar would be low and ketone bodies would be present in the urine 22 Insulin Pathways in the Muscle Diagram 23 Insulin Pathways in the Muscle Diagram 24 Insulin Pathways in the Muscle Description 25 Insulin Pathways in the Muscle Description • Muscle cells take up glucose and can use it for fuel for the Kreb’s cycle • Muscle cells store glycogen because they are energetic cells that need a lot of glucose – The glucose used by the muscle cells comes from the liver, gluconeogenesis, and the muscle cell’s own storage • The difference between the muscle and the liver is that in the muscle insulin must be present in order for glucose to be taken up by the muscle – Glucose can also be taken up by the muscle cell when the cell is exercising 26 Insulin Pathways in Fat Tissue Diagram 27 Insulin Pathways in Fat Tissue Diagram 28 Insulin Pathways in Fat Tissue Description 29 Insulin Pathways in Fat Tissue Description • Glucose entry into fat cells is insulin-dependent • The fat cell is the storage place for triglycerides • The pathway of taking triglycerides into the fat is promoted by insulin – In people with type 1 diabetes, insulin is not produced, so triglycerides are not taken into the fat cells • This explains why people with type 1 diabetes often lose weight before being diagnosed and gain weight when they go on insulin • If you just ate, triglyceride levels will be high and insulin will be high – When insulin is high, the body does not want/need to be breaking down fats because you have dietary fat – When insulin is lower, then you will break down the fats 30 Glucose, Amino Acid, and Free Fatty Acid Utilization by Muscle, Liver, and Fat Cells 31 Glucose, Amino Acid, and Free Fatty Acid Utilization by Muscle, Liver, and Fat Cells 32 In the liver, what is the name of the pathway that generates new glucose molecules from 3-carbon fragments? 33 In the liver, what is the name of the pathway that generates new glucose molecules from 3-carbon fragments? 25% 25% 25% 25% is ly s is co ge no es G ly og en co ne G lu sy n co ge G ly co ge n br ea kd nt he ow n si s Glycogen breakdown Glycogen synthesis Gluconeogenesis Glycogenolysis – glycogen breakdown G ly 1. 2. 3. 4. 34 Ways of Measuring the Effect of Insulin 35 Ways of Measuring the Effect of Insulin 1. Urine testing for glucose or ketones: a) Urine testing for glucose is no longer recommended. b) Presence of ketones in the urine signifies fat breakdown 2. Blood Sugar: blood testing for glucose is the most accurate. a) Normal fasting BS – 80-110 mg/dl b) Normal 2-hr post prandial (2 hr PP) <160 mg/dl - The person drinks a bottle of glucose - Come in, measure blood glucose, drink bottle of glucose solution, and then measure blood glucose again 3. Hemoglobin A1c : indicates about a 3-months average glucose level. a) Normal Hb A1c is about 5%. 36 Hemoglobin A1C 37 Hemoglobin A1C Glucose + protein (i.e., hemoglobin) Glycosylated protein (i.e., hemoglobin A1C) 38 The Basis of Hemoglobin A1C 39 The Basis of Hemoglobin A1C • If you take a protein (ex. albumin) and sit it in glucose, some of the glucose molecules will hitch onto the proteins • In the bloodstream, the glucose molecules are also being hitched onto proteins • Use hemoglobin because we know that the average lifespan of a red blood cell is 120 days – The average age of a red blood cell is 60 days – The degree of glycolyslation is indicative of the average blood sugar concentration over the last 60 days because the hemoglobin has been in the glucose for an average of 60 days • Shows how well the blood sugar has been controlled over the past 60 days • Normal is about 5% 40 Rate of Daily Self-monitoring of Glucose among Diabetic Adults 41 Rate of Daily Self-monitoring of Glucose among Diabetic Adults MMWR November 2, 2007 / 56(43);1142 42 Diabetic Symptomatology Presenting Symptoms of Type 1 43 Diabetic Symptomatology Presenting Symptoms of Type 1 1. Polyuria (frequent peeing) – the sugar in the urine acts similar exerts osmotic pressure, keeping the water in their urine 2. Polydipsia (frequent thirst)– dehydrated from peeing all of the time 3. Polyphagia (fat or muscle cells cannot take up adequate glucose because insulin is not present) 4. Possibly DKA. 44 Sources of Insulin 45 Sources of Insulin I. Beef or pork: no longer manufactured. - Not used now because people developed allergies to them II. Human insulin is produced recombinately in yeast and is identical to that produced by the pancreas (in those of us who do not have type 1 diabetes). III. Mutated human insulins (Lehne calls them “modified” insulins), produced recombinately in yeast, have different pharmacokinetic properties from unmutated human insulin. - This alters their pharmocokinetic properties 46 Insulin Strength and Dose 47 Insulin Strength and Dose I. Insulin is measured in units: this is a biological measurement that tells how much a given quantity of insulin will lower blood sugar in a test animal. II. Insulin preparations are in a concentration of 100 units/ml. Use an insulin syringe to inject. Some insulin come in a prefilled injection pen in addition to being available in a vial. - ex. the flex pen is advertised heavily on television •There is no set dose of insulin: each patient uses the amount that controls his/her blood sugar. 48 Types of Insulin 49 Types of Insulin INSULIN TYPE APPEARANCE ADDED PROTEI N PROFILE OF ACTION(hrs)* ONSET PEAK DURATION Lispro clear (pump use) none 0.2-0.5 1.5-2 3-5 Aspart clear (pump use) none 0.2-0.5 0.5-1 3-5 Glulisine clear (pump use) none 0.2-0.5 1-1.5 1.5-2.5 none 0.3-0.7 2-4 5-12 protamin e 1-2 6-12 18-24 None ~1.5 N/A ~16-24 Short duration: rapidacting Short duration: slower acting Regular clear (IV or SC) Intermediate-acting NPH cloudy Insulin demetir Clear (not used IV) Long-acting 50 Categories of Insulin 51 Categories of Insulin • Rapid-acting acts very quickly – They are all modified insulins that have a different structure that makes them easier to be absorbed form the subcutaneous tissue • Most insulin is injected subcutaneously • Short-duration • The mutant insulins are much more expensive but they can be injected right before or right after eating, rather than 20 minutes before eating • Because NPH is bound to the protamine, it has a longer onset and duration • Long-acting • Some of these can be used in the insulin pump – The pump is warm and there used to be precipitation in the tubing, but now it is okay • THE ONLY INSULIN THAT IS USED IN AN IV IS REGULAR INSULIN --- this will be on the test!!!!! 52 Profiles of Action of Various Insulins 53 Profiles of Action of Various Insulins 54 Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 666 Profiles of Action of Insulin and Insulin Analogs 55 Profiles of Action of Insulin and Insulin Analogs Hirsch, 2005, Insulin analogs, NEJM, 352:174-83 56 Insulin Mixtures 57 Insulin Mixtures • 70/30 insulin lispro protamine/lispro • 75/25 insulin aspart protamine/aspart • 70/30 NPH/regular • 50/50 NPH/regular 58 Insulin Administration 59 Insulin Administration I. Subcutaneous: All preparations II. Intravenous: Regular insulin only III. Inhalation: Regular insulin only (The only available inhaled insulin formulation has been taken off the market.) 60 Constant Insulin Infusion Pump 61 Constant Insulin Infusion Pump •A beeper-sized device containing a motor-driven syringe that the patient fills with a short-acting insulin (regular, lispro, aspart or glulisine). •Tubing from the syringe is connected to a needle the patient implants in the subcutaneous space. •The patient sets the device to deliver a basal level of insulin constantly, and can instruct it to deliver boluses to take care of meals. •The pumps are becoming very sophisticated 62 Which insulin can be used IV? 63 Which insulin can be used IV? 25% PH N eg u R em D la r iti r 25% 25% 25% ro Lispro Demitir Regular NPH Li sp 1. 2. 3. 4. 64 The Goal of Insulin Therapy 65 The Goal of Insulin Therapy • Euglycemic (normoglycemic) control: defined as blood sugar control that approximates that of a person without diabetes (normalization of blood sugar). • Virtually all newly diagnosed Type 1 diabetic patients are placed on this type of therapy because of the evidence that it decreases complications of diabetes. 66 Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications 67 Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Eng. J. Med., 329: 1993, p. 981 Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications Description 69 Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications Description • Compares the blood sugar testing with the goal of normal glucose values with the old method of urine testing and the fixed insulin regimen (conventional therapy) – The graphs showed retinopathy in patients • More patients in the conventional treatment has retinopathy than in the new treatment • This trial revolutionalized the treatment of diabetes • The goal to control the blood sugar as though the person is not diabetic has been shown with both type I and type II (more so type I) to reduce the complications associated with diabetes 70 Strategies for Insulin Therapy 71 Strategies for Insulin Therapy 1. Multiple insulin injections. 2. Constant insulin infusion pump. • With each strategy, patients must test their blood sugar 4-10 times per day, and make adjustments in their insulin dose based on their blood sugar measurements. 72 Strategies for Multiple Insulin Injections 73 Strategies for Multiple Insulin Injections Shade, et al, Intensive Insulin Therapy, Excerpta Medica, 1983, p. 133. 74 The Choice of Insulin Strategy is Based on Patient Preference 75 The Choice of Insulin Strategy is Based on Patient Preference • The pump may be harder to use and require more patient motivation and commitment. • Either strategy requires an intelligent patient with a good knowledge of their own disease. • Children and elderly patients may have problems related to their stage of development or comorbidities. 76 Comparison of Pump and Multiple Insulin Injections 77 Comparison of Pump and Multiple Insulin Injections The pump and multiple insulin injections both produce similar results when used optimally. The choice between the two is based 78 on patient preference. Insulin Use Across the Lifespan 79 Insulin Use Across the Lifespan • Children need close supervision but most prefer to prick their own fingers and give their own injections as soon as they are able. • Adolescents may rebel against the dietary restrictions and the need for continual monitoring. • Elderly may have difficulty with seeing test strips or manipulating syringes because of retinopathy or neuropathy. • Cognitive decline in the elderly may necessitate someone else taking responsibility for the insulin regimen. 80 Individualization of Insulin Protocols 81 Individualization of Insulin Protocols •Each patient’s regimen is shaped by their lifestyle, their blood sugar measurements, and their diet—but for type 1 diabetes, each patient’s goal should be euglycemia. •For type 2, the goal may be able to be a little bit above normal because the data supporting the benefit of euglycemia are not as strong in type 2 diabetics as in type 1 diabetics •Patients are instructed in a basic insulin regimen and given instructions on what to do in case of particular blood sugar measurements—this is called a sliding scale. 82 Example of a Sliding Scale 83 Example of a Sliding Scale Fasting blood sugar 60-80 Dose of regular insulin before breakfast 20 units 80-100 25 units 100-120 30 units 120-130 35 units 130-140 40 units 84 Adverse Effects of Insulin Hypoglycemia 85 Adverse Effects of Insulin Hypogylcemia Hypoglycemia: means low blood sugar Two sets of symptoms A. CNS symptoms: headache, confusion, drowsiness, and fatigue followed by coma, seizures, and possibly death. B. Peripheral symptoms: tachycardia, sweating, nervousness, all caused by activation of the sympathetic nervous system. 86 Treatment for Hypoglycemia 87 Treatment for Hypoglycemia •If conscious: p. o. sugar, i.e. a sugar cube, cake icing, glucose tablets, etc. •If unconscious: IV dextrose (glucose), 50 g. •If confronted with an unconscious diabetic patient, it is safest to assume that the problem is hypoglycemia and administer IV dextrose immediately. 88 Problematic Drug Interactions for Diabetics 89 Problematic Drug Interactions for Diabetics •Beta-blockers may mask the sympathetic symptoms of hypoglycemia. •Other drugs that affect blood sugar or insulin resistance may increase or decrease the activity of insulin. •Oral drugs for diabetes 90 To maintain euglycemic control, what measures must a diabetic patient use to measure his/her blood sugar? 91 To maintain euglycemic control, what measures must a diabetic patient use to measure his/her blood sugar? 25% 1. Urine testing 2. Home blood sugar testing once a day 3. Home blood sugar testing 4-6 times per day 4. Hemoglobin A1C testing H em og l ob i n A1 c 46X /D tin g te s e om H H om e U te s rin e tin g te st in 1X /D g 25% 25% 25% 92 Amylin A The Basis for a Drug for Type 1 and Type 2 Diabetics 93 Amylin A The Basis for a Drug for Type 1 and Type 2 Diabetics •What is amylin? •Amylin is a small protein that is made in the beta cells of the pancreas (just like insulin) and stored in secretory granules along with insulin. • When insulin is secreted, amylin is secreted along with it. •Until recently, we didn’t know the function of amylin. •BUT in type 1 DM, the beta cells die so there is no amylin!, just like they do not have any insulin 94 Functions of Amylin 95 Functions of Amylin 1. Potentiates the action of insulin on target cells. 2. Inhibits the secretion of glucagon (a pancreatic hormone that is made in alpha cells of the pancreas that opposes insulin). 3. Delays gastric emptying and thereby blunts postprandial blood glucose peaks because the food does not get into the intestines all at once, but rather does it slowly 4. Increases satiety and promotes weight loss. 96 Secretion Profile of Amylin and Insulin in Healthy Adults 97 Secretion Profile of Amylin and Insulin in Healthy Adults Symlin® prescribing information 98 Pramlintide (Symlin®) An Amylin Agonist 99 Pramlintide (Symlin®) An Amylin Agonist • A small protein very similar to amylin. • Inject subcutaneously before meals (cannot be mixed with insulin). • For injection, a 30 unit (0.3 ml) insulin syringe is used and a conversion chart tells what volume to draw up. 100 Conversion of Symlin Dose to Insulin Unit Equivalents 101 Conversion of Symlin Dose to Insulin Unit Equivalents 102 Starting a Type 1 Patient on Pramlintide 103 Starting a Type 1 Patient on Pramlintide •Because pramlintide potentiates the does of insulin, it decreases their previous dose of short-acting insulin by half. •Start pramlintide at 15μg before major meals. •If nausea occurs, continue that dose until it subsides (several days); then increase in 15 μg increments to 60 μg, each time waiting for nausea to subside. •After a stable dose is achieved at which there is no nausea, adjust the insulin dose to achieve euglycemic control. 104 Problems with Pramlintide 105 Problems with Pramlintide 1. Delayed absorption and lower peak levels of po drugs due to delayed gastric emptying (take them one hour before injecting pramlintide). 2. Should not be used with other drugs that delay gastric emptying or slow GI motility. 3. Potentiates insulin’s ability to cause hypoglycemia, increasing the risk of hypoglycemia 4. Nausea and vomiting are prominent side effects that may abate with continued use. 106 Mean Plasma Glucose Concentration in Type 1 DM Patients on Regular Insulin Compared with Pramlintide plus Regular Insulin 107 Mean Plasma Glucose Concentration in Type 1 DM Patients on Regular Insulin Compared with Pramlintide plus Regular Insulin Symlin® prescribing information 108 Possible Problems for Pregnant Diabetics 109 Possible Problems for Pregnant Diabetics 1. Increased incidence of birth defects. - This is possibly because insulin is a growth factor 2. Premature labor that may be related to the maturation of the placenta 3. Fetal macrosomia (big body) and organomegaly (big organs) 110 Infants of Diabetic Mothers 111 Infants of Diabetic Mothers 1. Glucose crosses the placenta. 2. Fetal pancreas responds to hyperglycemia by secreting high levels of insulin. - If the mother’s glucose is high, the baby’s pancreas will pour out insulin to decrease glucose, but it cannot because the glucose comes from the mother 3. Insulin stimulates fat deposition in infant, causing macrosomia. 4. Insulin stimulates glycogen deposition in infant, causing organomegaly. 5. Fetal hyperinsulinemia continues after delivery. - But when maternal glucose supply is cut off, this results in perinatal hypoglycemia because the glucose is no longer present 112 Pregnant Patients with Preexisting Type 1 DM 113 Pregnant Patients with Pre-existing Type 1 DM 1. Insulin requirements decrease at first and then continually increase as the pregnancy progresses. 2. With ideal control, fetal outcomes approach those of nondiabetic mothers. 3. Infants may require Caesarean section because of macrosomia and also should be monitored closely for hypoglycemia after birth. 4. Gestational and type 2 DM will be discussed later. 114 Type 2 Diabetes 115 Type 2 Diabetes •Part of a syndrome that includes insulin resistance. •People develop worsening insulin resistance over their lifetime and type 2 diabetes may be the result. •However, if people with insulin resistance take care of themselves and/or avoid weight gain, they can delay the onset or prevent type 2 diabetes. 116 What is Insulin Resistance? Diagram 117 What is Insulin Resistance? Diagram 118 Nestler, J.E., Assessment of insulin resistance. Scientific American Science and Medicine, 1: 1994, p. 59. Insulin Resistance 119 Insulin Resistance • The artificial pancreas machine was set to maintain their plasma insulin and glucose at 80mg – The insulin directed the cells to take up the glucose • For the normal people, the machine had to give a lot of glucose to maintain insulin, but for the hypertensives, the machine did not have to give as much glucose – The insulin was having greater effects on the controls than on the hypertensives • The hypertensive patients had insulin resistance and insulin did not work as well as in normal people 120 Explanation of Insulin Resistance Slide 121 Explanation of Insulin Resistance Slide • Two groups were compared – hypertensives and people without hypertension. • The subjects were hooked up to an “artificial pancreas” in the hospital. The machine can be set to maintain constant insulin and glucose levels in the subject. • The machine was set to maintain a plasma insulin level of 80 μU/ml and a plasma glucose of 80 mg/dl • Dextrose (glucose) was delivered through an IV line to maintain the plasma glucose at 80 mg/dl. • The normal subjects required higher quantities of dextrose via IV to maintain their blood sugar at 80 mg/dl than the hypertensive patients did. – Because their insulin was working better, whereas the hypertensives had insulin resistance Explanation of Insulin Resistance Slide (cont.) • The reason the normal subjects required more IV glucose was that the infused insulin was promoting glucose removal from the bloodstream – The removed glucose was being stored in the liver as glycogen or was entering fat and muscle cells. – Because it was removed from the bloodstream, in order for the subjects’ blood sugar to remain at 80 mg/dl, the machine replaced the removed glucose with the dextrose infusion. • In this experiment, the insulin infusion was more effective at causing glucose to be removed from the bloodstream in normal subjects than in the hypertensive subjects. • The hypertensive subjects had insulin resistance. Known Mediators of Insulin Resistance 124 Known Mediators of Insulin Resistance I. Acute: A. Cortisol increases insulin resistance B. Growth Hormone increases insulin resistance C. Epinephrine - increase D. Hyperinsulinemia - increase E. Hyperglycemia - increase II. Chronic: A. Receptor-mediated: Fewer insulin receptors on each cell (common in obesity) - as you gain weight, the number of insulin receptors on cells decreases, and if you lose weight the number increases B. Postreceptor: Second messenger system doesn’t work properly 125 Insulin Receptor Activation 126 Insulin Receptor Activation Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 703 127 Insulin Receptor Activation Description 128 Insulin Receptor Activation Description • When insulin binds to the receptor, the signaling proteins cause a number of effects within the cell – In post-messenger resistance, there is most likely something wrong inside of the cell – When insulin binds to its receptor, GLUT-4 becomes available to transport insulin • If there is a post-receptor problem, there will most likely be a problem in glucose and fat transport 129 The “Metabolic Syndrome” 130 The “Metabolic Syndrome” •A.K.A “syndrome X” or “diabesity” • Central obesity, hypertension, poorly regulated blood glucose, and dyslipidemia • A recent article states that ~1 in 3 Americans has the metabolic syndrome. • Not everyone with the metabolic syndrome develops type 2 DM, but such people are at increased risk when compared to people without the metabolic syndrome. • Lifestyle changes can delay or prevent type 2 DM. 131 Progression of Insulin Resistance to Type 2 DM and Beyond Diagram 132 Progression of Insulin Resistance to Type 2 DM and Beyond Insulin Sensitivity Normal glucose tolerance Insulin Secretion Diabetic HIGH NORMAL LOW Nonobese Normal Obese Normal Obese, Impaired Glucose Tolerance Obese, Diabetic Hyperinsulinemic Adapted from Nestler,JE, Assessment of Insulin Resistance,Science & Medicine, 1: 1994, p.58. Obese, Diabetic Hypoinsulinemic 13 3 Progression of Insulin Resistance to Type 2 DM and Beyond Description 134 Progression of Insulin Resistance to Type 2 DM and Beyond Description • A normal person who is not fat has normal insulin sensitivity or secretion • If the same person is fat, sensitivity decreases (resistance increases) and the pancreas secretes more insulin – The pancreas continues to increase the secretion of insulin in order to control the blood sugar • Fasting blood glucose is normal, but if given a glucose load (drink), the blood sugar will be too high – This is referred to as impaired glucose intolerance » Normally are fine, but if they has a lot of glucose, the pancreas cannot compensate • As the person ages, the secretion of insulin drops. It is still greater than normal, but it is not enough to control the fasting blood sugar. The person now has diabetes – The obese, diabetic hyperinsulinemic person can usually be treated with oral medications • The obese, hypoinsulinemic person may have to receive insulin because they do not have enough • With this bar graph, you can go forward and backward! – This is a good thing because the person can go back to normal (from obese, impaired) • Do not think that you can go all the way from obese, diabetic, hypoinsulinemic to normal 135 Commonalities of Type 2 Diabetes 136 Commonalities of Type 2 Diabetes 1. Pancreatic secretion of insulin is not sufficient to control blood sugar. - Insulin secretion may be very high, higher than in a normal person, but it cannot control the glucose because of the resistance 2. Receptor-mediated and postreceptor insulin resistance. - could be due to mutations on the proteins/receptors 3. Gluconeogenesis is not appropriately inhibited by insulin. 137 Type 2 DM is Composed of Multiple Vicious Cycles Diagram 138 Type 2 DM is Composed of Multiple Vicious Cycles 139 Vicious Cycles of Diabetes 140 Vicious Cycles of Diabetes • The type 2 people have several cycles that are working against them to make type 2 diabetes worse – Obesity – downregulation – resistance – hyperglycemia – resistance – High insulin – downreg. – resistance – Insulin – increased deposition of fat – obesity – downreg. – resistance – Decrease in pancreatic responsiveness – hyperglycemia – Gluconeogenesis – hyperglycemia 141 Presentation of Type 2 DM 142 Presentation of Type 2 DM 1. Most Type 2 patients are older and/or obese. - The age of onset is decreasing due to obesity 2. Present with complications of diabetes: fungal infections, UTI, vascular disease, etc. 3. Blood sugar may not be high enough for symptoms of polydipsia, polyuria, or polyphagia. 4. Evidently the amount of insulin present prevents ketosis and DKA. 143 Overview of Treatment for Type 2 144 Overview of Treatment for Type 2 1. Diet and exercise is the cornerstone treatment - Diet is even more important in type 2 than in type 1 2. Oral agents. 3. Insulin for those whose diabetes cannot be controlled with oral agents. 4. Home glucose monitoring is used for patients in all stages of type 2. 145 Diet and Exercise 146 Diet and Exercise • They are the cornerstone of treatment. • Diet lowers blood sugar and helps with weight loss. • Exercise lowers blood sugar without need for insulin and burns calories to help with weight loss • These strategies may be sufficient for mild cases. 147 Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 148 Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 149 Drugs for Type 2 DM to Increase the Secretion of Insulin – Sulfonylurea Drugs 150 Drugs for Type 2 DM to Increase the Secretion of Insulin – Sulfonylurea Drugs I. Most have a chemical structure called sulfonylurea. II. Stimulate “nonphysiologic” secretion of insulin independent of blood glucose concentrations. They can cause hypoglycemia. - if you have not eaten, insulin will go up III. Block an ATP-dependent potassium channel, preventing repolarization of the beta cell when the beta cell is depolarized and is secreting insulin 151 Mechanism of Action of the Sulfonylurea-like Drugs 152 Mechanism of Action of the Sulfonylurea-like Drugs Porth, Pathophysiology: Concepts of Altered Health States, 7th ed., 2005, Lippincott, Williams & Wilkins, p.990. 153 Drugs which Increase Insulin Secretion by Inhibiting ATP-sensitive K+ Channels 154 Drugs which Increase Insulin Secretion by Inhibiting ATP-sensitive K+ Channels •1st generation sulfonylureas: Acetohexamide Chlorpropamide Tolazamide Tolbutamide •2nd generation sulfonylureas are the ones that are used Glipzide Glyburide – the only one that is safe for pregnancy Glimepiride • Meglitinides (non-sulfonylurea, short acting) are used for meal control •Take them right before you eat and increase the secretion of insulin right before the meal and then they are metabolized quickly Repaglinide Nateglinide 155 More on Meliglitinides Repaglinide and Nateglinide 156 More on Meliglitinides Repaglinide and Nateglinide • Meliglitinides have been shown to interact with gemfibrozil, a lipid-lowering drug and with antifungals like ketoconazole and itraconazole, at the level of cytochrome P450 enzymes. •Metabolism of repaglinide and nateglinide may be delayed so that they reach higher plasma levels and have prolonged activity. •Hypoglycemia may result. 157 Adverse Effects and Contraindications of SulfonylureaLike Drugs 158 Adverse Effects and Contraindications of SulfonylureaLike Drugs 1. Hypoglycemia due to the non-physiologic secretion of insulin regardless of the blood glucose levels 2. Hepatotoxicity (elevated liver enzymes). 3. Patients with liver disease may metabolize these drugs more slowly, which will produce longer half-lives and higher peak concentrations. 4. Elderly patients with impaired renal function might also have slowed elimination. 5. N and V, rashes. (universal adverse effects) 6. Contraindicated in type 1, since the patient does not have insulin. 7. Contraindicated in pregnancy because of concerns about teratogenicity (except for glyburide). 159 Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 160 Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 161 Addressing the Cycle 162 Addressing the Cycle • Work by increasing insulin secretion – However, this will lead to the increased deposition of fat • This is a big problem, because then it increases the vicious cycle of obesity – These drugs are not used as often because there are better drugs 163 Drugs That Affect Insulin Resistance 164 Drugs That Affect Insulin Resistance Two Chemical Classes: A. Biguanides B. Thiazolidinediones (glitazones) 165 Biguanide Metformin 166 Biguanide Metformin • • Very widely used and good Decreases glucose production by the liver, increases glycogen synthesis, increases glucose utilization by fat and muscle, and inhibits lipolysis. • Insulin also does these • We don’t know how metformin does these things, but it does not do them by binding to the insulin receptor. • Can be used as monotherapy or in combination with a sulfonylurea or a glitazone. 167 Adverse Effects of Metformin 168 Adverse Effects of Metformin • May cause lactic acidosis in patients with any degree of renal impairment, which slows elimination of metformin and causes increased blood levels. • This is very serious 169 Beneficial Effects of Metformin 170 Beneficial Effects of Metformin • When used alone, it will not cause hypoglycemia because it does not affect the amount of insulin, it just makes its secretion more effective • When used as monotherapy, will not cause weight gain. 171 Patients with Renal Impairment? 172 Patients with Renal Impairment? •People that should not be given metformin •Elderly. •Diabetic. •Patients receiving contrast for radiologic procedures, such as angiography. Metformin must be withheld for several days prior to the procedure. •This is because the contrast causes renal impairment and may lead to lactic acidosis 173 Other Problems with Metformin 174 Other Problems with Metformin •Hepatic dysfunction may predispose the patient to lactic acidosis. •Nausea •Vomiting •Rashes •Metallic taste •One of the reasons that people stop taking metformin 175 Thiazolidinediones(glitazones) Mechanism of Action 176 Thiazolidinediones(glitazones) Mechanism of Action I. Pioglitazone II. Rosiglitazone (Avandia) • They interact with PPAR-gamma, a transcription factor important in differentiation of fat and muscle cells. • In some way, this improves insulin sensitivity, thus decreasing insulin resistance and decreasing blood sugar • These drugs are sometimes called “insulin sensitizers”. 177 Thiazolidinediones (glitazones) Uses and Advantages 178 Thiazolidinediones (glitazones) Uses and Advantages •May be used as monotherapy, or combined with a sulfonylurea, metformin, or insulin. •Will not cause hypoglycemia when used alone because they do not affect insulin secretion •Resumption of ovulation in anovulatory patients. •Ex. people with polycystic ovary syndrome (need to be aware of this in some people, because some diabetics may not want to ovulate) 179 Thiazolidinediones (glitazones) Adverse Effects 180 Thiazolidinediones (glitazones) Adverse Effects •Both pioglitazone and rosiglitazone cause edema which may worsen heart failure •Half-lives of both may be prolonged in patients with hepatic disease. • A previous member of this class (troglitazone) was removed from the market because of hepatotoxicity. This is probably not a concern with current drugs. •Possible cytochrome P450 interaction with birth control pills (probably not rosaglitazone). •The person may need to get a higher dose or use an alternative method of contraception 181 Safety of Rosiglitazone (Avandia) 182 Safety of Rosiglitazone (Avandia) • Although both rosiglitazone and pioglitazone have been shown to cause increased fluid retention and to exacerbate heart failure, a good bit of data suggests that rosiglitazone is worse in this regard than pioglitazone. – Rosiglitazone may be associated with increased cardiac morbidity and mortality due to heart failure • The FDA has issue the following recommendations. – Restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with Type 2 diabetes who cannot control their diabetes on other medications and are unable to take pioglitazone – GSK (the marketer) will develop a plan for restricted access to rosiglitazone • Stay tuned Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 184 Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways 185 Oral Drug Combinations 186 Oral Drug Combinations Glipizide/metformin 2 dosages Glyburide/metformin 2 dosages Rosiglitazone/metformin 3 dosages (Presumably will also have restricted access) Pioglitazone/metformin 2 dosages 187 The Problem with Oral Drug Combinations 188 The Problem with Oral Drug Combinations •With combinations, the likelihood of hypoglycemia may be increased. •This is especially true with combinations of metformin with a sulfonylurea-like drug. 189 Alpha-Glucosidase Inhibitors Ascarabose and Miglitol 190 Alpha-Glucosidase Inhibitors Ascarabose and Miglitol • These drugs prevent the absorption of sugars in the intestine by inhibiting the enzymes that degrade disaccharides (sucrose or lactose) to monosaccharides (glucose, galactose, and fructose). •Lactose – glucose and galactose •Those with lactose intolerance do not have the enzyme that breaks lactose into glucose and galactose, enzyme stays in the intestine, exerts osmotic pull, leads to a lot of gas •Sucrose – glucose and fructose? • Disaccharides cannot be absorbed by the intestine. • Since the disaccharides stay in the intestine, they provide increased food for bacteria, which produce a lot of gas and cramping • The disaccharides also increase the osmotic pressure of bowel contents, increasing the liquidity of the stool. •The drugs lead to lactose and sucrose intolerance, causing the symptoms of lactose intolerance 191 Alpha-Glucosidase Inhibitors Side Effects and Use 192 Alpha-Glucosidase Inhibitors Side Effects and Use Side Effects Diarrhea Flatulence •Antidiabetic activity is modest—these drugs are adjuncts to other treatment, not primary treatment. • Used in type 1 and type 2. 193 Effects of Classes of Diabetes Drugs 194 Effects of Classes of Diabetes Drugs 195 Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 814 Exenatide (Byetta®) 196 Exenatide (Byetta®) 1. A peptide drug that is an analog of a hormone called GLP-1 (a GLP-1 agonist). 2. Potentiates glucose-sensitive insulin secretion. - When your blood sugar is high, the pancreas secretes insulin and this drug will potentiate it so that it secretes more insulin - When the blood sugar is low, it will not do anything, so it will not cause hypoglycemia 3. Slows gastric emptying. 4. Approved for use with metformin, sulfonylureas or glitazones. 5. Not approved for type 1 (depends on pancreatic insulin secretion for effectiveness) - Because type 1 does not have a pancreas that can secrete insulin 197 Exenatide (Byetta®) Administration and Interactions 198 Exenatide (Byetta®) Administration and Interactions • Administered by subcutaneous injection 1 hour before breakfast and/or the evening meal. It is supplied in prefilled injection pens. • May cause hypoglycemia when administered with a sulfonylurea but not with metformin. • When initiating exenatide therapy, the dose of sulfonylurea should be reduced. •Not approved for use with nateglinide, repaglinide, or insulin. 199 Exenatide (Byetta®) Side Effects 200 Exenatide (Byetta®) Side Effects • Not to be used with alpha-glucosidase inhibitors. • Can delay onset of activity or lower the absorption of oral drugs (take them one hour before injection). • Nausea, vomiting, and diarrhea were the most frequent adverse events. • Pregnancy category C (evidence of fetal harm in animals) 201 Liraglutide (Victoza) a New GLP-1 Agonist 202 Liraglutide (Victoza) a New GLP-1 Agonist • Similar to exenatide, a peptide drug that must be injected. • Could be expected to behave very similarly to exenatide. • Unlike exenatide (at least to date) liraglutide caused thyroid tumors in animals. 203 DPP-4 Inhibitors 204 DPP-4 Inhibitors • Can be taken orally • DPP-4 is an enzyme that degrades several hormones secreted by the GI tract, including GLP-1 • These hormones, collectively called incretins, increase insulin secretion and decrease glucagon secretion in response to elevations in blood glucose. • DPP-4 inhibitors would be expected to have similar activity to exanatide (Byetta). But whereas Byetta must be injected because it is a protein that would be destroyed in the digestive tract, DPP-4 inhibitors are small molecules that remain effective when taken by mouth. 205 DPP-4 Inhibitors Sitagliptin (Januvia) and Saxagliptin (Onglyza) 206 DPP-4 Inhibitors Sitagliptin (Januvia) and Saxagliptin (Onglyza) • Used in Type 2 DM only (depends on pancreatic insulin secretion for effect). • Monotherapy (with diet and exercise) • Can be combined with metformin, a glitazone or glimepiride (sitagliptin) or glyburide (saxagliptin). • When taken alone, will not cause hypoglycemia. • Sitagliptin - renal excretion of unchanged drug (adjust for renal impairment) • Saxagliptin – both hepatic metabolism and renal excretion. Cytochrome P450 inhibitors slow metabolism (lower dose) • Once daily dosing 207 Pramlintide (Symlin®) 208 Pramlintide (Symlin®) • • Also approved for type 1 diabetes Approved for type 2 patients who require insulin with or without concurrent therapy with a sulfonylurea or metformin (not a glitazone). • Initial dose for type 2 patients is 60 μg to be increased to 120 μg when nausea subsides. • Insulin dose should be cut by half when initiating therapy. • After a stable dose of pramlintide (60 or 120 μg) is achieved, insulin dose should be titrated for optimal blood glucose control. • Other issues with pramlintide are the same as for type 1. 209 Insulin for Type 2 DM 210 Insulin for Type 2 DM • Can be used alone or in addition to oral agents. • Use is similar to that for type 1 •Newer evidence suggests that tight control of type 2 may be dangerous because the risk of hypoglycemia is great and not as beneficial as it is for type 1. Most clinicians will tolerate somewhat higher blood sugars in type 2 patients. 211 DKA and HHNC 212 DKA and HHNC HHNC is more common in type 2. DKA is more common in type 1. In HHNC, the pathway to ketone formation is not activated so there is no acidosis. Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 682 213 Diabetic Ketoacidosis 214 Diabetic Ketoacidosis • Out of control states of diabetes • DKA – There is an abundance of glucose but no insulin so the glucose cannot go into the cells – The body responds by breaking down triglycerides into fatty acids and then into ketones • The formation of ketones creates the ketoacidosis and gives off the fruity smell 215 HHNC • HHNC (hyperosmolar, hyperglycemic non-ketotic coma) – There is an abundance of glucose but it is not being used, which leads to the hyperglycemia • With too much glucose, osmotic diuresis occurs (glucose acts as a diuretic, like mannitol) – This leads to a loss of water, dehydration, and hemoconcentration • In HHNC, a lot of fluid is pulled into the vasculature and death may occur via cerebral edema 216 Acute Complications of Diabetes 217 Acute Complications of Diabetes • Diabetic ketoacidosis (DKA) is more common in type 1 • Hyperglycemic hyperosmolar non-ketotic (HHNC) coma is more common in type 2. • Treat both with an intravenous insulin infusion (regular insulin). Bring the blood sugar down slowly with frequent bedside blood sugar checks. • Ketonemia (ketones in the blood) of DKA may resolve more slowly than the hyperglycemia. If so, give D5W to keep the sugar up and do something with the ketones?* • Death may be due to cerebral edema caused by fluid shifts. • Hypoglycemia may result from too rapid insulin administration. 218 What is first line treatment for type 2 diabetes? 219 What is first line treatment for type 2 diabetes? 25% e D ie t & ex er ci s tid e Pr am lin ul in In s la ge nt s Oral agents Insulin Pramlintide Diet and exercise O ra 1. 2. 3. 4. 25% 25% 25% 220 Pregnancy in Type 2 Diabetics 221 Pregnancy in Type 2 Diabetics •Most oral diabetes drugs should not be used in pregnancy (except glyburide) because they might be teratogenic •They may be teratogenic. •They may not control blood glucose well enough to avoid complications in the infant. •Glyburide or insulin are the choices for pregnant type 2 diabetics. 222 Gestational Diabetes 223 Gestational Diabetes •Gestational diabetes is almost always type 2 diabetes that develops in a pregnant women because of the hormones •Hormones of pregnancy synthesized by the placenta increase insulin resistance. •If the woman had some degree of baseline insulin resistance (most likely due to pregnancy), she can be pushed over into the category of frank diabetes. 224 Gestational Diabetes Complications 225 Gestational Diabetes Complications •The pregnancy and infant are at risk for complications of a diabetic pregnancy, as mentioned before. •Organomegaly, macrosomia •After delivery, the placenta is delivered, insulin resistance returns to baseline and is again successfully compensated for by increased insulin secretion. •The mother is at risk for development of type 2 later in life. •There is some baseline resistance that could get worse if she gains weight or as she gets older 226 Gestational Diabetes Treatment 227 Gestational Diabetes Treatment • Gestational diabetics may be successfully treated with strict diet. • If not, treat with intensive insulin therapy. • Recent data confirms that gestational diabetes should be treated aggressively for good outcome of the pregnancy. 228