Therapy of Diabetes Mellitus

Transcription

1 2016 edition by Jayne S. Reuben, PhD Department of Biomedical Sciences University of South Carolina School of Medicine Greenville Originally developed by Elliott Chideckel, MD Department of Medicine Robert C. Byrd Health Sciences Center West Virginia University and Michael Mawhinney, PhD Departments of Urology and Pharmacology-Toxicology Robert C. Byrd Health Sciences Center West Virginia University Note to Students The fundamental purposes of all activities in the health-care professions are to help other people. Like all behavior, helping behavior becomes more effective and natural with practice. This exercise enables you to practice by helping your fellow students to learn basic science. Your skill at helping your fellow students should relate to your ability to help your patients in the future. This is a Patient-Oriented Problem-Solving (POPS) exercise designed for four students. Before beginning this session, you should have (a) studied the objectives designed to prepare you for it, (b) taken the pretest, and (c) reviewed the topics listed at the end of the pretest. Now, each of you should take one of the four color-coded parts and follow the directions in it. If your group has only three students, one of you should take two parts. If your group has more than four students, two should take turns with a part. Please begin by discussing the answers to the pretest.

2 Correct Answers to Pretest Questions In the discussion to follow, you are given the correct answers to some of the 10 pretest questions, along with explanations. Other students in your group have been given the answers to other questions. This allocation of answers and explanations is designed to encourage all members of your group to actively exchange ideas and concepts. First, study the answers in your booklet, and then EXPLAIN them to your group. Please don't simply read them to your classmates, and don't let your classmates read their answers to you. In explaining something to another person, most people gain and often transmit a better understanding of the subject. The pretest discussion and patient-oriented problem-solving parts of this activity are "open book ; be sure to refer to textbooks, notes, and other written resources whenever questions arise. To help you review any questions that you may have missed, you probably will want to make notes on your pretest answer sheets. However, avoid "collecting pages" for 'later study and understanding." Learn the concepts now so that later you will only need to review them. 2. (D) is correct. Insulin stimulates the activity of the facilitated diffusion (carrier-mediated transport with the concentration gradient that is not directly dependent upon ATP hydrolysis) of glucose into skeletal muscle and fat. In the liver, insulin stimulates glycogen synthesis via an increase in glycogen synthase activity but does not directly increase the rate of glucose uptake. 3. (B) is correct. Patients may excrete over 5 L of urine per day, which may contain over 100 g of glucose. Normal ranges for 24 h urine volume and glucose are 0.75 to 2.0 L and 0.25 to 0.6 g, respectively. In diabetic patients, the concentrations of filtered glucose presented to the proximal renal tubule exceed its maximal reabsorptive capacity. Excretion of ketoacids also contributes to the osmotic diuresis, but it is of secondary importance relative to the glucose load. It should be recognized that an osmotic diuresis, once under way, is characterized by inefficient tubular function, resulting in decreased reabsorption of glucose and many other molecules. In such a manner, the patient develops a net negative balance for phosphate, sodium, magnesium, and other ions/molecules. When your group has finished discussing the pretest, read Instructions for the Clinical Problem. 2

3 HANDOUT 1. Pharmacokinetics of the most commonly used insulin preparations. Type of Insulin Brand Name Generic Name Onset Peak Duration NovoLog Insulin aspart 15 min 30 to 90 min 3 to 5 hr Rapid-acting Apidra Insulin 15 min 30 to 90 min 3 to 5 hr glulisine Humalog Insulin lispro 15 min 30 to 90 min 3 to 5 hr Short-acting Humulin R Regular (R) 30 to 60 min 2 to 4 hr 5 to 8 hr Novolin R Intermediateacting Long-acting Pre-mixed NPH (intermediateacting) and regular (short-acting) Pre-mixed insulin lispro protamine suspension (intermediateacting) and insulin lispro (rapid-acting Pre-mixed insulin aspart protamine suspension (intermediateacting) and insulin aspart (rapid-acting) Humulin N NPH (N) 1 to 3 hr 8 hr 12 to 16 hr Novolin N Levemir Insulin 1 hour Peakless 20 to 26 hr detemir Lantus Insulin glargine Humulin 70% NPH and 30 to 60 min Varies 10 to 16 hr 70/30 30% regular Novolin 70/30 Humulin 50/50 Humalog Mix 75/25 Humalog Mix 50/50 NovoLog Mix 70/30 50% NPH and 50% regular 75% insulin lispro protamine and 25% insulin lispro 50% insulin lispro protamine and 50% insulin lispro 70% insulin aspart protamine and 30% insulin aspart 30 to 60 min Varies 10 to 16 hr 10 to 15 min Varies 10 to 16 hr 10 to 15 min Varies 10 to 16 hr 5 to 15 min Varies 10 to 16 hr

4 Instructions for the Clinical Problem In the remainder of this exercise, management of T1D and T2D diabetic patients will be discussed. Each of the four members of your group has the information about one episode in the medical history of one of these patients. Thus, you must share information and work together to solve the medical problems presented. When the episode for which you are responsible comes up, read it to the group and lead a discussion of the questions included with the episode. Pose each question to a different member of the group. Use the Discussion Notes provided as a guide for the discussion. DO NOT SIMPLY READ THE NOTES to the group. Learning is facilitated by active processes such as thinking about the questions and their possible solutions. Do not leave a question until every member of the group is satisfied completely with the answer. During the discussion, members of the group may consult textbooks, notes, and any other reference material. This is a group effort. Work together and teach one another. The group member whose part contains Episode 1 should now begin the discussion. 3

5 HANDOUT 2 - for use with Episode 1 METABOLIC SEQUENCE FOR THE DEVELOPMENT OF DIABETIC KETOACIDOSIS Insulin lack results in 1. a. Hyperglycemia due to i. decreased glucose uptake in skeletal muscle and fat, ii. increased hepatic glycogenolysis, and iii. increased muscle proteolysis and release of amino acids, which in the liver undergo increased conversion to glucose (gluconeogenesis). b. Hyperketonemia due to increased lipolysis and release of fatty acids, which in the liver undergo increased conversion to ketoacids. 2. Osmotic diuresis, because the hyperglycemia overwhelms the ability of the kidney to reabsorb glucose. 3. Hypovolemia, because renal fluid loss exceeds ability to match fluid intake. 4. Sympathetic nervous discharge that directly and indirectly (via increased glucagon secretion) exacerbates hyperglycemia and hyperketonemia. 5. Acidosis due to excessive ketoacid concentrations. 6. Compensatory hyperventilation (deep and rapid respirations, called Kussmaul breathing) in an attempt to compensate for the acidosis, but compensation is usually incomplete. 7. Reduced consciousness and possible coma due to a. hyperosmolarity (primarily), b. acidosis, and c. other unknown factors. 8. Greater hypovolemia due to difficulty in maintaining adequate fluid intake with reduced consciousness.

6 Episode 2 In the next clinic visit, the glucose values thus obtained showed that the patient s fasting glucose in the morning was 110 mg/dl (normal 80 to 120 mg/dl) but increased to 250 mg/dl prior to lunch. Throughout the rest of the day, her blood glucose values were in the low 100s. Her morning regular insulin was increased by 15 units and her glucose levels dropped to 105 mg/dl before lunch. To minimize glucose fluctuations, dietary instructions were given simultaneously with the new insulin regimen. The patient was told to avoid consuming rapidly absorbable carbohydrates to minimize major fluctuations in blood glucose. A diet was also designed to maintain ideal body weight and to minimize saturated fat intake. The patient was provided with a dietitian to help her develop recipes with the same distribution of calories for each of her three major meals. Within a month after starting the patient on the new insulin regimen, the patient had gained 10 pounds and started reducing her total daily caloric intake. As a result, she started experiencing frequent anxiety attacks in which she became very confused. In addition, she would sweat (diaphoresis), have palpitations (tachycardia), and feel as if she were going to pass out (vertigo). Because of these symptoms, the patient ultimately stopped the insulin therapy. She did well for approximately 9 months without exogenous insulin; after which, she experienced the return of polyuria and polydipsia. She returned to the clinic and the original insulin regimen was reinstituted. Please use the following questions and the Discussion Notes to guide the group discussion. Each member of the group should take the lead in answering at least one of the questions. 2.1 What dietary manipulations will alter lipid fractions and decrease the risk of atherosclerosis? 2.2 What are the changes in plasma lipids in the diabetic and what is their clinical significance? 2.3 What are the mechanisms for the increase in triglycerides in diabetes? 2.4 If the patient had maintained the appropriate diet and the established insulin regimen, what is the likely cause of the attacks of feeling faint? Why would the patient have palpitations? 4

7 Six years later, the patient married and became pregnant. By the third trimester, her blood glucose concentrations were running higher during the daytime and lower in the early morning. Her fasting blood glucose concentration at 7 AM had fallen below 60 mg/dl, while her pre-meal blood glucose values were abnormally high at over 200 mg/dl. She was still following the originally prescribed insulin regimen, which consisted of a 30 units of NPH human insulin and 10 units of regular human insulin one half hour prior to breakfast, 5 units of the regular insulin one half hour prior to lunch, 8 units of the regular insulin one half hour prior to dinner, and 10 units of NPH insulin at bedtime (11 PM). 2.5 Explain the morning hypoglycemia and the daytime hyperglycemia. What adjustments are necessary in her insulin regimen? What adjustment should be made postpartum? Use the Discussion notes on the next page and lead a discussion of the answers. 5

8 Discussion Notes for Questions in Episode Because weight gain is a common problem with insulin therapy (as well as some oral hypoglycemic medications), all patients diagnosed with diabetes should receive education about diet and exercise in order to enhance quality of life and to improve therapeutic outcomes. Maintenance of normal body weight is desired, since obesity causes elevations in triglycerides and depresses HDL cholesterol levels. Obesity also contributes to hypertension. Reductions in cholesterol and saturated fat intake will minimize elevations in LDL cholesterol. 2.2 Excess fatty acids in that are not oxidized or used for ketone synthesis in the liver can be converted to triacylglycerol which is packaged into very low-density lipoproteins (VLDL). In very poorly controlled type I diabetes, LDL cholesterol and plasma triglycerides (in the form of VLDL and chylomicrons) may be increased, representing significant risk factors for atherosclerosis. In better controlled type I diabetes, lipid levels resemble those of the nondiabetic population, except for modest increases in LDL cholesterol, which can be lowered with intensive insulin therapy. Intensive insulin therapy (DCCT study) may reduce the risk of macrovascular disease. Meta-analyses of more recent clinical trials (UKPDS, VADT, ACCORD, ADVANCE with or without PROactive) found that intensive glucose control reduced the risk for coronary heart disease and non-fatal myocardial infarction but did not significantly affect stroke, allcause or cardiovascular mortality. UKPDS: United Kingdom Prospective Diabetes Study, VADT: Veterans Affairs Diabetes Trial, ACCORD: Action to Control Cardiovascular Risk in Diabetes, ADVANCE: Action in Diabetes and Vascular Disease, Preterax and Diamicron MR Controlled Evaluation, PROactive: Prospective Pioglitazone Clinical Trial in Macrovascular Events. 2.3 Both an overproduction and impaired clearance of the VLDL are evident in the insulindeficient state. Increased hepatic synthesis of the VLDL triglyceride is driven by the elevated plasma levels of glucose and free fatty acids. Reduced clearance can be attributed to the reduced activity of an insulin-sensitive lipoprotein lipase on the capillary endothelial cell surface. This enzyme cleaves fatty acids from VLDL triglycerides, providing for fatty acid assimilation by adipose tissue. 2.4 The patient is exhibiting classic signs of insulin-induced hypoglycemia. Insulin levels have become excessive in this patient because she is receiving exogenous insulin and endogenous insulin production has also returned. As is often the case after the initial treatment and stabilization of juvenile diabetics, this patient has entered the honeymoon phase," in which insulin treatment has allowed the remaining pancreatic β-cells to temporarily recover from hyperstimulation. Such patients may not require insulin for months or years. Her palpitations are due to the increased release of catecholamines in response to the hypoglycemia. 2.5 The early morning hypoglycemia results from the combination of the normal overnight fast and the increased fetal consumption of glucose from the maternal circulation. Throughout the day, the intake of carbohydrate and protein combined with the normally 6

9 elevated levels of diabetogenic hormones of pregnancy (glucocorticoids, placental lactogen, estrogens, and progestins) produce hyperglycemia. Placental lactogen (chorionic somatomammotropin) has growth-hormone-like activity and is antagonistic to insulin action. Its principal action is to increase the supply of glucose to the fetus by altering maternal secretion of insulin which decreases maternal stores of fatty acids. Glucocorticoids increase plasma glucose through the multiple processes. (Defined in the answer to pretest question 9.) While estrogens alone do not cause glucose intolerance, estrogens enhance the diabetogenic effects of progestins. It is known that estrogen can increase plasma levels of growth hormone and cortisol, but the relationship of these changes to the hormone-induced glucose intolerance has not fully been defined. The patient's insulin requirement should be modified by lowering the dose of the bedtime NPH insulin and increasing the dose of the morning NPH insulin as well as the doses of regular insulin throughout the day. After pregnancy, the situation will reverse. Unless her postpartum insulin regimen is restored to what it was prior to pregnancy, hypoglycemic episodes will occur during the day and hyperglycemia will be manifest before breakfast. It should be noted that some of the latest guidelines for insulin use by the AACE show a preference for rapid acting analogs rather than regular insulin because of their better pharmacokinetic predictability and that the longer acting analogs are replacing NPH as the basal insulin because of their better glycemic control. The group member whose booklet contains Episode 3 should now take over as discussion leader. 7

10 HANDOUT 3 - for use with Episodes 3 and 4 Table of Major Antidiabetic Drugs and their Mechanisms of Action Insulins Drug Class Sulfonamides 1 st and 2 nd Generation Meglitinides (-glinides) Biguanide (metformin) Glitazones (-glitazone) α-glucosidase inhibitors DPP4 inhibitors (-gliptin) GLP-1 Receptor Agonists (-glutide) SGLT2 Inhibitors (-gliflozin) Amylin Mimetic (Pramlintide) Mechanism of Action Stimulate glucose transport into target cells via GLUT proteins. Approved for T1D and T2D. Stimulate insulin release by binding to a specific site on the β cell K-ATP channel complex (the sulfonylurea receptor, SUR) and inhibiting its activity. Stimulate insulin secretion by blocking K-ATP channels in pancreatic β cells. Lowers blood glucose by reducing hepatic glucose production and increasing peripheral glucose uptake via AMPK. Bind peroxisome proliferation activating receptor γ (PPARγ) receptors, resulting in enhanced glucose transport and utilization. Reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of α-glucosidase in the intestinal brush border. Increase insulin synthesis and release by inhibiting the inactivation of incretin hormones, GLP-1 and GIP. Synthetic GLP-1 receptor agonists whose binding results increases glucose-dependent insulin synthesis and secretion, decreases glucagon secretion, and delays gastric emptying. Inhibit renal glucose reabsorption in the PCT to cause glycosuria and lower serum glucose levels in patients with type 2 diabetes. Synthetic analog of human amylin which is packaged and co-secreted with insulin to control postprandial glucose. Binding to its receptors causes reduces glucagon release, delays gastric emptying, and promotes satiety. Approved for T1D and T2D. GLUT :glucose transporter; AMP:5' adenosine monophosphate-activated protein kinase; PCT: proximal convoluted tubules; GLP-1:glucagon-like peptide-1; GIP : glucose-dependent insulinotropic polypeptide (aka gastric inhibitory peptide)