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Pathophysiology & Diagnosis of Diabetes Mellitus

Pathophysiology & Diagnosis of Diabetes Mellitus. Presented by Dr. Otis W. Kirksey.

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Pathophysiology & Diagnosis of Diabetes Mellitus

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  1. Pathophysiology & Diagnosis of Diabetes Mellitus Presented by Dr. Otis W. Kirksey

  2. A.H. is a slender, 18 year old female, is referred to a the Diabetes clinic because a routine exam revealed glucosuria; a random plasma glucose ordered was 250 mg/dL. About 4 weeks before this visit, A.H. moved across the country to attend college. In retrospect, she has noted polydipsia, nocturia (3 times/night), fatigue, and a 12 lb weight loss over this period, which she attributed to the anziety associated with her move away from home and adjustment to her new environment. Her past medical history is remarkable for recurrent upper respiratory infections and 3 cases vaginal monilia over the past 6 months. Her family history is negative for diabetes, she is not taking any medications. Her physical exam is unremarkable. Ht 5’5”, Wt. 50kg, FPG 280 mg/dL, A1C 14%,

  3. Lecture Objectives Upon completion of this lecture series the student should be able to • Discuss the pathophysiolgical differences between type 1 diabetes and type 2 diabetes • Discuss the pathophysiolgical causes of secondary diabetes • Discuss the pathophysiolgical functions of insulin • Demonstrate understanding of normal carbohydrate metabolsim as well as the alterations which occur as a result of diabetes. • Recognize the common signs and symptoms associated with diabetes • Discuss criteria used to diagnosed diabetes • Differentiate between type 1 diabetes and type 2 diabetes in children

  4. Definition of Diabetes Mellitus Diabetes mellitus consists of a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both.

  5. Classification of Diabetes: Type 1 • Develops at any age, but most cases are diagnosed before the age of 30 years • Affected individuals experience significant weight loss, and signs of hyperglycemia which appear abruptly • Dependent on exogenous insulin to prevent ketoacidosis and sustain life • Coma and death can result from delayed diagnosis and/or treatment

  6. Classification of Diabetes: Type 2 • Approximately 90% of patients with diabetes have this type with disproportionate representation among the elderly and certain ethnic populations. • Usually diagnosed in the 3rd or 4th decade of life • Frequently asymptomatic at the time of diagnosis, but as many as 20% present with evidence of end organ damage. • Approximately 80% are obese at time of diagnosis

  7. Endogenous insulin levels may be normal, increased, or decreased; the need for exogenous insulin is variable • Insulin resistance is typically present with impaired glucose in the initial steps • Not prone to ketosis

  8. Classification of Diabetes: 2nd Diabetes 1. Maturity Onset Diabetes of the Young (MODY), glycogen synthase deficiency, and mitochondrial DNA markers 2. Pancreatic disorder such as, chronic pancreatitis, and pancreatectomy 3. Hormonal disorder such as Cushing syndrome, thyrotoxicosis, and acromegaly 4. Drug induced

  9. Classification of Diabetes: Gestational • Applies only in women in whom glucose intolerance develops or is first discovered during pregnancy

  10. Glucose Homeostasis Insulin Glucagon Amylin Catecholamines Growth Hormone Cortisol 70 – 140 mg/dl

  11. Physiologic Functions of Insulin • Primary role is to decrease blood glucose levels • Stimulates the storage of glucose as glycogen in liver and muscle (Glycogenesis) • Stimulates the synthesis of fatty acids and triglycerides • Promotes the uptake of glucose by adipose tissue to provide glycerol for triglyceride synthesis • Inhibits lipolysis and the resulting production of ketones • Enhances the incorporations of amino acids into proteins

  12. Physiologic Function of Glycogen and Other Counter Regulatory Hormones • Glucogon acts only in the liver to maintain blood glucose levels • Inhibits hepatic glycogen synthesis and stimulates glycogenolysis to release glucose • Stimulates gluconeogenesis • During prolonged fasting or starvation • Facilitates ketogenesis by allowing oxidation of FFA’s to keytones • Catecholamines, growth hormone and cortisol help to promote gluconeogenesis

  13. Carbohydrate Metabolism in the Fed State • Blood glucose concentrations rise after a meal • There is a subsequent release of insulin in response to the increase blood glucose Phase I occurs 10-20 minutes after stimulation, and is aimed at decreasing hepatic glucose production. Phase II, continued response to long term glucose stimulation, allows glucose to enter peripheral cells

  14. Fasting State Carbohydrate Metabolism • Falling blood glucose concentrations inhibit pancreatic insulin and Amylin release and stimulate the release of glucagon. • Glucagon stimulates glycogenolysis and gluconeogenesis to ensure a minimum blood glucose concentration ( at least 40 mg/dl) is maintained

  15. Carbohydrate Metabolism in the Patient With Diabetes • Due to the relative or absolute lack of insulin, blood glucose levels remain high after eating. • Despite abnormally high glucose levels, low insulin levels promote glucagon release which accelerates hepatic glucose production • Hyperglycemia is a result of excessive glucose production and under utilization • Chronic exposure to hyperglycemia can cause irreversible inability of the beta cell to secrete insulin (GLUCOSE TOXICITY)

  16. Signs and Symptoms • When blood glucose concentrations exceed the renal threshold of 180 mg/dl, glucose spill into the urine. This leads to symptoms of: • polyuria • polydipsia • polyphagia • weight loss • blurred vision • fatigue • poor wound healing • infections

  17. Sites of Action by Therapeutic Options Presently Available to Treat Type 2 Diabetes LIVER MUSCLE ADIPOSE TISSUE PANCREAS Biguanides Thiozolidindiones PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) INSULIN Secretion Sulfonylureas Meglitinides Insulin INTESTINE GLUCOSE ABSORPTION Alpha-glucosidase inhibitors Biguanides Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

  18. Emerging Strategies Major Metabolic Defects in Type 2 Diabetes • Peripheral insulin resistance in muscle and fat • Decreased pancreatic insulin secretion • Increased hepatic glucose output Haffner SM, et al. Diabetes Care, 1999

  19. Sulfonylureas Mechanism of Action • Pancreatic Effects • Sulfonylurea agents sensitize beta cells to glucose, increasing insulin secretion indirectly • Glucagon release from the pancreas is inhibited • Extrapancreatic Effects • Increasing insulin-receptor binding affinity • Increasing insulin effect by postreceptor action • Decreasing hepatic insulin extraction

  20. First Generation Acetohexamide (Dymelor) Chlorpropamide (Diabenese) Tolazamide (Tolinase) Tolbutamide (Orinase) Second Generation Glipizide (Glucotrol, Glucotrol XL) Glyburide (Diabeta, Mironase, Glynase) Glimepiride (Amaryl) ORAL SULFONYLUREAS

  21. Sulfonylureas Chemical Properties • Structurally related to thiazide diuretics and sulfonamide antibiotics • The second generation agents differ chemically from the first generation agents in that the side chain attached to the basic sulfonylurea structure is large and relative nonpolar. This change confers a more than 100-fold increase in hypoglycemic activity.

  22. Pharmacokinetic properties: • Chlorpropamide • The longest acting sulfonylurea (24-72 hours) • Approx. 80% metabolized in the liver to inactive and weakly active compounds. • Unchanged portion excreted in urine varies from 10-60% • Average half-life is 36 hours • Because of long half-life and variable renal excretion, should be used with caution in elderly and patients with renal impairment.

  23. Pharmacokinetic properties: • Glipizide • Intermediate acting with a duration of action of 12-24 hours. • Half-life is about 2-4 hours • Extensively metabolized by the liver to inactive products. • Food delays the rate of absorption but not its bioavailability. Administer 30 minutes before meals.

  24. Pharmacokinetic properties: • Glyburide • Duration of action is about 24 hours • Half-life is approximately 1.5-4 hours • Metabolized completely by the liver into inactive and weakly active compounds • 50% of metabolites excreted in the urine, the remainder excreted via the biliary tract. • Food does not delay the rate or extent or absorption.

  25. Drugs That Effect Protein Binding of Sulfonylureas

  26. Drugs That Effect The Metabolsim of Sulfonylureas • Decreased hepatic metabolism: • Phenylbutazone • Chloramphenicol • Dicumerol • Increased hepatic metabolism: • Chronic alcoholism • Phenobarbitol • Rifampin

  27. Pharmocodynamic Interactions That Decrease the Hypoglycemic Effect of Sulfonylureas

  28. Pharmacodynamic Interactions That Increase The Hypoglycemic Effects of Sulfonylureas

  29. Gastrointestinal Anorexia Heartburn Nausea and Vomiting Abdominal distention Flatulence Morbilliform, maculo-papular or urticarilial rash Alcohol flushing syndrome (chlorpropamide only) Hyponatremia (chlorpropamide, rarely tolbutamide Common Adverse Effects of Sulfonylureas:

  30. Skin reactions Photosensitivity Lichenoid eruptions Erythema multiforme Exfoliative dermatitis Hepatic disorders intrahepatic cholestasis (chlorpropamide) Hepatitis (glyburide) Hematologic disorders Leukopenia Agranulocytopenia Thrombocytopenia Aplastic anemia Hemolytic anemia Rare Adverse Effects of Sulfonylureas:

  31. Dosing of Sulfonylureas • Chlorpropamide • 0.1-0.5gm QD • Caution in elderly and patients with renal impairement. • Glyburide • 5-20mg QD or BId • Caution elderly and patients with renal impairement. Doses > 10mg should be divided

  32. Dosing of Sulfonylureas • Micronized Glyburide • 1.0-12mg QD • Daily doses > 6mg should be divided • Glipizide • 2.5-40mg QD or BID • Daily doses > 15mg should be divided • Glipizide Extended-Release • 5-20mg QD

  33. Dosing of Sulfonylureas • Glimepiride • Initially 1-2mg QD with breakfast or first main meal; • After reaching a dose of 2mg increase by up to 2mg at 1-2 week intervals if needed • The maximum recommended dose is 8 mg daily

  34. Prandin (Repaglinide) Mechanism of action - a nonsulfonylurea which increases insulin release from the pancreas. Different from sulfonylureas, dosed prior to meals in order to prevent increase in blood glucose after meals

  35. Clinical Efficacy of Meclinides • Monotherapy • Lowers HbA1c 2.1% for those not previously treated with insulin secretagogues • Lowers HbA1c 1.7% for those previously treated with insulin secretagogues • Combination with metformin • Additional 1% reduction in HbA1c

  36. Adverse Effects • Gastrointestinal • Diarrhea, constipation, vomiting • Hypoglycemia (16%) • Use cautiously in patients with liver impairment

  37. Drug Interactions • Metabolized by microsomal enzymes • levels may be elevated by: ketoconazole, itraconazole and erythromycin • levels may be decrease by: rifampicin, barbituates, and carbamazepine

  38. Dosing • HbA1c < 8% 0.5mg tid ac (Individuals not previously treated) • HbA1c > 8% 1-2 mg tid (Individuals previously treated) • Increase dose at one week intervals • Maximum dose 16 mg daily, or 4mg/dose

  39. Biguanides • Metformin (Glucophage) is an antihyperglycemic agent, marketed in 1995 in the USA for oral treatment of patients with Type 2 diabetes not adequately controlled by diet alone

  40. Metformin:Mechanism of Action • Decreases glucose production in the liver, increases insulin sensitivity and increases glucose uptake into the cells. It does not effect glucagon • Decreases glucose absorption in the stomach • Has no effect on pancreatic insulin secretion, but does require the presence of insulin to be effective • It has slightly favorable effect on serum lipids and promotes weight loss

  41. Clinical Efficacy of Metformin • Lowers fasting blood glucose approximately 60% • Lowers HbA1c 1 to 2% • Decreases Triglycerides (16%) • Decreases LDL (8%) • Decreases Total Chol (5%) • Increases HDL (2%) • Lowers endogenous insulin levels

  42. Adverse Effects • Hypoglycemia is rare • Unpleasant GI effects - a metallic taste, diarrhea, nausea, vomiting, and anorexia • Metformin should be temporarily (48 hours after) withheld in patients undergoing radiologic studies involving parenteral administration of iodinated contrast materials

  43. Lactic Acidosis- The occurrence appears to be rare with currently recommended doses. • All biguanides inhibit lactate metabolism, therefore increased concentrations due to renal impairment can cause lactic acidosis

  44. Symptoms of Lactic Acidosis • Weakness • Fatigue • Generalized muscle pain • Dizziness • Lightheadedness • Anemia

  45. Drug Interactions • Cimetidine increases serum concentrations of metformin • Metformin can decrease absorption of vitamin B12 and folic acid causing deficiency of these vitamins

  46. Dosage • 500 mg bid with morning and evening meals is usually the starting dose. • The usual dose is 850 mg bid • Maximum dose is 850 tid

  47. Monitoring Parameters • Serum glucose levels • GI side effects • Serum LFTs • Serum creatinine

  48. Contraindications • Renal dysfunction • Avoid in males with SrCr >1.5 or 1.4 in females • Cardiovascular failure • CHF (requiring pharmacology) • Dehydration • 48 hours after the use of radiographic contrast dye • recent myocardial infarction • Alcoholism or binge drinking • metabolic acidosis • Liver Disease • Pregnancy • Known Hypersensitivity

  49. Alpha Glucosidase Inhibitors • Arcarbose - approved in 1995 • do not mistake with aldose reductase inhibitors • Mechanism of action - blocks enzyme alpha glucosidase in the small intestines and reduces the absorption of carbohydrates. • Causes a blunted rise in postprandial blood glucose

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