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DIABETES MELLITUS

This reference provides information about diabetes mellitus, its impact on muscle and fat cells, and the role of insulin in regulating blood glucose levels. It also discusses the classification of diabetes and factors that can contribute to its development.

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DIABETES MELLITUS

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  1. References: Harrison’s Principles of Internal Medicine 17th edition http://cadre-diabetes.org/r_treatment_guidelines.asp http://care.diabetesjournals.org/cgi/reprint/31/Supplement_1/S12 http://www.aace.com/meetings/consensus/dcc/pdf/dccwhitepaper.pdf DIABETES MELLITUS

  2. ANATOMY • Endocrine pancreas (islet cells) Alpha cells: glucagon Beta cells: insulin

  3. Prevalence of Glycemic Abnormalities in the United States US Population: 275 Million in 2000 Undiagnosed diabetes 5.9 million Diagnosed type 1 diabetes ~1.0 million Additional 24.6 million with IGT Diagnosed type 2 diabetes 10 million Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm; Harris MI. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK; 1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001 10

  4. What happens when insulin production and secretion fails?  • destruction of Islet beta cells (diabetes type 1) • or loss of response to insulin (diabetes type 2/insulin resistance)

  5. INSULIN ACTION IN MUSCLE AND FAT CELLS • 1. Insulin finds and docks onto its receptor. • 2. A signal is sent to a pool of glucose transport proteins (Glut 4 Protein) located inside the cell. • 3. These Glut 4 proteins move rapidly up to the cell membrane and cause glucose channels to open. • 4. Glucose is "escorted " to the interior of the cell where enzymes will begin to break it down to fuel the work of the cell.

  6. Overall Effects of Insulin on Muscle and Fat • MUSCLE • blood glucose levels and availability of energy for muscle contraction • Conversion of glucose into glycogen • entry of amino acids from the blood • breakdown of existing muscle proteins into glucose

  7. Overall Effects of Insulin on Muscle • What is the effect of diabetes on muscle? • lack quick fuel to do their work. • Muscle cells then begin to convert glycogen stores to glucose • Muscle cells turn to fat and protein as fuel sources • The result is elevated blood glucose, loss of muscle mass, weight loss, weakness and fatigue.

  8. Overall Effects of Insulin on FAT • Storage of both excess blood glucose and blood fats inside the fat cell. • provides the body with an energy reserve that can be utilized during prolonged exercise or fasting. • Depositing of blood fats (triglycerides) into fat cells is increased

  9. What is the effect of diabetes on fat? • Glucose cannot get in to the fat cell to be converted to fat. • Fat is then broken down for energy • produces ketoacidosis in persons with Type I diabetes and gestational diabetes

  10. Factors that can contribute Reduced insulin secretion Decreased glucose utilization Increased hepatic glucose production

  11. Figure 338-1

  12. Criteria for Diagnosis • Symptoms of diabetes (3 P’s, etc) plus RBS >11.1 mmol/L (200 mg/dL) or • FBS>7 mmol/L (126 mg/dL) or • 2 hour PG>11.1 mmol/L (200 mg/dL) during OGTT (75 gm glucose) • Screening for people >45 yrs. every 3 yrs

  13. Regulation of Postprandial Glucose • A meal contains 6 to 20 times the glucose content of the blood • Normally, postprandial hyperglycemia is regulated by • Clearance of ingested glucose by the liver • Suppression of hepatic glucose production • Peripheral clearance of glucose

  14. Impaired Regulation ofPostprandial Glucose • In impaired glucose tolerance or diabetes, glucose regulation is impaired by • Delayed and reduced insulin secretion • Lack of suppression of glucagon • Hepatic and peripheral insulin resistance • Postprandial hyperglycemia results

  15. Who Should Be Tested for Diabetes? Symptoms suggesting diabetes: weight loss, hunger, urinary frequency, blurred vision Age >45 (>30 if patient has other risk factors) Prior IGT or IFG or family history of diabetes Prior gestational diabetes or baby weighing >9 lb Women with polycystic ovarian syndrome (PCOS) Obesity (BMI 25 kg/m2), especially adolescents African, Latino, Asian, or Native American ancestry History of vascular disease or hypertension American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14;AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82 19

  16. Classification of Diabetes Mellitusby Etiology Type 1 -cell destruction—complete lack of insulin Type 2 -cell dysfunction and insulin resistance Gestational -cell dysfunction and insulin resistance during pregnancy Other specific types • Genetic defects of -cell function • Exocrine pancreatic diseases • Endocrinopathies • Drug- or chemical-induced • Other rare forms 11

  17. Type 1 injury to β-cells of the pancreas, leading to complete β-cell destruction and total insulin deficiency 5% to 10% of all cases of diabetes and is most frequently diagnosed in children and adolescents Islet destruction mediated by T lymphocytes Genetic susceptibility (islet cell autoantibodies-GAD 65)

  18. Type 1 unrestrained glucose production by the liver and impaired uptake of glucose by peripheral target tissue Environmental factors Viruses (coxsackie, rubella) Bovine milk proteins Nitrosourea compounds (cured meat, cheese)

  19. Natural History Of “Pre”–Type 1 Diabetes Putative trigger -Cell mass 100% Cellular autoimmunity Circulating autoantibodies (ICA, GAD65) Loss of first-phase insulin response (IVGTT) Clinical onset— only 10% of-cells remain Glucose intolerance (OGTT) Genetic predisposition Insulitis-Cell injury “Pre”-diabetes Diabetes Time Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 14

  20. Type 2 Pathophysiology Impaired insulin secretion Insulin resistance Excessive hepatic glucose production Abnormal fat metabolism

  21. Pathogenesis of Type 2 DiabetesTwo Defects Impaired insulin secretion Hepatic insulin resistance Muscle/fat insulin resistance Hyperglycemia Excessive glucose production Impaired glucoseclearance Less glucose entersperipheral tissues More glucose entersthe blood stream Glycosuria 16

  22. Etiology of Type 2 DiabetesImpaired Insulin Secretion and Insulin Resistance Impaired insulin secretion Insulin resistance Genes and environment + Impaired glucose tolerance Type 2 diabetes

  23. Natural History of Type 2 Diabetes Impaired glucose tolerance Undiagnosed diabetes Known diabetes Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Microvascular complications Macrovascular complications Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 17

  24. Acute Complications • Absolute/relative insulin deficiency • Volume depletion • Acid-base abnormalities • Hyperglycemia + Ketosis • Hyperglycemic Hyperosmolar State • Type 2 • DKA

  25. Signs and symptoms of dehydration Nausea, vomiting, abdominal pain, thirst, polyuria Trigger: infection, inadequate insulin, cocaine, pregnancy

  26. DKA Hyperglycemia Ketosis Increased anion gap metabolic acidosis Bicarbonate <10 mmol/L Arterial pH 6.8-7.3 Low sodium Leukocytosis Serum ketones > 1:8 β-hydroxybutyrate Kidney function tests Fluid deficit 3-5 liters

  27. Goals of Treatment Hydration: 2-3 L 0.9 saline over the first 3 hours 0.45 saline at 150-300 ml/hr Short acting Insulin (IV 0.1 units/kg) then 0.1 units/kg/hr by continuous IV infusion K supplement Monitor anion gap, serum electrolytes, VS, I & O Glucose level: 150-250 mg

  28. Hyperosmolar Hyperglycemic State Elderly type 2 diabetic Trigger: other illness, sepsis, pneumonia, stroke, AMI Causes: inadequate fluid intake, relative insulin deficiency Absence of nausea, vomiting, abdominal pain, Kussmaul breathing

  29. Hyperglycemia Hyperosmolar >350 Prerenal azotemia Moderate ketonuria (sec. to starvation)

  30. Mechanisms of Complications 4 theories Exact mechanism???

  31. Microvascular Complications of Diabetes Retinopathy (proliferative and non-proliferative) Leading cause of blindness for ages 20-74 in the USA Neovascularization (hallmark - proliferative)

  32. Nephropathy -Annual urinary microalbumin screen (normal <30 mg/g creatinine) -leading cause of ESRD (USA) -Microalbuminuria 30-300 µg/mg (spot collection)

  33. Neuropathy -Annual foot exam with 10-g monofilament test - 50% of patients - poly, mono, autonomic - Distal symmetric neuropathy (most common)

  34. Gastointestinal Gastroparesis (most prominent) GUT Erectile dysfunction Lower Extremity Complications DM – leading cause of nontraumatic lower extremity amputation

  35. Macrovascular Complications CAD PAD CVD

  36. Enhanced coagulation process and impaired fibrinolysis (development of thrombosis)

  37. Identifying Cardiovascular Complications of Diabetes Assess CV risk factors annually and screen for coronary artery disease Perform stress ECG testing if Cardiac symptoms or abnormal ECG Peripheral or carotid vascular disease Multiple risk factors Plans to begin vigorous exercise program Refer to cardiologist if Positive exercise ECG test Unable to perform exercise test

  38. RISK FACTORS Dyslipidemia Hypertension

  39. A1C Reflects Both Fasting and Postprandial Hyperglycemia Plasma glucose (mg/dL) 300 Postprandial hyperglycemia 200 Fasting hyperglycemia 100 Normal 0 0600 1200 1800 2400 0600 Time of day Riddle MC. Diabetes Care. 1990;13:676-686 6

  40. Glycated hemoglobin hemoglobin A1C, HbA1c, or A1C reflects the glycemic exposure of a patient’s red blood cells over a 60- to 90-day period and has become the standard indicator of glycemic control in diabetes

  41. The CADRE Recommended A1C Normal A1C (nondiabetes): 4.0% - 6.0% Target A1C in diabetes: Lowest A1C possible without unacceptable hypoglycemia* Action recommended: A1C >7.0%

  42. ADA Treatment Goals Table 338-8 A1c <7% Premeal 90-130 mg/dL Peak postmeal <180 mg/dL BP < 130/80 Lipids LDL <100 mg/dL HDL >40 mg/dL TG <150 mg/dL

  43. Nutrition Table 338-9 Fat 20-35% Saturated<7% <200 mg/day of dietary cholesterol 2 or more servings of fish/week Carbohydrate 45-65% Protein 10-35%

  44. Antihyperglycemic AgentsMajor Sites of Action Glitazones -Glucosidase inhibitors – Plasma glucose + Carbohydrate absorption Glucose uptake GI tract Muscle/Fat + Glucose production – – Injected Metformin + Liver insulin – Insulin secretion + Secretagogues Pancreas

  45. Oral Antihyperglycemic Agentsfor Type 2 Diabetes Class Agents Secretagogue Sulfonylureas Repaglinide, nateglinide Biguanide Metformin α-Glucosidase inhibitor Acarbose, miglitol Glitazone (TZD) Pioglitazone, rosiglitazone

  46. Insulin SecretagoguesSulfonylureas, Repaglinide, and Nateglinide Mechanism of action Increase basal and/or postprandial insulin secretion Efficacy depends upon Functioning -cells Power Sulfonylureas, repaglinide: decrease A1C 1%–2% Nateglinide: decreases A1C 0.5%–1% Dosing Sulfonylureas: 1 or 2 times dailyRepaglinide, nateglinide: 3 or 4 times daily with meals Side effects Weight gain, allergy (rare) Main risk Hypoglycemia

  47. BiguanidesMetformin Primary mechanism Decreases hepatic glucoseof action production Efficacy depends upon Presence of insulin Power Decreases A1C 1%–2% Dosing 2 or 3 times daily (metformin) 1 or 2 times daily (metformin XR) Side effects Diarrhea, nausea Main risk Lactic acidosis

  48. α-Glucosidase InhibitorsAcarbose and Miglitol Mechanism of action Delay carbohydrate absorption Efficacy depends upon Postprandial hyperglycemia Power Decrease A1C 0.5%–1% Dosing 3 times daily Side effects Flatulence Main risk Liver enzyme elevation (rare) Riddle MC. Am Fam Physician. 1999;60:2613-2620; Lebovitz HE. Endocrinol Metab Clin North Am. 1997;26:539-551

  49. Glitazones (TZDs)Pioglitazone and Rosiglitazone Mechanism of action Enhance tissue response to insulin Efficacy depends upon Presence of insulin and resistanceto its action Power Decrease A1C 0.9%–1.6% Dosing Once daily Side effects Edema, weight gain, anemia Main risk Congestive heart failure

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