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  2. 2. Session Outline  Introduction  Epidemiology  Etiologic factors  Pathogenesis & Pathophysiology  Clinical Presentation  Diagnosis  Treatment  Complications (Acute & Long term)  Diabetic health education 2
  3. 3. Introduction Diabetes mellitus (DM) is a chronic metabolic syndrome having hyperglycemia as a cardinal biochemical feature. There are two major types: Type – I and Type – II. Type-I DM: Common endocrine-metabolic disorder of childhood, caused by insulin deficiency due to damage to pancreatic β-cells. Type-II DM: Due to insulin resistance at the level of a skeletal muscles, liver, and adipose tissue. Morbidity and mortality from DM is related to acute and long term complications. Other types include: Gestational DM, Neonatal DM, Maturity onset diabetes of the young (MODY). 3
  4. 4. Type-I Vs. Type-II DM: Differentiation Demographics Type-I DM Type-II DM Family History 3-5% 74-100% Age Variable >10 years / Pubertal Gender Male = Female Female > Male Asymptomatic Presentation Rare Common BMI at Diagnosis < /=75 percentile >/= 85 percentile Autoimmune markers Common Uncommon 4
  5. 5. Epidemiology (Type-I DM) It accounts for 10% of all diabetes. Most cases of diabetes in children is type-I. (This presentation focuses on type-I Diabetes) However, it is not limited to children; 50% of individuals with Type-I DM present as adults. The incidence is currently on the rise. Globally 400,000 total new cases of type-I diabetes occur annually in all children under age 14 years. 5
  6. 6. Etiologic Factors (Type-I DM)  Type-I DM is characterized by autoimmune-mediated destruction of pancreatic beta cells culminating in absolute insulin deficiency.  Diabetes develops as a result of an interplay between both genetics and the environment. 1) Genetics: Evidences  Prevalence in siblings is 6% compared to 0.4% in the general population.  Risk increases when parents have diabetes.  Concordance rate among monozygotic twins is 30-65%. However majority of patients with type-I DM do not have family member with the disease (85%), so family history alone is not a reliable tool to identify those at risk of future diabetes. 6
  7. 7. Etiologic Factors (Type-I DM) 2) The environment: several observations support the role of the environment in the development of type-I DM: 50% monozygotic twins are discordant for type-I DM. Variation in incidence between urban and rural areas populated by the sane ethnic group. Change in incidence that occurs with migration(see later). Occurrence of seasonality 7
  8. 8. Etiologic Factors (Type-I DM)  The rate in Puerto Rico,17.4, is similar to that in Pennsylvania, but the rate in neighboring and ethnically similar Cuba is only 2.9.  Israeli children living in Canada have a fourfold greater incidence than those in Israel.  Where T1DM in the Indian population is very low, Indian children migrating to England from South Africa developed incidence rates comparable with those of English children in the community.  Japanese living in Hawaii are five times more likely to have T1DM than those in Japan.  Ethnic French and Italian children in Montreal have twice the incidence of diabetes as those in their native lands.  Factors like viral infections, diet, & stressors are believed to play a role in the causation of type-I DM. 8
  9. 9. Pathogenesis & Pathophysiology (Type-I DM)  In type-I DM, a genetically susceptible host develops autoimmunity to pancreatic β cells. What triggers this autoimmunity is unknown.  The natural history goes through the following events: 1) Initiation of autoimmunity: most occur before 2 years of age, with presence of multiple autoantibodies. This gap between appearance of antibodies & development of the disease may offer an opportunity for prevention. 2) Preclinical autoimmunity with progressive β cell loss. 3) Onset of clinical disease: time of onset depends on the number of autoantibodies, genetics, & environment. 4) Transient remission: Honeymoon period 5) Established disease 6) Development of complications. 9
  10. 10. Pathogenesis & Pathophysiology (Type-I DM) Pathophysiology: Insulin plays a major role in energy utilization by cells. Post prandial its level rises for energy storage (anabolic) and its level should drop during fasting state to mobilize stored energy for use (catabolic). Type-I DM is a progressive low insulin catabolic state. With insulinopenia, glucose use by muscle & adipose tissue decreases; plus glucose production by the liver via glycogenolysis & gluconeogenesis increases, both leading to hyperglycemia. Hyperglycemia causes osmotic diuresis with loss of calories, electrolytes → dehydration& physiologic stress. Secretion of stress hormones then follow. 10
  11. 11. Pathogenesis & Pathophysiology (Type-I DM) Pathophysiology: (Cont.) The stress hormones then, decompensate the metabolic process further: 1)Impair insulin secretion- Epinephrine 2)Antagonize insulin action – Epinephrine, Cortisol, GH. 3)Promote glucose production, lipolysis, and ketogenesis – Glucagon, Epinephrine, Cortisol, Growth hormone. 4)Decrease glucose utilization & clearance- Epinephrine, Cortisol, and Growth hormone (GH). Insulin depletion coupled with glucagon excess leads to further lipolysis and accumulation of free fatty acids which is shunted towards production of ketone bodies → METABOLIC ACIDOSIS. 11
  12. 12. Clinical Presentation (Type-I DM)  The clinical picture correlates with progressive loss of β cells.  Polyuria develops with further loss of the cells.  Nocturia  Compensatory polydipsia and polyphagia then occurs.  Weight loss follows when the dietary intake can not cope with urinary calorie loss.  With extremely low insulin level ketoacids accumulate and patient develop diabetic ketoacidosis (DKA).  About 20-40% of patients with type-I DM present with DKA for the first time. 12
  13. 13. Diagnosis (Type-I DM) The diagnosis of DM is usually straight forward. Presence of poly-symptoms, with dehydration and weight loss suggests the possibility of diabetes. Diagnostic criteria: 1)Impaired Glucose tolerance (IGT): Fasting blood sugar (FBS) 100-125mg/dL, or 2hour plasma glucose during OGTT > 140mg/dL and < 200mg/dL. 2)Diabetes Mellitus: Symptoms of diabetes plus: Random blood sugar (RBS) > 200mg/dL, or Fasting blood sugar (FBS) > 126mg/dL or 2hour plasma glucose during OGTT > 200mg/dL. NB: DKA must be looked for once diagnosis of DM is made. OGTT: Oral Glucose Tolerance Test 13
  14. 14. Treatment (Type-I DM)  Type of therapy depends on the patients initial clinical presentation and whether DKA has occurred or not.  Hence two groups of patients: 1) Patients with ketotic onset 2) Patients without ketosis on presentation.  Principles of therapy:  Insulin replacement  Life style modification  Regular follow up to assess glycemic control and look for complications. 14
  15. 15. Treatment (Type-I DM): Insulin 1) Children with non ketotic onset: 60-80% of cases.  These children have moderate symptoms, no/minimal dehydration, and not yet progressed to DKA.  The insulin dose required depends on pubertal status, but needs to be manipulated based on glycemic control.  The usual requirement is 0.7IU/Kg/day (Pre-pubertal), 1IU/Kg/day (Pubertal) & 1.2IU/Kg/day(Post-pubertal).  Therapy may be started with 60-70% of the above dose and adjusted as needed.  Frequent blood sugar check needs to be done especially during first few weeks, to adjust insulin dosage.  Self blood sugar monitoring is particularly helpful and this must be thought to the patient as part of care. 15
  16. 16. Treatment (Type-I DM): Insulin 2) Children with DKA: a)Those presenting with DKA for the 1st time: treatment is transitioned to that described for those with non ketotic onset once DKA has resolved. b)Those with history of DM developing DKA: these will be put on their previous insulin regimen used before the onset of DKA after resolution of the DKA. 16
  17. 17. Treatment (Type-I DM): Diet There is no much special dietary arrangement for the diabetic child; however, the following points need to be taken in to consideration: The caloric mixture should comprise approximately 55% carbohydrate, 30% fat, and 15% protein. 70% of the carbohydrate content should be derived from complex carbohydrates such as starch. Sucrose, highly refined sugars, & carbonated beverages should be limited. These are absorbed rapidly & cause wide swings in metabolic pattern. 17
  18. 18. Treatment (Type-I DM): Exercise No form of exercise should be prohibited for the diabetic child, but the following care needs to be taken: For patients with poor glycemic control, vigorous exercise may precipitate DKA. When planning a vigorous exercise additional carbohydrate need to be taken, and glucose from such sources as juice must be made available during and after the exercise. Watch for delayed hypoglycemia several hours after the exercise. On the other hand regular exercise has a beneficial effect on glycemic control by increasing the number of insulin receptors, and therefore it has to be encouraged. 18
  19. 19. Acute Complication of DM:DKA INTRODUCTION:DKA A common and life threatening medical emergency in patients with type I diabetes. May be an initial presentation of DM in a child in 20 – 40% of the time; for adults it is mostly a complication of established diabetes. Absolute/relative insulin deficiency resulting in hyperglycemia, dehydration and accumulation of ketone bodies in the blood with subsequent metabolic acidosis (pH < 7.30; serum bicarbonate < 15 mmol/L). 19
  20. 20. Acute Complication of DM:DKA Biochemical triad: ketonemia, hyperglycemia, and acidemia. One in 100 children with DKA dies in the USA. The severe the DKA, the higher the mortality and complications. Severity is defined by venous blood PH:  Mild DKA: PH 7.25 – 7.35  Moderate DKA: PH 7.15 – 7.25  Severe DKA: PH < 7.15 (Requires Intensive Care Rx) 20
  21. 21. Acute Complication of DM:DKA Causes/Precipitating factors: Initial presentation of type I diabetes mellitus (Delay in diagnosis of DKA in a young child with no history of diabetes)  Missed insulin injections Inadequate insulin dosage in a known diabetic patient Stress: Emotional, trauma, surgery without adequate insulin adjustment. Intercurrent illness/infection without proper insulin adjustment. 21
  22. 22. Acute Complication of DM:DKA Risk Factors: Low socioeconomic status/Less education Poorly controlled diabetes Previous history of DKA Peripubertal ages and adolescents Psychiatric illness Unstable family dynamics Use of insulin pump therapy 22
  23. 23. Acute Complication of DM:DKA Pathophysiology of DKA: A relative / absolute insulin deficiency is the factor. Insulin helps move glucose in to cells as a source of energy. In its absence body goes in to a catabolic state with breakdown of glycogen, protein, and fat in muscle, liver, and adipose tissue. Counter regulatory hormones stimulate glycogenolysis, gluconeogenesis, proteolysis, lipolysis, and ketogenesis in an attempt to provide more fuel to cells. Brain which consumes 20 % of body’s metabolic need cannot use fatty acids as energy, and depends on ketones produced by hepatic oxidation of fatty acids stimulated by glucagon. 23
  24. 24. Acute Complication of DM:DKA Hall Marks of DKA: Metabolic acidosis: caused by elevated plasma concentrations of the ketoacids acetoacetate and beta- hydroxy butyrate. Lactic acidosis occurs in large part from anaerobic glycolysis in hypoperfused tissues secondary to hypovolemia from osmotic diuresis. Hyperosmolality: in DKA, glucose is elevated about 400 mg/dL above normal, and the BUN is elevated by about 15 mg/dL. These elevations result in an additional osmolar load of about 22 and 5 mOsm/L, respectively. 24
  25. 25. Acute Complication of DM:DKA Hall Marks of DKA… Cont. Dehydration: secondary to osmotic diuresis and glycosuria. May progress to hypovolemic shock. Electrolyte disturbance: Hyponatremia: may be an artifact due to shift of water to ECF secondary to hyperglycemia. Correct true value by adding 2.8 mEq/L to obtained value for every 100mg/dL increase in serum glucose. Potassium: Initially, artificially elevated b/c during acidosis, K+ is exchanged for H+I (Intracellular K+ moves to ECF) Patients are usually total body K+ depleted and serum K+ levels will drop rapidly with correction of acidosis. Best way to confirm is to see U wave and flat T wave on ECG. Hypophosphatemia: due to osmotic diuresis. 25
  26. 26. Acute Complication of DM:DKA Clinical evaluation: History: Triads of polydipsia, polyuria, polyphagia Vomiting, abdominal pain, difficult breathing Symptoms of infection Last insulin dose, ? Missed dose Any stressful situation? Physical: Vital signs, Hydration status, 26
  27. 27. Acute Complication of DM:DKA Diagnosis: Diagnosis of DKA is established biochemically as: A venous pH <7.3 or Serum bicarbonate concentration <15 mmol/L, Serum glucose concentration >200 mg/dL together with ketonemia, glucosuria, & Ketonuria and associated clinical features. 27
  28. 28. Acute Complication of DM:DKA Work Up: Blood sugar Urine ketones Serum electrolytes CBC and infection screen BUN and Creatinine Imaging studies guided by clinical scenario Venous blood PH 28
  29. 29. Acute Complication of DM:DKA PRINCIPLES OF THERAPY: 1) Maintain ABC of life 2) Correct Dehydration: Fluids & Electrolytes 3) Correct hyperglycemia: Insulin 4) Address any precipitating factor, if identified. 5) Prevent future recurrence: Patient education. 29
  30. 30. Acute Complication of DM:DKA ABC of Life: Assess air way, breathing and circulation. Patients with GCS < 8 may need intubation to secure air way and prevent aspiration. Gastric decompression (NGT) to reduce risk of aspiration. Administer oxygen if patient is in shock or low oxygen saturation. 30
  31. 31. Acute Complication of DM:DKA FLUID THERAPY: Critical part of treating patients with DKA. The presence of even mild form of dehydration indicates at least 3L of fluid has been lost !! Give 10 – 20mL/Kg in the 1st hour; then replace deficit of 8.5% body weight and maintenance over next 23 hours. Fluid type: NS / RL until blood sugar reaches 200mg/dL when glucose containing fluid should be used. ELECTROLYTE: Potassium is the major concern. Should be started after initial fluid bolus and before commencing insulin therapy. Add 20 – 40 mEq/L of KCL to each bag of fluid if serum 31
  32. 32. Acute Complication of DM:DKA HYPERGLYCEMIA: Goal: to reduce blood sugar at 70 – 100 mg/dL/hr. The optimal administration of insulin is through insulin infuser at 0.1 IU/Kg/Hr. Continue insulin infusion until resolution of DKA (pH > 7.30, bicarbonate > 15 mEq/L), which usually takes longer than normalization of blood glucose level. Dose: Mix 50 IU of insulin in 50mL NS, and run at 0.1mL/Kg/Hr = 1mL per hour for a 10 Kg child. In our setting, short of infuser we use the older system of 4hourly insulin based on blood sugar level: >600mg/dL – 1IU/Kg, 300 – 600mg/dL – 0.5IU/Kg, 180 – 300mg/dL – 0.25IU/Kg, No insulin when blood sugar is less than 180mg/dL. 32
  33. 33. Acute Complication of DM:DKA Complication of DKA: Cerebral edema is a feared complication, specially related with therapy. Mechanism not well known, may be osmotic or vasogenic. Avail mannitol at the bed side in every critically sick DKA patient under therapy. Consider intubation and mechanical ventilation Alternative: hypertonic saline(3%) 5-10mL/Kg over 30 min can be used. 33
  34. 34. Chronic Complications of DM  The development of these complications depend on the extent of glycemic control, duration of diabetes and genetics.  How well the glycemic control has been is measured by the level of glycosylated hemoglobin. HbA1c represents the fraction of hemoglobin to which glucose has been non enzymatically attached.  HbA1c values of 6-7.9% represent good control, values of 8.0-9.9%, fair control, and values of 10% or higher, poor control.  HbA1c measurement reflects glucose level of preceding 2-3 months.  It has to be measured 3-4 times per year. 34
  35. 35. Chronic Complications of DM There are three major categories of chronic complications of DM: 1)Microvascular: Retinopathy, Nephropathy 2)Macrovascular: Coronary artery disease, cerebrovascular disease, & peripheral vascular disease. 3)Neuropathies: Peripheral and autonomic. 35
  36. 36. Chronic Complications of DM Pathogenesis of microvascular complications: several mechanisms have been proposed: Protein glycation: glucose binds irreversibly to proteins (collagens) by non enzymatic means, giving advanced glycation end products(AGE). The AGE accumulates in vascular intracellular proteins &cause structural tissue alterations with progressive occlusion of blood vessels. Example: Binding to Hemoglobin, Renal basement membrane. Polyol pathway: Sorbitol is formed from glucose by an enzyme aldose reductase. High sorbitol level in tissues (lens, nerves) causes and increased pressure & leakage in blood vessels → decreased vessel wall elasticity and microvascular hypertension, leading to local ischemia. 36
  37. 37. Diabetic Health Education Should address the following issues: Adherence to therapy & proper dosing. Self injection techniques & injection site care. Appropriate drug storage. Symptoms of hypoglycemia. Dietary management. Regular exercise & caution with vigorous exercise. Need for regular follow up & hygiene (oral, foot,…) Self blood sugar monitoring & interpretation of results. Awareness & avoidance of precipitating factors of DKA. Psychosocial support & counseling. 37