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Diabetes Mellitus MZ.Zamanpour MD 2 Definition & Diagnosis (1) Fasting serum glucose concentration ≥126 mg/dL, (2) a random venous plasma glucose ≥200 mg/dL with symptoms of hyperglycemia, (3) an abnormal oral glucose tolerance test (OGTT) with a 2-hour postprandial serum glucose concentration ≥200 mg/dL, and (4) a HgbA1c ≥6.5%. impaired fasting glucose (IFG) → (FBS: 100-125 mg/dl) impaired glucose tolerance (IGTT) → 2-hour plasma glucose following an OGTT is 140 to 199 mg/dL Sporadic hyperglycemia (Stress Hyperglycemia) 3 Insulin-dependent (type 1) Diabetes Mellitus Autoimmune destruction of insulin-producing beta cells (islets) (T cell– mediated)(Destruction of 80-90%) Environmental factors: Cow’s milk feeding at an early age Viral infectious agents (Coxsackie virus, cytomegalovirus, mumps, rubella) Vitamin D deficiency Perinatal factors Islet cell antibodies, Insulin autoantibodies, antibodies to tyrosine phosphatase IA-2, antibodies to glutamic acid decarboxylase, and others 1 antibody: 10-15% risk, 2 antibodies: 55-90% 4 5 Epidemiology &Genetics Siblings or offspring of patients with diabetes have a risk of 2% to 8% Identical twin has a 30% to 50% risk Class II DR and DQ HLA alleles (HLA DR3 and HLA DR4) increase the risk. More than 90% of children with DM1 possess HLA DR3 alleles, HLA DR4 alleles, or both 6 Clinical Manifestations Insulin deficiency usually first causes postprandial hyperglycemia and then fasting hyperglycemia Ketogenesis is a sign of more complete insulin deficiency Glycosuria occurs when the serum glucose concentration exceeds the renal threshold for glucose reabsorption (from 160 to 190 mg/dL). Polydipsia occurs as the patient attempts to compensate for the excess fluid losses Weight loss results from the persistent catabolic state and the loss of calories through glycosuria and ketonuria The classic presentation of DM1 includes polyuria, polydipsia, polyphagia, and weight loss Schematic representation of the autoimmune evolution of diabetes in genetically predisposed individuals 7 8 Diabetic Ketoacidosis Diagnosis: (1) The arterial pH is below 7.3 (2) The serum bicarbonate level is below 15 mEq/L (3) Ketones are elevated in serum or urine Pathophysiology Absence of adequate insulin secretion → Persistent partial hepatic oxidation of fatty acids to ketone bodies → High anion gap metabolic acidosis 9 Pathophysiology 10 Clinical Presentation Polyuria, polydipsia, nausea, and vomiting, Abdominal pain Abdomen may be tender from vomiting or distended secondary to a paralytic ileus. Küssmaul respirations fruity odor of acetone Altered mental status can: ranging from disorientation to coma 11 Laboratory Studies hyperglycemia (glucose concentrations ranging from 200-1000 mg/dL). Arterial pH <7.30, and the serum bicarbonate concentration <15 mEq/L. Serum Na concentrations may be elevated, normal, or low BUN can be elevated with prerenal azotemia secondary to dehydration WBC is usually elevated and can be left-shifted without implying the presence of infection Fever is unusual and should prompt a search for infectious sources 12 Careful replacement of fluid deficits Correction of acidosis and hyperglycemia via insulin administration Correction of electrolyte imbalances Monitoring for complications of treatment Complications cerebral edema 1-5% the most serious complication mortality rate of 20% to 80%. Subclinical cerebral edema is common in patients with DKA, occurs 6 to12 hours after therapy Risk factors: higher initial BUN concentration lower initial Pco2 failure of the serum sodium concentration to increase as glucose concentration decreases treatment with bicarbonate 13 Complications cerebral edema Clinical manifestation: Obtundation, Papilledema, Pupillary dilation or inequality, Hypertension, Bradycardia, and Apnea Treatment: Rapid use of IV mannitol, endotracheal intubation, and ventilation and may require the use of a subdural bolt 14 15 Other complications Intracranial thrombosis or infarction ATN with ARF caused by severe dehydration pancreatitis arrhythmias caused by electrolyte abnormalities pulmonary edema bowel ischemia Peripheral edema occurs commonly 24 to 48 hours after therapy is initiated and may be related to residual elevations in antidiuretic hormone and aldosterone 16 Transition to Outpatient Management Correction of acidosis: Ph≥7.3 & HCO3 ≥15 Patient tolerates oral feedings First SC insulin dose should be given 30 to 45 minutes before discontinuation of the IV insulin infusion (0.1 U/Kg) Insulin Dose: 0.5-0.7 U/kg/24h for prepubertals, 0.7-1 U/kg/24h for adolescents Available Insulin: fast-acting (bolus) insulin (lispro, aspart, or glulisine insulin) and long-acting (basal) insulin (glargine or detemir) at bedtime. BS monitoring: before each meal, at bedtime, and periodically at 2 to 3 am Honeymoon 17 Goals Intensive insulin therapy Maintaining blood glucose concentrations as close to normal as possible Delay the onset and slow the progression of complications of diabetes Attaining this goal can increase the risk of hypoglycemia Target glucose: Children younger than 5 years old: 80-180 mg/dl School-age children (5-12 y): 80-150 mg/dl Adolescents (12-18): 70-130 mg/dl 18 Available Insulin 19 Insulin Regimens Calculate total daily dose of insulin 30% to 50% are given as long-acting insulin Remainder is given as fast-acting insulin Correct for hyperglycemia Determine the insulin sensitivity using the 1800 rule Insulin:carbohydrate ratio: to calculate insulin for the carbohydrate content of food using 450 rule Newly diagnosed patients in the honeymoon period may require 0.4 to 0.6 U/kg/24 hours 20 Nutrition Calculate calorie according to patient’s age, activity Carbohydrates: 50% to 65% of the total calories Three meals & three snacks Protein 12% to 20% of the total calories Fat <30% of the total calories Saturated fat should contribute <10% of the total caloric intake Cholesterol intake should be less than 300 mg/24 hours 21 Blood Glucose Testing NPH & Regular: 6a.m, 10 a.m, 4 p.m, 10 p.m, 4-5 a.m Asp & Glr: Before each meal and 2-3 a.m During periods of illness or when blood glucose concentrations are higher than 300 mg/dL, urine ketones also should be tested Continuous glucose monitors (CBG) hemoglobin A1c (HgbA1c) reflect the average blood glucose concentration over the preceding 3 months HgbA1c should be measured four times a year children less than 6 years: 7.5%-8.5% ages 6 to 13 years HgbA1c target of less than 8% ages 13 to 18 years HgbA1c target of less than 7.5% 22 Complications & Other Disorders Retinopathy: Annual ophthalmologic examination After 3-5 y Nephropathy: Annual 24h urine for microalbuminuria After 3-5 y ACE-inhibitors for proteinuria Annual cholesterol measurements and periodic assessment of blood pressure are recommended Chronic autoimmune lymphocytic thyroiditis (Hashimoto Thyroiditis) TFT: Annually Celiac disease, IgA deficiency, Addison disease, and peptic ulcer disease 23 Hypoglycemia Patients in adequate or better control,: once or twice a week Severe episodes of hypoglycemia: 10% to 25% of these patients per year Defective counterregulatory responses also contribute to hypoglycemia Abnormal glucagon responses: within the first few years of the disease Abnormalities in epinephrine release: after a longer duration Hypoglycemia unawareness: 25% of patients Symptoms resulting from neuroglycopenia (headache, visual changes, confusion, irritability, or seizures) symptoms resulting from the catecholamine response (tremors, tachycardia, diaphoresis, or anxiety) Non-insulin−dependent (Type 2) Diabetes Mellitus 25 Pathophysiology & Epidemiology Peripheral insulin resistance Compensatory hyperinsulinemia Failure of the pancreas to Maintain adequate insulin secretion Prevalence of DM2 in children is increasing in parallel with childhood obesity Risk factors: Obesity, X syndrome, ethnicity, and a family history of DM2 Auto-antibodies to the pancreas are present among some NIDDMs Clinical Manifestations & Differential Diagnosis The same as those for DM1 Differentiating DM2 from DM1 in children on only clinical grounds can be challenging Acanthosis nigricans: Hyperkeratotic pigmentation in the nape of the neck and in flexural areas Ketoacidosis occurs far more commonly in DM1 Insulin or C-peptide responses to stimulation with oral carbohydrate Absence of islet cell autoreactivity 26 27 Therapy Asymptomatic patients with mildly elevated glucose values (126-200) Initially with lifestyle modifications→ dietary adjustments & ↑exercise New-onset, uncomplicated DM2 → oral agents (first line) Metformin Insulin secretagogue Lactic acidosis (rarely in renal insufficiency) Gastrointestinal upset (the most common) Insulin If adequate glycemic control is not achieved with lifestyle modifications and metformin If ketonuria or ketoacidosis occurs May be discontinued within weeks with continuation of oral medications Maturity-onset Diabetes Of Youth (MODY) Dominantly inherited Relatively mild diabetes Insulin resistance does not occur Insufficient insulin secretory response to glycemic stimulation 28