26

• Diabetes Mellitus


  A metabolic disorder of multiple etiologies, characterised by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both
• Diabetes mellitus is the most common endocrine disease in childhood and adolescence
• Etiologic Classifications of Diabetes Mellitus


  • Type I diabetes (absolute insulin deficiency due to β-cell destruction)
  • Type 2 diabetes (defects in insulin secretion or action)
  • Other specific types (Genetic defects of β-cell function or insulin action, Diseases of the exocrine pancreas, Endocrinopathies, Drug-or Chemical- induced, Infections, Gestational diabetes mellitus, Neonatal diabetes mellitus)
• Neonatal diabetes mellitus


  Transient (without recurrence, disappears in 4-6 weeks or recurrence 7–20 yr later) or Permanent from onset – familial form of DM, often associated with other congenital anomalies and syndromes
• Type 1 Diabetes mellitus


  • A chronic autoimmune disease, girls and boys are equally affected, over 80% of childhood and adolescent diabetes, affects physical and emotional development, triggered by environmental factors in genetically susceptible individuals, both humoral & cell-mediated immunity are stimulated
• Overall, approximately 80,000 children under 15 years are estimated to develop type 1 diabetes annually worldwide
• Individuals with T1DM


  Confront serious lifestyle alterations that include: an absolute daily requirement for exogenous insulin, the need to monitor their own glucose level, need to pay attention to dietary intake
• Peaks of presentation of T1DM

  1. At 5–7 yr of age (increased exposure to infectious agents coincident with the beginning of school)

  2. At puberty(10-14 yrs) (correspond to the pubertal growth spurt induced by gonadal steroids and the increased pubertal growth hormone secretion)
• Morbidity and mortality of T1DM

  From acute metabolic derangements and from long-term complications related to metabolic disturbances (hyperglycemia)
• Environmental Factors for T1DM

  • Cow's milk?
  • Viruses ?
  • Nitrates?
• Genetic Susceptibility for T1DM

  • IDDM1: HLA
  • IDDM2: Insulin promoter
• Autoimmunity & Insulitis


  Destruction of pancreatic β cells
• Genetic/Familial Risk Of T1DM

  • Mother: 3-4%
  • Father: 5-6%
  • Siblings: 6%
  • Monozygotic Twins: 30 – 65%
  • Dizygotic twins: 6-10%
  • General Population (no family history): 0.4%
• T1DM is associated with other autoimmune diseases such as Thyroiditis, Celiac disease, Multiple sclerosis, and Addison disease
• Autoimmunity in T1DM


  Circulating antibodies against b-cells and insulin, immunofluorescent antibodies & lymphocyte infiltration around pancreatic islet cells, evidence of immune system activation with circulating immune complexes and high IgA & low interferon levels
• Risks for development of clinical T1DM

  • Number of antibodies (30% with 1 antibody, 70% when 2 antibodies and 90% when 3 are present)
  • High antibody titer
  • Age at which autoimmunity develops
• Environmental factors that trigger immune response in genetically susceptible individuals

  • Viral infections (Coxaschie B, Mumps, Rubella)
  • Vaccination
  • Diet (Cow's milk protein, Contaminated sea food)
  • Drugs
• Other modifying factors for T1DM

  • Counter-regulatory hormones (Glucagon, Cortisol, Catecholamines, Thyroxin, GH & somatostatin)
  • Sex hormones
  • Emotional stress
• Natural history of T1DM

  1. Initiation of autoimmunity (no dysglycemia, asymptomatic)

  2. Preclinical autoimmunity (with progressive loss of β-cell function)

  3. Onset of clinical disease

  4. Transient remission – "honeymoon period"

  5. Established disease

  6. Development of complications
• Impaired Glucose Tolerance (IGT)


  A metabolic stage that is intermediate between normal glucose homeostasis and diabetes, not a clinical entity but rather a risk factor for future diabetes and cardiovascular disease
• Pathogenesis of T1DM


  Genetic susceptibility → environmental triggering factors → Antigens similar to component of β cells (islet cell, insulin, glutamic acid decarboxylase) → Auto antibodies → Autoimmune attack leads to gradual and progressive destruction of β cells, with loss of insulin secretion
• It is estimated that 80–90% of the pancreatic islets are destroyed at clinical onset of T1DM
• Honeymoon Period


  Due to β-cell reserve optimal function & initiation of insulin therapy, leads to normal blood glucose level without exogenous insulin, observed in 50-60% of newly diagnosed patients & it can last up to one year but it always ends
• Pathophysiology of T1DM


  Insulin performs a critical role in the storage and retrieval of cellular fuel, its secretion in response to feeding is modulated by the interplay of neural, hormonal, and substrate-related mechanisms, T1DM is a progressive low-insulin catabolic state in which feeding does not reverse but rather exaggerates these catabolic processes, leading to postprandial hyperglycemia then fasting hyperglycemia
• Presentations of Childhood Type 1 Diabetes


  • Classic new onset (Non-emergency presentations)
  • Diabetic ketoacidosis (Emergency presentations)
  • Silent (asymptomatic) incidental discovery
• Classic new onset presentation

  Hyperglycemia without acidosis is the most common, symptoms are caused by hyperglycemia and include polyuria, polydipsia, weight loss despite increased appetite initially (polyphagia), and lethargy
• Progression of Diabetes Symptoms

  Initially, when only insulin reserve is limited, occasional hyperglycemia occurs, as diabetes develops, symptoms steadily increase with intermittent polyuria or nocturia, persistent diuresis, often with nocturnal enuresis, and polydipsia, females may develop monilial vaginitis due to the chronic glycosuria, vomiting, dehydration, abdominal pain and cerebral obtundation
• Diagnostic Criteria for Impaired Glucose Tolerance and Diabetes Mellitus

  • Impaired Glucose Tolerance (IGT): Fasting glucose 100-125 mg/dL, 2-hr plasma glucose during OGTT ≥140 mg/dL, but <200 mg/dL
  • Diabetes Mellitus (DM): Symptoms of DM plus RBS ≥200 mg/dL, or FBS ≥126 mg/dL, or 2-hr plasma glucose during OGTT ≥200 mg/dL
• Lab Investigations for Diabetes

  • RBS/FBS
  • Urine ketone & glucose
  • Hemoglobin A1c
  • Lipid profile (if obese)
• HbA1c


  A reliable index of long-term glycemic control, represents the fraction of hemoglobin to which glucose has been non enzymatically attached in the bloodstream, reflects the average blood glucose concentration from the preceding 2-3 months, will be measured 3-4 x /year, in non diabetic individuals it is usually less than 6%, in diabetics, values of 6–7.5% represent good metabolic control, values of 7.6–9.9%, fair control, and values of 10.0% or higher, poor control, the target HbA1c of <7.5% is the same regardless of the patient's age
• Diabetic Ketoacidosis (DKA)


  Children with type 1 diabetes often present with DKA (hyperglycemia and ketoacidosis), symptoms are similar but usually more severe than those of patients without acidosis, young children (<6 years of age) or from a low socioeconomic background are more likely to have DKA as their initial presentation
• Symptoms of DKA


  • Moderate to severe dehydration
  • Frequent vomiting and in some cases, abdominal pain
  • Continuing polyuria despite the presence of dehydration
  • Weight loss due to fluid loss and loss of muscle and fat
  • Flushed cheeks due to ketoacidosis
  • Acetone detected on the breath
  • Hyperventilation of diabetic ketoacidosis (Kussmaul respiration)
  • Disordered sensorium (disoriented, semi-comatose, or rarely comatose)
  • Shock (rapid pulse rate, poor peripheral circulation with peripheral cyanosis)
  • Hypotension (a very late sign and rare in children with diabetic ketoacidosis)
• Diagnosis of DKA


  Hyperglycemia, blood glucose > 200 mg/dl and Metabolic acidosis, venous pH < 7.30 and/or plasma bicarbonate < 15 meq/l and ketonuria
• DKA and its complications are the most common cause of mortality and morbidity in children with T1DM
• DKA occurs in 20-40% of children with new-onset diabetes and in children with known diabetes who omit insulin doses or who do not successfully manage an intercurrent illness
• DKA


  Characterized by severe depletion of water and electrolytes from both the intra- and extracellular fluid (ECF) compartments, despite their dehydration, patients generally continue to maintain normal or even have high blood pressure, possibly due to elevated plasma catecholamine concentrations, increased release of antidiuretic (ADH) in response to hyperosmolality, which increases blood pressure via V2 receptors, or other factors, considerable urine output persists because of glucosuria until extreme volume depletion leads to a critical decrease in renal blood flow and glomerular filtration
• Risk Factors for DKA

  • As initial presentation: Young age: < 5 years, Low socioeconomic background, Delayed diagnosis, Countries with low prevalence of type 1 diabetes mellitus
  • In established T1DM: Higher HbA1c (poor metabolic control), Peripubertal and adolescent girls, Psychiatric (including eating) disorders, Longer duration, Insulin omission, Previous episodes of DKA, Gastroenteritis with persistent vomiting and inability to maintain hydration, Challenging social and family circumstance
• Extracellular fluid (ECF) compartments

  Despite dehydration, patients generally continue to maintain normal or even have high blood pressure
• Reasons for high blood pressure in dehydrated patients

  • Elevated plasma catecholamine concentrations
  • Increased release of antidiuretic (ADH) in response to hyperosmolality, which increases blood pressure via V2 receptors
  • Other factors
• Considerable urine output persists because of glucosuria until extreme volume depletion leads to a critical decrease in renal blood flow and glomerular filtration