UPDATE ON CHILDHOOD DIABETES MELLITUS

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UPDATE ON CHILDHOOD DIABETES MELLITUS

• Abdelaziz Elamin
• MD, PhD, FRCPCH Professor of Child Health
• Sultan Qaboos University

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DEFINITION

• The term diabetes mellitus describes
• a metabolic disorder of multiple
• etiologies characterized by chronic
• hyperglycemia with disturbances of
• carbohydrate, fat and protein
• metabolism resulting from defects of
• insulin secretion, insulin action or
• both.

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DIABETES EPIDEMIOLOGY

• Diabetes is the most common endocrine problem
  is a major health hazard worldwide.
• Incidence of diabetes is alarmingly increasing
  all over the globe.
• Incidence of childhood diabetes range between
  3-50/100,000 worldwide in Oman it is estimated
  as 4/100000 per year.

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OLD CLASSIFICATION (1985)

• Type 1, Insulin-dependent (IDDM)
• Type 2, Non Insulin-dependent (NIDDM)
• obese
• non-obese
• MODY
• IGT
• Gestational Diabetes

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WHO CLASSIFICATION 2000

• Is based on etiology not on type of treatment or
  age of the patient.
• Type 1 Diabetes
• (idiopathic or autoimmune b-cell destruction)
• Type 2 Diabetes
• (defects in insulin secretion or action)
• Other specific types

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WHO CLASSIFICATION/2

• Both type 1 type 2 can be further subdivided
  into
• Not insulin requiring
• Insulin requiring for control
• Insulin requiring for survival
• Gestational diabetes is a separate entity
• Impaired Glucose Tolerance (IGT) indicates blood
  glucose levels between normal diabetic cut off
  points during glucose tolerance test.

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DIAGNOSTIC CRITERIA

• Fasting blood glucose level
• Diabetic
• Plasma gt7.0 mmol
• Capillary gt6.0 mmol
• IGT
• Plasma 6.0-6.9 mmol
• Capillary 5.6-6.0 mmol

• 2 hours after glucose load
• (Plasma or capillary BS)
• IGT
• 7.8-11.0
• Diabetic level
• gt 11.1 (200 mg)

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Types of Diabetes in Children

• Type 1 diabetes mellitus accounts for gt90 of
  cases.
• Type 2 diabetes is increasingly recognized in
  children with presentation like in adults.
• Permanent neonatal diabetes
• Transient neonatal diabetes
• Maturity-onset diabetes of the young
• Secondary diabetes e.g. in cystic fibrosis or
  Cushing syndrome.

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MODY

• Usually affects older children adolescents
• Not rare as previously considered
• 5 subclasses are identified, one subclass has
  specific mode of inheritance (AD)
• Not associated with immunologic or genetic
  markers
• Insulin resistance is present

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TRANSIENT NEONATAL DIABETES

• Observed in both term preterm babies, but more
  common in preterm
• Caused by immaturity of islet b-cells
• Polyuria dehydration are prominent, but baby
  looks well suck vigorously
• Highly sensitive to insulin
• Disappears in 4-6 weeks

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PERMANENT NEONATAL DIABETES

• A familial form of diabetes that appear shortly
  after birth continue for life
• The usual genetic immunologic markers of Type 1
  diabetes are absent
• Insulin requiring, but ketosis resistant
• Is often associated with other congenital
  anomalies syndromes e.g. Wolcott-Rallison
  syndrome.

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TYPE 1 DIABETES ETIOLOGY

• Type 1 diabetes mellitus is an autoimmune
  disease.
• It is triggered by environmental factors in
  genetically susceptible individuals.
• Both humoral cell-mediated immunity are
  stimulated.

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GENETIC FACTORS

• Evidence of genetics is shown in
• Ethnic differences
• Familial clustering
• High concordance rate in twins
• Specific genetic markers
• Higher incidence with genetic syndromes or
  chromosomal defects

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AUTOIMMUNITY

• Circulating antibodies against b-cells and
  insulin.
• Immunofluorescent antibodies lymphocyte
  infiltration around pancreatic islet cells.
• Evidence of immune system activation. Circulating
  immune complexes with high IgA low interferon
  levels.
• Association with other autoimmune diseases.

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ENVIRONMENTAL INFLUENCE

• Seasonal geographical variation.
• Migrants take on risk of new home.
• Evidence for rapid temporal changes.
• Suspicion of environmental agents causing disease
  which is confirmed by case-control experimental
  animal studies.

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ENVIRONMENTAL SUSPECTS

• Viruses
• Coxaschie B
• Mumps
• Rubella
• Reoviruses
• Nutrition dietary factors
• Cows milk protein
• Contaminated sea food

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OTHER MODIFYING FACTORS

• The counter-regulatory hormones
• glucagon
• cortisol,
• catecholamines
• thyroxin,
• GH somatostatin
• sex hormones
• Emotional stress

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ETIOLOGIC MODEL

• The etiologic model of type 1 diabetes resembles
  that of Rheumatic fever.
• Rheumatic fever was prevented by elimination of
  the triggering environ. factor (b-streptococci).
• Similarly type 1 diabetes may be prevented by
  controlling the triggering factors in high risk
  persons.

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CLINICAL PRESENTATIONS

• Classical symptom triad
• polyuria, polydipsia and weight loss
• DKA
• Accidental diagnosis
• Anorexia nervosa like illness

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DIAGNOSIS

• In symptomatic children a random plasma glucose
  gt11 mmol (200 mg) is
  diagnostic.
• A modified OGTT (fasting 2h) may be needed in
  asymptomatic children with hyperglycemia if the
  cause is not obvious.
• Remember acute infections in young non-diabetic
  children can cause hyperglycemia without
  ketoacidosis.

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NATURAL HISTORY

• Diagnosis initiation of insulin
• Period of metabolic recovery
• Honeymoon phase
• State of total insulin dependency

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METABOLIC RECOVERY

• During metabolic recovery the patient may
• Develop one or more of the following
• Hepatomegaly
• Peripheral edema
• Loss of hair
• Problem with visual acuity
• These are caused by deposition of
  glycogen metabolic re-balance.

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HONEYMOON PERIOD

• Due to b-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.
• Can confuse patients parents if not educated
  about it early.

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COMPLICATIONS OF DIABETES

• Acute
• DKA
• Hypoglycemia
• Late-onset
• Retinopathy
• Neuropathy
• Nephropathy
• Ischemic heart disease stroke

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TREATMENT GOALS

• Prevent death alleviate symptoms
• Achieve biochemical control
• Maintain growth development
• Prevent acute complications
• Prevent or delay late-onset complications

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TREATMENT ELEMENTS

• Education
• Insulin therapy
• Diet and meal planning
• Monitoring
• HbA1c every 2-months
• Home regular BG monitoring
• Home urine ketones tests when indicated

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EDUCATION

• Educate child care givers about
• Diabetes
• Insulin
• Life-saving skills
• Recognition of Hypo DKA
• Meal plan
• Sick-day management

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INSULIN

• A polypeptide made of 2 b-chains.
• Discovered by Bants Best in 1921.
• Animal types (porcine bovine) were used before
  the introduction of human-like insulin
  (DNA-recombinant types).
• Recently more potent insulin analogs are produced
  by changing aminoacid sequence.

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FUNCTION OF INSULIN

• Insulin being an anabolic hormone stimulates
  protein fatty acids synthesis.
• Insulin decreases blood sugar
• By inhibiting hepatic glycogenolysis and
  gluconeogenesis.
• By stimulating glucose uptake, utilization
  storage by the liver, muscles adipose tissue.

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TYPES OF INSULIN

• Short acting (neutral, soluble, regular)
• Peak 2-3 hours duration up to 8 hours
• Intermediate acting
• Isophane (peak 6-8 h duration 16-24 h)
• Biphasic (peak 4-6 h duration 12-20 h)
• Semilente (peak 5-7 h duration 12-18 h)
• Long acting (lente, ultralente PZI)
• Peak 8-14 h duration 20-36 h

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INSULIN CONCENTRATIONS

• Insulin is available in different concentrations
  40, 80 100 Unit/ml.
• WHO now recommends U 100 to be the only used
  insulin to prevent confusion.
• Special preparation for infusion pumps is soluble
  insulin 500 U/ml.

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INSULIN REGIMENS

• Twice daily either NPH alone or NPHSI.
• Thrice daily SI before each meal and NPH only
  before dinner.
• Intensive 4 times/day SI before meals NPH or
  Glargine at bed time.
• Continuous s/c infusion using pumps loaded with
  SI.

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INSULIN ANALOGS

• Ultra short acting
• Insulin Lispro
• Insulin Aspart
• Long acting without peak action to simulate
  normal basal insulin
• Glargine

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NEW INSULIN PREPARATIONS

• Inhaled insulin proved to be effective will be
  available within 2 years.
• Nasal insulin was not successful because of
  variable nasal absorption.
• Oral insulin preparations are under trials.

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ADVERSE EFFECTS OF INSULIN

• Hypoglycemia
• Lipoatrophy
• Lipohypertrophy
• Obesity
• Insulin allergy
• Insulin antibodies
• Insulin induced edema

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PRACTICAL PROBLEMS

• Non-availability of insulin in poor countries
• injection sites technique
• Insulin storage transfer
• Mixing insulin preparations
• Insulin school hours
• Adjusting insulin dose at home
• Sick-day management
• Recognition Rx of hypo at home

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DIET REGULATION

• Regular meal plans with calorie exchange options
  are encouraged.
• 50-60 of required energy to be obtained from
  complex carbohydrates.
• Distribute carbohydrate load evenly during the
  day preferably 3 meals 2 snacks with avoidance
  of simple sugars.
• Encouraged low salt, low saturated fats and high
  fiber diet.

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EXERCISE

• Decreases insulin requirement in diabetic
  subjects by increasing both sensitivity of muscle
  cells to insulin glucose utilization.
• It can precipitate hypoglycemia in the unprepared
  diabetic patient.
• It may worsen pre-existing diabetic retinopathy.

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MONITORING

• Compliance (check records)
• HBG tests
• HbA1 every 2 months
• Insulin meal plan
• Growth development
• Well being life style
• School hobbies

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ADVANCES IN MONITORING

• Smaller accurate meters for intermittent BG
  monitoring
• Glucowatch continuous monitoring using reverse
  iontophoresis to measure interstitial fluid
  glucose every 20 minutes
• Glucosensor that measures s/c capillary BG every
  5 minutes
• Implantable sensor with high low BG alarm

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ADVANCES IN MANAGEMENT

• Better understanding of diabetes allows more
  rational approach to therapy.
• Primary prevention could be possible if the
  triggering factors are identified.
• The DCCT studies proves beyond doubt that chronic
  diabetic complication can be controlled or
  prevented by strict glycemic control.

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TREATMENT MADE EASY

• Insulin pens new delivery products
• Handy insulin pumps
• fine micro needles
• Simple accurate glucometers
• Free educational material
• computer programs for comprehensive management
  monitoring

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TELECARE SYSTEMS

• IT has improved diabetes care
• Internet sites for education support
• Web-based systems for telecare are now available.
  The patient feeds his HBGM data and get the
  physician, nurse dietician advice on the
  required modification to diet insulin treatment.

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PITFALLS OF MANAGEMENT

• Delayed diagnosis of IDDM
• The honey-moon period
• Detection treatment of NIDDY
• Problems with diagnosis treatment of DKA
  hypoglycemia
• Somogis effect (dawn phenomenon) may go
  unrecognized.

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FUTURE PROMISES

• The cure for IDDM is successful islet cell
  transplantation, which will be available in the
  near future.
• Primary prevention by a vaccine or drug will be
  offered to at risk subjects identified by genetic
  studies.
• Gene modulation therapy for susceptible subjects
  is a promising preventive measure.

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Pancreas Islet Cell Transplantation

• Pancreas transplants are usually given to
  diabetics with end stage renal disease.
• Islet cell transplants, the ultimate treatment of
  type 1 diabetes is under trial in many centers in
  the US Europe with encouraging results but
  graft rejection recurrence of autoimmunity are
  serious limitations.

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IMMUNE MODULATION

• Immunosuppressive therapy for
• Newly diagnosed
• Prolonged the honey moon
• For high risk children
• Immune modulating drugs
• Nicotinamide
• mycophenolate

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GENE THERAPY

• Blocks the immunologic attack against islet-cells
  by DNA-plasmids encoding self antigen.
• Gene encode cytokine inhibitors.
• Modifying gene expressed islet-cell antigens like
  GAD.

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PREDICTION OF DIABETES

• Sensitive specific immunologic markers
• GAD Antibodies
• GLIMA antibodies
• IA-2 antibodies
• Sensitive genetic markers
• HLA haplotypes
• DQ molecular markers

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PREVENTION OF DIABETES

• Primary prevention
• Identification of diabetes gene
• Tampering with the immune system
• Elimination of environmental factor
• Secondary prevention
• Immunosuppressive therapy
• Tertiary prevention
• Tight metabolic control good monitoring

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Dreams are the seedlings of realities