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UPDATE ON UPDATE ON CHILDHOOD CHILDHOOD
DIABETES MELLITUSDIABETES MELLITUSAbdelaziz Elamin MD, PhD, FRCPCH Professor of Child
HealthSultan Qaboos
University
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.
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.
OLD CLASSIFICATION (1985)
Type 1, Insulin-dependent (IDDM) Type 2, Non Insulin-dependent
(NIDDM)– obese– non-obese– MODY
IGT Gestational Diabetes
WHO CLASSIFICATION 2000
Is based on etiology not on type of treatment or age of the patient.
Type 1 Diabetes (idiopathic or autoimmune -cell
destruction) Type 2 Diabetes
(defects in insulin secretion or action) Other specific types
WHO CLASSIFICATION/2
Both type 1 & type 2 can be further subdivided into:Not insulin requiringInsulin requiring for controlInsulin 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.
DIAGNOSTIC CRITERIA Fasting blood
glucose level Diabetic
Plasma >7.0 mmolCapillary >6.0 mmol
IGT Plasma 6.0-6.9 mmol Capillary 5.6-6.0 mmol
2 hours after glucose load
(Plasma or capillary BS)
IGT7.8-11.0
Diabetic level> 11.1 (200 mg)
Types of Diabetes in Children
Type 1 diabetes mellitus accounts for >90% 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.
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
TRANSIENT NEONATAL DIABETES
Observed in both term & preterm babies, but more common in preterm
Caused by immaturity of islet -cells Polyuria & dehydration are prominent,
but baby looks well & suck vigorously Highly sensitive to insulin Disappears in 4-6 weeks
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.
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.
GENETIC FACTORSEvidence of genetics is shown
in Ethnic differencesFamilial clusteringHigh concordance rate in twinsSpecific genetic markersHigher incidence with genetic
syndromes or chromosomal defects
AUTOIMMUNITY Circulating antibodies against -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.
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.
ENVIRONMENTAL SUSPECTS
VirusesCoxaschie BMumpsRubellaReoviruses
Nutrition & dietary factorsCow’s milk proteinContaminated sea food
OTHER MODIFYING FACTORS
The counter-regulatory hormones:glucagoncortisol,catecholaminesthyroxin,GH & somatostatinsex hormones
Emotional stress
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 (-streptococci).
Similarly type 1 diabetes may be prevented by controlling the triggering factors in high risk persons.
CLINICAL PRESENTATIONS
Classical symptom triad: polyuria, polydipsia and
weight lossDKAAccidental diagnosisAnorexia nervosa like illness
DIAGNOSIS In symptomatic children a random
plasma glucose >11 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.
NATURAL HISTORY
Diagnosis & initiation of insulin Period of metabolic recovery Honeymoon phase State of total insulin
dependency
METABOLIC RECOVERYDuring metabolic recovery the patient
mayDevelop 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.
HONEYMOON PERIOD Due to -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.
COMPLICATIONS OF DIABETES
Acute:DKAHypoglycemia
Late-onset:Retinopathy NeuropathyNephropathyIschemic heart disease &
stroke
TREATMENT GOALS Prevent death & alleviate symptoms Achieve biochemical control Maintain growth & development Prevent acute complications Prevent or delay late-onset
complications
TREATMENT ELEMENTS Education Insulin therapy Diet and meal planning Monitoring
HbA1c every 2-monthsHome regular BG monitoring Home urine ketones tests when
indicated
EDUCATION Educate child & care givers
about: Diabetes Insulin Life-saving skills Recognition of Hypo & DKA Meal plan Sick-day management
INSULIN A polypeptide made of 2 -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.
FUNCTION OF INSULIN
Insulin being an anabolic hormone stimulates protein & fatty acids synthesis.
Insulin decreases blood sugar 1. By inhibiting hepatic
glycogenolysis and gluconeogenesis.
2. By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue.
TYPES OF INSULIN Short acting (neutral, soluble, regular)Short acting (neutral, soluble, regular)
Peak 2-3 hours & duration up to 8 hours Intermediate actingIntermediate 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)Long acting (lente, ultralente & PZI)Peak 8-14 h & duration 20-36 h
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.
INSULIN REGIMENS Twice daily: either NPH alone or
NPH+SI. 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.
INSULIN ANALOGS Ultra short actingUltra short acting
Insulin Lispro Insulin Aspart
Long acting without peak Long acting without peak action to simulate normal action to simulate normal basal insulinbasal insulin Glargine
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.
ADVERSE EFFECTS OF INSULIN
Hypoglycemia Lipoatrophy Lipohypertrophy Obesity Insulin allergy Insulin antibodies Insulin induced edema
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
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.
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.
MONITORING Compliance (check records) HBG tests HbA1 every 2 months Insulin & meal plan Growth & development Well being & life style School & hobbies
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
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.
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
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.
PITFALLS OF MANAGEMENT
Delayed diagnosis of IDDM The honey-moon period Detection & treatment of NIDDY Problems with diagnosis &
treatment of DKA & hypoglycemia Somogi’s effect (dawn
phenomenon) may go unrecognized.
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.
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.
IMMUNE MODULATION Immunosuppressive therapy
forNewly diagnosedProlonged the honey moonFor high risk children
Immune modulating drugsNicotinamidemycophenolate
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.
PREDICTION OF DIABETES
Sensitive & specific immunologic markersGAD AntibodiesGLIMA antibodiesIA-2 antibodies
Sensitive genetic markers• HLA haplotypes• DQ molecular markers
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
Dreams are the seedlings of realities