UPDATE ON CHILDHOOD DIABETES MELLITUS

Abdelaziz Elamin MD, PhD, FRCPCH Professor of Child Health Sultan 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 F-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 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.

DIAGNOSTIC CRITERIA
 Fasting blood glucose level  Diabetic
 Plasma >7.0 mmol  Capillary >6.0 mmol

 2 hours after glucose load

(Plasma or capillary BS)

 IGT
 7.8-11.0

 IGT
 Plasma 6.0-6.9 mmol  Capillary 5.6-6.0 mmol

 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 F-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 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

AUTOIMMUNITY
 Circulating antibodies against F-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
 Viruses
 Coxaschie B  Mumps  Rubella  Reoviruses

 Nutrition & dietary factors

 Cow s milk protein  Contaminated sea food

OTHER MODIFYING FACTORS

 The counter-regulatory hormones:
glucagon cortisol, catecholamines thyroxin, GH & somatostatin sex 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 (F-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

loss

 DKA  Accidental diagnosis  Anorexia 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 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.

HONEYMOON PERIOD
 Due to F-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: DKA Hypoglycemia  Late-onset: Retinopathy Neuropathy Nephropathy Ischemic 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-months  Home 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 F-chains.  Discovered by Bants & Best in 1921.  Animal types (porcine & bovine) were used before the introduction of humanlike 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)
 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

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 acting
Insulin Lispro Insulin Aspart

 Long acting without peak action to simulate normal basal 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  Somogis 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 for Newly diagnosed Prolonged the honey moon For high risk children  Immune modulating drugs Nicotinamide mycophenolate

GENE THERAPY
 Blocks the immunologic attack against islet-cells by DNAplasmids encoding self antigen.  Gene encode cytokine inhibitors.  Modifying gene expressed isletcell antigens like GAD.

PREDICTION OF DIABETES
 Sensitive & specific immunologic markers
 GAD Antibodies  GLIMA antibodies  IA-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