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 b-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 b-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 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.

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

Cows 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 (b-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 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.

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 b-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