UPDATE ON UPDATE ON CHILDHOOD CHILDHOOD

DIABETES MELLITUSDIABETES MELLITUS

Abdelaziz 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

DiabeticPlasma >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 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 -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