NELSONS HOUR:

DIABETES MELLITUS IN
CHILDREN
REY KEVIN Q. GARCIA
POST-GRADUATE INTERN

OBJECTIVES
Know the natural history of insulin-dependent
diabetes mellitus (type 1)
Know the principles of effective management: insulin,
diet and exercise
Know the value of Hgb A1c as an index of long term
glycemic control

CLASSIFICATION OF DM
Type 1 Diabetes Mellitus
(T1DM)
Insulin-dependent DM/
Juvenile Diabetes
Results from the deficiency of
insulin secretion because of
pancreatic cell damage

Type 2 Diabetes Mellitus

(T2DM)
Non-insulin dependent DM/
Adult-onset DM
A consequence of insulin
resistance occurring at the level of
the skeletal muscle, liver and
adipose tissue, with various
degrees of B-cell impairment

Onset occurs predominantly in

childhood with a median age of 715 years

Most prevalent in adults; Children

and adolescents with this type are
usually obese

CLASSIFICATION OF DM (CONT.)
Type 1 Diabetes Mellitus
(T1DM)

Usually ill at the time of

diagnosis; presentation rarely
spans more than a few weeks
Autoantibodies to B-cell
antigens are detected in
affected subjects
Associated with other
autoimmune diseases such as
thyroiditis, celiac disease and

Type 2 Diabetes Mellitus

(T2DM)
Seek medical help due to
excessive weight gain and fatigue
and/or incidental finding of
glycosuria
Acanthosis nigricans (dark
pigmentation of skin creases in
the nape of the neck) is present in
majority

IMPAIRED GLUCOSE TOLERANCE

Metabolic stage that is intermediate between normal
glucose homeostasis and diabetes
Euglycemic in daily lives with normal and nearly
normal glycated hemoglobin levels
Manifest hyperglycemia only when challenged with
oral glucose load used after the standardized oral
glucose tolerance test

TYPE 1 DIABETES MELLITUS

TYPE 1 DM: EPIDEMIOLOGY

Accounts for 10% of all cases of DM affecting 15
million people in the world
Accounts for most cases of DM in childhood; 50% of
individuals with T1DM present as adults
Girls and boys are equally affected
Peak presentation in two age groups:
5-7 year of age
Time of puberty

TYPE 1 DM: EPIDEMIOLOGY

Relative
Affected
Sibling
Father
Mother
Child
Gen
Population

Risk of
Diabetes
6%
5-6%
3-4%
3%
0.4%

Type of
Twin
Monozygotic
Dizygotic

Concordance
Rate
30-65 %
6-10 %

* 85% of newly diagnosed type 1 DM patients DO

NOT have a family member with T1DM

TYPE 1 DM: PATHOGENESIS & NATURAL

HISTORY
The natural history of type 1 DM involves the ff steps:
Initiation of autoimmunity

Preclinical autoimmunity with progressive loss of beta

cell function
Onset of clinical disease
Transient remission (honeymoon period)
Established Disease
Development of Complications

1. INITIATION OF AUTOIMMUNITY
A genetically susceptible host develops autoimmunity
against the hosts own beta cells.
Genetic susceptibility is determined by several genes with
the largest contribution coming from variants of HLA; the
major histocompatibility complex is a large genomic
region that contains a number of genes related to immune
system function
HLA Class II genes are the ones strongly associated with
T1DM and explains 40-50% of the genetic risk of T1DM
HLA DR3/4-DQ2/8 genotype has a 1 in 20 genetic risk
(compared to 1 in 300 in the general population)

 What triggers this autoimmune response remains

unclear but the following are implicated
Viral infections (Rubella, enterovirus, mumps virus)
Diet in infancy (early introduction of Cows milk)
Lack of exposure to certain infections (Hygiene
hypothesis)
Psychologic stress

 Development of autoimmunity is associated with the appearance

of several autoantibodies:
1. Islet cell autoantibodies (ICAs)
2. Insulin autoantibodies (IAAs)
3. Glutamic acid decarboxylase 65 kDa
4. Tyrosine phosphatase insulinoma-associated 2
5. Zinc transporter 9 antibodies
Onset of autoimmunity: 2 years old

2. PRECLINICAL AUTOIMMUNITY W/
PROGRESSIVE LOSS OF BETA-CELL FUNCTION
Antibodies are a marker for the presence of
autoimmunity but the actual damage to beta cells is
primarily T-cell mediated.
Histologic analysis of the pancreas from pts with
recent-onset TID reveals insulitis, with an infiltration
of the iselts of Langerhans by mononuclear cells,
including T and B lymphocytes,
monocytes/macrophages and NK cells

ROLE OF AUTOANTIBODIES
The risk of clinical disease increases dramatically with an
increase in the number of autoantibodies:
30% of children with 1 antibody progress to DM
70% when 2 antibodies are present
90% when 3 antibodies are present
The higher antibody titers are more likely to progress to clinical
disease
Children in whom IAAs appeared within the 1st 2 yr of life
rapidly developed anti-islet cell antibodies and progressed to
diabetes more frequently

ROLE OF GENETICS IN DISEASE

PROGRESSION
High-risk HLA alleles (e.g. HLA DR3/4-DQ2/8 genotype)
are more likely to develop multiple antibodies and
progress to disease
Appearance of antibodies is more likely to predict
diabetes in those with a family history of diabetes vs
those with no family history of T1DM
Environmental factors induce transient autoimmunity
in many children, but those with genetic susceptibility
are more likely to see progression of autoimmunity and
eventual development of diabetes.

ROLE OF ENVIRONMENTAL FACTORS

Environmental factors may act as accelerators of

T1DM after the initial appearance of autoimmunity

3. ONSET OF CLINICAL DISEASE

Progressive beta cell destruction will eventually
present with clinical T1DM
It was thought that 90% of the total beta cell mass is
destroyed by the time clinical disease develops
Destruction is more rapid and more complete in
younger children
In older children and adults, the proportion of
surviving beta cells is greater (10-20%) and some
beta cells survive up to 30 yr after onset of diabetes.

4 . TRANSIENT REMISSION

A.k.a. Honeymoon Period

At the time of diagnosis, some viable beta cells are
still present and these may produce enough insulin to
lead to partial remission of the disease

5. ESTABLISHED DISEASE

Over time, almost all beta cells are destroyed

Patient becomes totally dependent on exogenous
insulin for survival.

6. COMPLICATIONS
Some patients develop secondary complications of diabetes
that appear to be related to how well-controlled the diabetes
has been
Microvascular Complications

Macrovascular Complications

Diabetic retinopathy

Coronary artery disease

Diabetic neuropathy

Peripheral arterial disease

Diabetic nephropathy

Stroke

CLINICAL MANIFESTATIONS
Decreasing B-cell mass with worsening insulinopenia,
progressive hypergylcemia and eventual ketoacidosis all
imply that symptoms steadily increase, from early
intermittent polyuria to DKA and coma, over weeks usually,
rather than months
Initially, intermittent polyuria or nocturia
Chronic hyperglycemia triggers more persistent diuresis,
nocturnal enuresis and polydipsia
Females may develop monilial vaginitis from the chronic
glycosuria

CLINICAL MANIFESTATIONS
Calories are lost in the urine (glycosuria), triggering a
compensatory hyperphagia
If hyperphagia does not keep pace with glycosuria, loss of body fat
ensues, with clinical weight loss and diminished subcutaneous
fat ensues
When extremely low levels of insulin are reached, ketoacids
accumulate and produce abdominal discomfort, nausea and
emesis; dehydration accelerates causing weakness or
orthostasis but polyuria persists
Ketoacidosis exacerbates symptoms and leads to Kussmaul
respirations, fruity breath odor, prolonged corrected Q-T
interval, diminished neurocognitive function and coma

CLINICAL MANIFESTATIONS
Younger Children/Infants
Progression of symptoms happens more quickly (over a few weeks)
Most weight loss is acute water loss as they will not have had
prolonged urinary loss of calories from glycosuria
Increased incidence of DKA at diagnosis
Adolescents
Course is usually more prolonged (over a few months)
Most weight loss represents fat loss from prolonged starvation
Progression of symptoms may be accelerated by stress or an
intercurrent illness or trauma.

TREATMENT
Excellent diabetes control involves many goals:
To maintain a balance between tight glucose
control and avoid hypoglycemia
To eliminate polyuria and nocturia
To prevent ketoacidosis
To permit normal growth and development with
minimal effects on lifestyle

INSULIN THERAPY
Initial daily dose is usually higher in (1) prepubertal children
and those (2) with DKA at the time presentation
Optimal insulin dose can only be determined empirically, with
frequent self-monitored blood glucose levels and insulin
adjustment by the diabetes team.

1. REGULAR INSULIN
Form hexamers which must dissociate into monomers
subcutaneously before being absorbed into the
circulation
Requires delaying the meal 30-60 mins after
injection for optimal effect
Profile limits postprandial glucose control, produces
prolonged peaks with excessive hypoglycemic effects
between meals and increases risk of nighttime
hypoglycemia.

2. NPH & LENTE

Inherent limits because they do not create a peakless
insulin level
Produces a significant hypoglycemic effect during
the midrange of their duration
Difficult to predict their interaction with fast-acting
insulins
When regular insulin is combined with NPH or Lente,
the composite insulin poorly mimics normal
endogenous insulin secretion

3. LISPRO & ASPART

Insulin analogs
Absorbed much quicker because they do not form
hexamers
Provide discrete pulses wih little if any overlap and
short tail effect
Allows better control of postmeal glucose increase
and reduces between-meal or nighttime
hypoglycemia

4. GLARGINE
Long-acting analog
Much flatter 24 hr profile; easier to predict the combined
effect of rapid bolus (lispro or aspart) on top of the basal
insulin
Postprandial glucose elevations are better controlled and
between-meal and nighttime hypoglycemia are reduced
Basal insulin glargine should be 25-30% of the total dose in
toddlers and 40-50% in older children
Remaining portion of the total daily dose is provided as
bolus insulin dosed by both the carbohydrate content of the
meal and the preprandial glucose value

4. GLARGINE
Long-acting analog
Much flatter 24 hr profile; easier to predict the combined
effect of rapid bolus (lispro or aspart) on top of the basal
insulin
Postprandial glucose elevations are better controlled and
between-meal and nighttime hypoglycemia are reduced
Basal insulin glargine should be 25-30% of the total dose in
toddlers and 40-50% in older children
Remaining portion of the total daily dose is provided as
bolus insulin dosed by both the carbohydrate content of the
meal and the preprandial glucose value

INSULIN THERAPY

Frequent blood glucose monitoring and insulin

adjustment are necessary in the 1st weeks as child
returns to routine activities and adapts to a new
nutritional schedule
The major physiologic limit to tight glucose control is
hypoglycemia

NUTRITIONAL MANAGEMENT
Nutrition is of critical
importance during childhood
and adolescence, when
appropriate energy intake is
required to meet the needs for
energy expenditure, growth
and pubertal development

NUTRITIONAL MANAGEMENT
Nutrient

% of
Calories

Recommended Daily Intake

Carbohydrates

55

70% should be derived from complex

carbohydrates

Fat

30

< 10% should be from saturated fats

Up to 10% from polyunsaturated fats
Remaining should be from
monounsaturated fats

Protein

15

----

Cholesterol

300mg

Sodium

Avoid excessive sodium; limit to 3,0004,000 if hypertensive

Fiber

>20 g/day

NUTRITIONAL MANAGEMENT
Sucrose and highly refined sugars should be limited as
they are rapidly absorbed and cause wide swings in the
metabolic pattern
Carbohydrate counting has become a mainstay in the
nutrition education and management of patients with DM.
This allows patient to adjust their insulin dosage to their
mealtime carbohydrate intake
Diet with high fiber content are useful in improving
control of blood glucose

NUTRITIONAL MANAGEMENT
Dietary fats from animal sources are reduced and
replaced by polyunsaturated fats from vegetable sources;
Substitute:
Margarine for butter
Vegetable oil for animal oils in cooking
Lean cuts of meat, poultry and fish for fatty meats

The intake of cholesterol is reduced by limiting the

number of egg yolks consumed

NUTRITIONAL MANAGEMENT

Ocassional excesses (treats) for birthdays and other

parties are permissible and tolerated to not foster
rebellion and stealth in obtaining desired food
Cakes and even candies are permissible on special
occasions as long as the food carbohydrate content is
adjusted to meal plan

EXERCISE
No form of exercise, including competitive sports, should be
forbidden from a child with diabetes
The major complication of exercise is the presence of a
hypoglycemic reaction during or within hours after
exercise
Regular exercise improves glucoregulation by increasing
insulin receptor number
In patients who are in poor metabolic control, vigorous
exercise may precipitate ketoacidosis because of the
exercise-induced increase in the counterregulatory
hormones

GLYCOSYLATED HEMOGLOBIN
A reliable index of long-term glycemic control
HbA1c represents the fraction of hemoglobin to which glucose
has been nonenzymatically attached in the blood stream
The formation of HbA1c continues irreversibly throughout the
red blood cells life span of approximately 120 days.
The higher the blood glucose concentration and the longer
the red blood cells exposure to it, the higher is the fraction
ofHbA1c
HbA1c measurement reflects the average blood glucose
concentration from the preceding 2-3 mo.

GLYCOSYLATED HEMOGLOBIN
Recommended that HbA1c measurements be obtained 34 times a year
The lower the HbA1c level, the more likely that
microvascular complications will be less severe, delayed
in appearance or even avoided altogether
Spuriously elevated in thalassemia (or other conditions
with elevated hemoglobin F)
Spuriously lower in sickle cell disease (or other
conditions with high red blood cell turnover)

Category

Individuals w/ diabetes, fair metabolic control

<6
6-7.5
7.6-

Individuals w/ diabetes, poor metabolic control

9.9
10%

Individuals without diabetes

Individuals w/ diabetes, good metabolic control

Age Group

Target Hba1c (%)

<5

7.5-9.0

5-11

6.5-8.0

12-15

6.0-7.5

16-18

5.5-7.0

REFERENCES

Nelsons Textbook of Pediatrics, 20th

edition