NELSONS HOUR:

3. Impaired Glucose Tolerance

DIABETES MELLITUS IN CHILDREN

By Rey Kevin Q. Garcia, AUFMC PGI

Objectives:
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glucose homeostasis and diabetes.

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Fasting glucose between 100-125 mg/dL

Euglycemic in daily lives with normal and nearly

Know the natural history of insulin dependent

diabetes mellitus (type 1)

Metabolic stage that is intermediate between normal

normal glycated hemoglobin levels

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Manifest hyperglycemia only when challenged with

Know the principles of effective management:

oral glucose load used after the standardized oral

insulin, diet and exercise

glucose tolerance test

Know the value of Hgb A1c as an index of long term

glycemic control

In the absence of pregnancy, it is not a clinical entity

but rather, a risk factor for future diabetes and CV
disease

Classification of Diabetes Mellitus

Often associated with insulin resistance syndrome

1. Type 1 Diabetes Mellitus (T1DM)

(syndrome X, metabolic syndrome) consisting of

Insulin-dependent DM / Juvenile diabetes

insulin resistance, compensatory hyperinsulinemia,

Results from the deficiency of insulin secretion

obesity, dyslipidemia of the high-triglyceride or low-

because of pancreatic cell damage

or high density lipoprotein type or both and

Most common endocrine-metabolic disorder of

hypertension.

childhood and adolescence

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Onset occurs predominantly in childhood with a

median age of 7-15 years

Autoantibodies to B-cell antigens such as islet cell

cytoplasm (ICA), insulin autoantibody (IAA),
antibodies to glutamic acid carboxylase and ICA512
are detected in affected subjects

Associated with other autoimmune diseases such as

thyroiditis, celiac disease and Addisons disease

2. Type 2 Diabetes Mellitus (T2DM)

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Non-insulin-dependent DM/ Adult-onset diabetes

A consequence of insulin resistance occurring at the

level of the skeletal muscle, liver and adipose tissue,
with various degrees of B-cell impairment

Most prevalent in adults; Children and adolescents

with this type are usually obese

More insidious; often seek of medical care due to

excessive wt gain and fatigue

Acanthosis nigricans (dark pigmentation on skin

creases in the nape of the neck especially), a sign of
insulin resistance, is present in majority

TYPE 1 DIABETES MELLITUS

Epidemiology
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Accounts for 10% of all cases of DM affecting more

than 15 million people in the world

Approximately 15,000 youths are diagnosed with

T1DM each year

It accounts for most cases of diabetes in childhood

50% of individuals with T1DM present as adults

Incidence of is increasing in almost all populations

Girls and boys are equally affected

Peak presentation occurs in two age groups:

the HLA system

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What triggers autoimmune response is unclear;

coincident in the beginning of school

prenatal influences, diet in infancy, viral infections,

Time of puberty: correspond to pubertal

lack of exposure to certain infections, and

growth spurth induced by gonadal steroids

psychologic stress are implicated but their exact role

and increased pubertal GH secretion (which

and mechanisms by which they trigger or aggravate

antagonizes insulin)

autoimmunity remains uncertain.

Pathogenesis and Natural History of Type 1 Diabetes

Initiation of autoimmunity is a necessary but not a

sufficient condition for T1DM

Mellitus
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Genetic susceptibility is determined by several genes

with the largest contribution coming from variants of

5-7 yr of age: correspond to time of

increased exposure to infectious agents

The natural history of type 1 DM involves the ff

In most cases of T1DM diagnosed in childhood, the

onset of autoimmunity occurs very early in life, with

steps:

Initiation of autoimmunity

Preclinical autoimmunity with progressive

first signs appearing before 2 years of age.

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Development of autoimmunity is associated with the

appearance of several autoantibodies:

loss of beta cell function

Onset of clinical disease

IAAs (first to appear)

Transient remission (honeymoon period)

Glutamic acid decarboxylase 65 kDa

Established Disease

Tyrosine phosphatase insulinoma-associated

Development of Complications

2

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Zinc transporter 9 antibodies

Earliest antibodies are predominantly IgG subclass

2. Preclinical Autoimmunity with Progressive Loss

of Beta Cell Function
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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
Schematic of the natural history of T1DM

The risk of clinical disease increases dramatically

with an increase in the number of autoantibodies:

1. Initiation of Autoimmunity
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A genetically susceptible host develops

autoimmunity against the hosts own beta cells.

30% of children with 1 antibody progress to DM;

70% when 2 antibodies are present; 90% when 3
antibodies are present

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The higher antibody titers are more likely to progress

6. Development of Complications

to clinical disease

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Children in whom IAAs appeared within the 1 2 yr

diabetes that appear to be related to how well-

of life rapidly developed anti-islet cell antibodies and

controlled the diabetes has been.

progressed to diabetes more frequently

Microvascular

Macrovascular

Complications

Complications

Diabetic retinopathy

Coronary artery disease

High-risk HLA alleles are more likely to develop

Diabetic neuropathy

Peripheral arterial disease

multiple antibodies and progress to disease

Diabetic nephropathy

Stroke

Role of Genetic in Disease Progression

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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

Some patients develop secondary complications of

Treatment
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Environmental factors induce transient autoimmunity

Excellent diabetes control involves many goals:

in many children, but those with genetic

control and avoid hypoglycemia

susceptibility are more likely to see progression of

autoimmunity and eventual development of diabetes.

To eliminate polyuria and nocturia

To prevent ketoacidosis

To permit normal growth and development

Role of Environmental Factors

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Environmental factors may act as accelerators of

T1DM after the initial appearance of autoimmunity

To maintain a balance between tight glucose

with minimal effects on lifestyle

Insulin Therapy
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Initial daily dose is usually higher in (1) prepubertal

children and those (2) with DKA at the time

3. Onset of Clinical Disease

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presentation

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

Optimal insulin dose can only be determined

empirically, with frequent self-monitored blood

beta cells survive up to 30 yr after onset of diabetes.

glucose levels and insulin adjustment by the diabetes

team.

4. Transient Remission
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Initial insulin schedule should be directed toward the

A.k.a. Honeymoon Period

At the time of diagnosis, some viable beta cells are

optimal degree of glucose control in an attempt to

still present and these may produce enough insulin to

duplicate the activity of the beta cell

lead to partial remission of the disease

1. Regular Insulin
5. Established Disease

Form hexamers which must dissociate into monomers

Over time, almost all beta cells are destroyed

subcutaneously before being absorbed into the

Patient becomes totally dependent on exogenous

circulation

insulin for survival.

Requires delaying the meal 30-60 mins after injection

for optimal effect

Frequent blood glucose monitoring and insulin

Profile limits postprandial glucose control, produces

adjustment are necessary in the 1st weeks as child

prolonged peaks with excessive hypoglycemic effects

returns to routine activities and adapts to a new

between meals and increases risk of nighttime

nutritional schedule

hypoglycemia.

2. Neutral Protamine Hagedorn (NPH) & Lente

The major physiologic limit to tight glucose control is

hypoglycemia

Insulin
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Inherent limits because they do not create a peakless

insulin level

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Insulin Pump Therapy

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Continuous subcutaneous insulin infusion (CSII) via

Produces a significant hypoglycemic effect during the

battery-powered pumps provides a closer

midrange of their duration

approximation of normal plasma insulin profiles and

Difficult to predict their interaction with fast-acting

increased flexibility regarding timing of meals and

insulins

snacks compared with conventional insulin injection

When regular insulin is combined with NPH or

regimens

Lente, the composite insulin poorly mimics normal

endogenous insulin secretion

3. Lispro and Aspart

Can be programmed with a patients personal insulin

dose algorithms

The patient can enter the patients blood glucose level

Insulin analogs

and the carbohydrate content of the meal and the

Absorbed much quicker because they do not form

pump computer will calculate the proper insulin

hexamers

bolus dose

Provide discrete pulses wih little if any overlap and

short tail effect

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One benefit may be a reduction in severe

hypoglycemia.

Allows better control of postmeal glucose increase

and reduces between-meal or nighttime
hypoglycemia

4. Glargine
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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

Maybe given every 12 hr in young children if a single

daily dose does not produce complete 24 hr basal
coverage

Basal insulin glargine should be 25-30% of the total

Continuous Glucose Monitoring System

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measure interstitial fluid glucose

dose in toddlers and 40-50% in older children

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Remaining portion of the total daily dose is provided

Subcutaneeous glucose sensors that continuously

Do not directly control insulin administration but

as bolus insulin dosed by both the carbohydrate

provide glucose readings to permit finer control of

content of the meal and the preprandial glucose value

insulin administration by patients and families

To avoid hypoglycemia, the glucose sensor sounds an

Sodium

Avoid excessive sodium;

alarm

limit to 3,000-4,000 if
hypertensive

Nutritional Management
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Fiber

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
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>20 g/day
The caloric mixture should be approximately 55%
carbohydrate, 30% fat and 15% protein

Approximately 70% of the carbohydrate content

Food preferences including cultural and ethnic ones,

should be derived from complex carbohydrates such

must be considered

as starch that require prolonged digestion and

Total recommended intake is based on size or surface

absorption so that plasma glucose levels increase

area

slowly
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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

Intake of fat is adjusted so that the

polyunsaturated:saturated fatty acid ratiois 1.2:1.0
rather than the usual average of 0.3:1.0

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Nutrient
Carbohydrates

Fat

% of

Recommended Daily

Calories

Intake

55%

30%

70% should be derived

Dietary fats from animal sources are reduced and

replaced by polyunsaturated fats from vegetable
sources

Substitute:

from complex

Margarine for butter

carbohydrates

Vegetable oil for animal oils in cooking

< 10% should be from

Lean cuts of meat, poultry and fish for fatty

saturated fats
Up to 10% from

meats
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polyunsaturated fats
Remaining should be

The intake of cholesterol is reduced by limiting the

number of egg yolks consumed

Less than 10% of calories should be derived from

from monounsaturated

saturated fats; up to 10% from polyunsaturated fats;

fats

the remaining fat-derived calories should be derived

from monounsaturated fats

Protein
Cholesterol

15%

---300 mg

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

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)

Exercise
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Category

No form of exercise, including competitive sports,

Individuals without diabetes

should be forbidden from a child with diabetes

Individuals w/ diabetes, good metabolic control

The major complication of exercise is the presence of

Individuals w/ diabetes, fair metabolic control

7.6-9.9

a hypoglycemic reaction during or within hours after

Individuals w/ diabetes, poor metabolic control

10%

<6
6-7.5

exercise
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The major contributing factor to hypoglycemia is an

Target HbA1c of <7.5% is the same regardless of age

increased rate of absorption of insulin from its

injection site
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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

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

Reference:
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Glycosylated Hemoglobin
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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 is a slow reaction that is

dependent on the prevailing concentration of blood
glucose; it 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, which is expressed as a
percentage of total hemoglobin.

HbA1c measurement reflects the average blood

glucose concentration from the preceding 2-3 mo.

It is recommended that HbA1c measurements be

obtained 3-4 times a year to obtain a profile for longterm glycemic control

The lower the HbA1c level, the more likely that

microvascular complications will be less severe,
delayed in appearance or even avoided altogether

Nelsons Textbook of Pediatrics, 20th edition