CHAPTER 1

INTRODUCTION

1.1 Background
Diabetes mellitus (DM) is a group of metabolic disorders characterized by a chronic
hyperglycemic condition resulting from defects in insulin secretion, insulin action or both.
Permanent neonatal diabetes is caused by glucokinase deficiency, and is an inborn error of the
glucose-insulin signaling pathway. The prevalence of diabetes is increasing rapidly worldwide
and the World Health Organization (2003) has predicted that by 2030 the number of adults with
diabetes would have almost doubled worldwide, from 177 million in 2000 to 370 million.
Experts project that the incidence of diabetes is set to soar by 64% by 2025 meaning that a
staggering 53.1 million citizens will be affected by the disease. The estimated worldwide
prevalence of diabetes among adults in 2010 was 285 million (6.4%) and this value is predicted
to rise to around 439 million (7.7%) by 2030.7
Indonesian Pediatric Society found 825 type 1 DM children from their registration
program all over Indonesia during 41months registry period (February 2009-July 2012, with
diagnosis period from 1991 to 2012). Based on hospital registry data, overall incidence rate of
type 1 DM in 2000 was 0,00388 per 100,000 population with 0,00292 per 100,000 male
population and 0,00483 per 100,000 female population. In 2010, the overall incidence rate
increased to 0,02819 per 100,000 with 0,03884 per 100,000 male popu-lation and 0,01761 per
100,000 female population.8 There are two main type of diabetes called :
i) Type 1 diabetes, also called insulin dependent diabetes mellitus (IDDM), is caused by lack of
insulin secretion by beta cells of the pancreas.
ii. Type 2 diabetes, also called non-insulin dependent diabetes mellitus (NIDDM), is caused by
decreased sensitivity of target tissues to insulin.

CHAPTER 2
LITERATURE REVIEW

2.1. Definition
T1DM is characterized by an absolute insulin deficiency caused by T-cellmediated
autoimmune destruction of pancreatic b-cells. It is the predominant form of DM during
childhood and adolescence but can present in adulthood, with the typical symptoms of polyuria,
polydipsia, and weight loss.7

2.2. Epidemiology
Type 1 diabetes represents around 10% of all cases of diabetes, affecting approximately
20 million people worldwide. Although type 1 diabetes affects all age groups, the majority of
individuals are diagnosed either at around the age of 4 to 5 years, or in their teens and early
adulthood. The incidence of type 1 diabetes is rising. Across Europe, the average annual increase
in the incidence in children under 15 years is 3.4% with the steepest rise in those under 5 years
old. Type 1 diabetes is the result of an autoimmune reaction to proteins of the islets cells of the
pancreas.9

Figur
e 1 : Epidemiology of T1DM
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2.3. Etiology7
Some causes of insulin resistance :
1 Obesity/overweight (especially excess visceral adiposity)
2 Excess glucorticoids (cushings syndrome or steroid therapy)
3 Excess growth hormone (acromegaly)
4 Pregnancy, gestational diabetes
5 Polycystic ovary disease
6 Lipodystrophy (acquired or genetic, associated with lipid accumulation in liver)
7 Autoantibodies to the insulin receptor
8 Mutations of insulin receptor
9 Mutations of the peroxisome proliferators activator receptor (PPAR )
10 Mutations that cause genetic obesity (e.g., melanocortin receptor mutations)
11 Hemochromatosis (a hereditary disease that causes tissue iron accumulation).
Source: Guyton and Hall (2006)

2.4. Pathogenesis 7
Type 1 diabetes mellitus is a chronic autoimmune disease associated with selective
destruction of insulin producing pancreatic -cells (Figure 1). The onset of clinical disease
represents the end stage of -cell destruction leading to type 1 diabetes mellitus. Al Homsi and
Lukic (1992) explained that several features characterize type 1 diabetes mellitus as an
autoimmune disease:
1. Presence of immuno-competent and accessory cells in infiltrated pancreatic islets;
2. Association of susceptibility to disease with the class II (immune response) genes of the major
histocompatibility complex (MHC; human leucocyte antigens HLA);
3. Presence of islet cell specific autoantibodies;
4. Alterations of T cell mediated immunoregulation, in particular in CD4+ T cell compartment;
5. The involvement of monokines and TH1 cells producing interleukins in the disease process;
6. Response to immunotherapy and;

7. Frequent occurrence of other organ specific autoimmune diseases in affected individuals or in

their family members.

Figure 2 : Pathogenesis of T1DM

2.5. Clinical manifestations5

1) Polyuria or nocturia
2) Persistent diuresis (with nocturnal enuresis, and polydipsia becomes more apparent)
3) Polyphagia
4) Weight loss
5) Ketoacidosis (leads to Kussmaul respirations, fruity breath odour (acetone), diminished
neurocognitive functions, and possible coma)

Table 1 : Clinical Characteristics of patients with Type 1 and Type 2 Diabetes Mellitus7

2.6. Diagnosis
The diagnosis of Type 1 Diabetes Mellitus can be made by taking into account the result
of HbA1C, random plasma glucose, and fasting plasma glucose.

Table 2 : Diagnosis of T1DM

2.7. Treatment
2.7.1. Pharmacological Treatment
The diabetes management are insulin, controlling diet, exercise and education with home
monitoring. The aim of insulin therapy in children and adolescents with type 1 diabetes mellitus
is to replicate the insulin secretion of a normally functioning pancreas.6 Nowadays intensive
regimens with differential substitution of basal and prandial insulin are becoming the gold
standard also in pediatric diabetology.7 To achieve glucose homeostasis, the pancreas releases
both (1) continuous,background insulin to help maintain euglycemia in the fasting state (basal
insulin); and (2) short bursts of insulin in response to plasma glucose levels rising above 80100
mg/dL (bolus insulin), such as those occurring shortly after a meal Thus, an insulin replacement
regimen for type 1 diabetes mellitus consists of both basal and bolus insulin components, along
with extra insulin required to lower serum glucose into the target range when hyperglycemia
occurs.6 On basal-bolus regimens the night-time intermediate-acting insulin may represent
between 30% (typical for regular insulin) and 50% (typical for rapid-acting insulin) of total daily
insulin. Approximately 50% as rapid-acting or approximately 70% as regular insulin is divided
up between three and four premeal boluses. When transferring to glargine as basal insulin, the
total dose of basal insulin needs to be reduced by approximately 20% to avoid hypoglycemia.
The rapid-acting analogs may require postprandial BG tests approximately 2 h after meals to
assess their efficacy.2
Basal insulin is started at the time of diagnosis of diabetes or at the time of transition
from an intravenous insulin infusion, if this has been necessary for resolution of DKA. The first
dose of subcutaneous basal insulin is given 30 min prior to stopping the intravenous insulin
infusion. Initiation of bolus insulin is determined by practical considerations and generally
coincides with the introduc-tion of basal insulin. A majority of children are now prescribed one
of the three available rapid-acting analogs, which are given multiple times per day to coincide
with meals, significant snacks, and the need for additional doses to correct hyperglycemia
between meals. If glargine or detemir is chosen as the basal insulin, the proportion of the TDD
given as rapid-acting insulin is generally 5060 %.6

In practice, total insulin doses of 0.50.75 U/kg/day are typically chosen at type 1
diabetes mellitus onset, and the dose is then adjusted on a daily basis to achieve target glycemia.
The obese [or pubertal child typically requires more insulin. 6 Dosage depends on many factors
such as : age, weight, stage of puberty, duration and phase of diabetes, state of injection sites,
nutritional intake and distribution, exercise patterns, daily routine, results of blood glucose
monitoring and glycated hemoglobin, intercurrent illness. The dose of insulin are :2
During the partial remission phase, the total daily insulin dose is often<0.5 IU/kg/d.
Prepubertal children (outside the partial remission phase) usually require 0.7 1.0 IU/kg/d.
During puberty, requirements may rise substantially above 1.2 IU/kg/d and even up to 2
IU/kg/d.
Blood glucose monitoring is essential in the safe management of childhood and
adolescent diabetes to help prevent acute and chronic complications, and also educate and
empower the child and family. Blood glucose monitoring should ideally be carried out
4-6 times a day.

Table 3. Recommended Target Blood Glucose Levels4

Timing

Random Blood Glucose

Before meals

4-7 mmol/l (72-126 mg/dl)

After meals
At bed time
At 3am

5-10 mmol/l (90-180 mg/dl)

6-10 mmol/l (108180 mg/dl)
5-8 mmol/l (90-144 mg/dl

HbA1c (glycated haemoglobin) provides information about average blood glucose levels
over the last 2-3 months. This test measures the amount of glucose that attaches to haemoglobin.
Ideally HbA1c is measured four times per year. The target HbA1c for all age groups is a value
less than 7.5% (58 mmol/mol).4
Correction doses (also called insulin sensitivity factor, correction factor) can be used
according to the 1800 rule, i.e., divide 1800 by total daily insulin dose to get the mg/dL that 1
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U of rapid-acting insulin will lower the blood glucose. For regular insulin, a 1500 rule can be
used for results in mg/dL.2

Table 4. Type of insulins

2.7.2. Non Pharmacological Treatment

Nutrition therapy is recommended for all children and adolescents with type 1 diabetes.
Implementation of an individualized meal plan with appropriate insulin adjustments can improve
glycemic control. Energy intake varies greatly within subjects on a daily basis due to age, growth
rate, physical activity, and other important environmental factors such as the type and availability
of food. Energy intake should be sufficient to achieve optimal growth and maintain an ideal body
weight. During puberty, energy intake and nutritional demands increase substantially along with
significant increase in insulin dosage.6 Three meals a day incorporating a wide variety of
nutritious foods from all food groups, The total daily caloric intake is divided to provide 20% at
breakfast, 20% at lunch, and 30% at dinner, leaving 10% for each of the midmorning,
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midafternoon, and evening snacks, if they are desired. 1The optimal macronutrient distribution
varies depending on an individualized assessment of the young person. As a guide, carbohydrate
should approximate 50 55% of energy, fat<35% of energy, protein 10-15% of energy. 10
Approximately 70% of the carbohydrate content should be derived from complex carbohydrates
such as starch; intake of sucrose and highly refined sugars should be limited. Complex
carbohydrates require pro-longed digestion and absorption so that plasma glucose levels increase
slowly, whereas glucose from refi ned sugars, including carbonated beverages, is rapidly
absorbed and may cause wide swings in the metabolic pattern; carbonated beverages should be
sugar free. Priority should be given to total calories and total carbohydrate consumed rather than
its source.1
Therapy consists not only of initiation and adjustment of insulin dose but also of
education of the patient and family. Teaching is most efficiently provided by experienced
diabetes educators and nutritionists. In the acute phase, the family must learn the basics,
which includes monitoring the childs blood glucose and urine ketones, preparing and injecting
the correct insulin dose subcutaneously at the proper time, recognizing and treating low blood
glucose reactions, and having a basic meal plan.1

2.8. Complications3
a) Acute Complications
1) Hypoglycemia
Hypoglycemia (or insulin reaction) is defined as a blood glucose level below 60 mg/dL.
For preschool children, values below 70mg/dL should be cause for concern. The common
symptoms of hypoglycemia are hunger, weakness, shakiness, sweating, drowsiness, headache,
and behavioural changes. If low blood sugar is not treated immediately with simple sugar, the
hypoglycemia may result in loss of consciousness or convulsions. If hypoglycemia is left
untreated for several hours, brain damage or death can occur.
2) Ketonuria, Ketonemia, Ketoacidosis

Families must be educated to check blood or urine ketone levels during any illness
(including vomiting even once) or any time a fasting blood glucose level above 240 mg/dL, or a
randomly measured glucose above 300mg/dL. If moderate or significant ketonuria is detected
above 1,0, health care provider must be called. Usually 1-20% of the total daily insulin dosage is
given subcutaneously every 2-3 hours until the elevated ketones are gone. Repeated episodes of
ketoacidosis usually result from missed insulin injections and signify that counseling may be
needed.
Treatment of diabetic ketoacidosis is based on physiologic principles :
i) Restoration of fluid volume
ii) Inhibition of lipolysis and return to glucose utilization
iii) Replacement of body salts
iv) Correction af acidosis
v) Management of cerebral edema

b) Chronic complications
1) Renal Failure
2) Loss of vision

2.9. Prognosis5
TIDM is a serious chronic disease.IT has been estimated that the average lifespan of
individuals with diabetes is about b10 years shorter than that of the non diabetic populations.
Although diabetic children eventually attain a height within the normal adult range, puberty may
be delayed, and the final height may be less than the genetic potential. The introduction of
portable devices (insulin pump)is one approach to the resolution of these long term problems.
The changing pattern of metabolic control is having a profound influence on reducing the
incidence and severity of certain complications.
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