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University of Khartoum
The Graduate College
Medical and Health Studies Board
PREVALANCE OF DYSLIPIDEMIA IN
CHILDREN WITH TYPE 1 DIABETES
IN KARTOUM STATE
By
Dr.Jihan Osman Ahmed
M.B.B.S (University of Khartoum)
A thesis submitted in partial fulfillment for the requirement of the
degree of Clinical MD in Pediatrics and Child Health.
Supervisor
Dr.Mohamed Sir El Khatim Hashim
(FRCPCH, FRCP, DTCH, DCH)
Associate Professor
Department of Pediatrics & Child Health,
Faculty of Medicine, U.of. K.
January 2005
-1-
DEDICATION
To my parents
Who gave me the gift of life
To My Mother
May her soul rest in peace
To my lovely sister
Julia
Who lightens up my life
To my dear friends
Who make the world more
Special just by being in it
-2-
‫ﺑﺴﻢ ﺍﷲ ﺍﻟﺮﲪﻦ ﺍﻟﺮﺣﻴﻢ‬
‫َ‬
‫ ﻭﻗﻞ ﺭﺏ ﺯﺩﻧﻲ ﻋﻠﻤﺎ ً‬
‫ﻗﺎﻝ ﺍﷲ ﺗﻌﺎﱄ ‪:‬‬
‫‪114‬ﺳﻮﺭﺓ ﻃﻪ‬
‫ﺻﺪﻕ ﺍﷲ ﺍﻟﻌﻈﻴﻢ‬
‫‪-3-‬‬
Table of Contents
Page
Acknowledgement
V
Abstract
Vi
Abstract in Arabic
vii
List of Tables
viii
List of Figures
X
List of Abbreviations
xi
CHAPTER ONE
1. INTRODUCTION AND LITERATURE REVIEW
1.1. Historical Background and Definition of Diabetes Mellitus
1
1.2. Pathogenesis and Epidemiology of Type 1diabetes
7
1.3. Clinical Presentation and Management.
14
1.4. Complications and Prevention
24
1.5. Lipids of Physiologic Significance
27
1.6. Clinical Application……………………… …………..
36
1.7. Diabetes and Lipids
43
1.8 Management of Dyslipidemia
50
1.9. Studies Done on Lipid Profile
57
-4-
CHAPTER TWO
2. JUSTIFICATION AND OBJECTIVES
2.1. Justification
63
2.2. Objectives
64
CHAPTER THREE
3. PATIENTS & METHODES………………………
3.1. study design
65
3.2. study area
65
3.3. study period
65
3.4. study population
65
3.5. inclusion criteria
65
3.6. exclusion criteria
66
3.7. sample size
66
3.8. ethical approval
66
3.9. study tools
67
3.10. statistics
68
3.11. potential difficulties
68
3.12. input of the author
68
3.13. other participants in the study
69
3.14. fund and grants
69
-5-
CHAPTER FOUR
4. RESULTS
4.1. Demographic Characteristics of the Study Group:
70
4.2. Family and Social History of the Study Group:
73
4.3. Child Education
79
4.4. Exercise
83
4.5. Diabetes Mellitus Variables
83
4.6. Anthropometric Measures of the Study Group
87
4.7. Investigations
93
4.8. Relation between Dyslipidemia and Risk Factors
98
CHAPTER FIVE
5. DISCUSSION
5.1. Demographic Characteristics of the Study Group
117
5.2. Family and Social History of the Study Group:
118
5.3. Child Education
119
5.4. Exercise
119
5.5. Diabetes Mellitus Variables
120
5.6. Anthropometric Measures of the Study Group.
121
-6-
5.7. Investigations…
122
5.8. Relation between Dyslipidemia and Risk Factors
124
CONCLUSION
127
RECOMENDATIONS.
128
REFFERENCES
129
APPENDIX
145
-7-
ACKNOWLEDGEMENT
My sincerest appreciation to my supervisor Dr.Mohammed Sir K Hashim
for his supervision, valuable support and encouragement.
I am deeply indebted to all patients who gave me the chance to conduct
this study.
With great appreciation I would like to thank Dr. Mohammed
Babikir(pediatrician) for his great help with meticulous patience through out the
stages of the study. My thanks also extended to Dr. Khalid Alsir(pediatric
registrar) and Dr. Sana Altayb (biochemist)for their great support.
I feel greatly indebted to my family for their endless support and care.
-8-
ABSTRACT
Diabetes mellitus is one of risk factors that contributes to the development of
dyslipidemia, which is a leading cause of coronary heart disease in adult life.The aims
of the study were to determine the prevalence of dyslipidemia in children with type 1
diabetes and to study the correlation between dyslipidemia and some of the risk
factors. A cross sectional prospective hospital based study was carried out during the
period from August 2004 to January 2005. The study was conducted at Gaffer Ibn
Auf Children Emergency Hospital, Ahmed Gasim Teaching Hospital and Gabir Abu
Aleiz Diabetes Center.
Two hundred children were enrolled in the study; one hundred diabetics and
their controls matched according to sex and age group (mean age of diabetics 12.0 ±
3.6SD and 12.1 ± 2.5SD for control). The prevalence of dyslipidemia in the fasting
state was increased in the diabetic group (43%) compared to control group (21%).
Hypercholesterolemia was found in 10% of diabetic group and hypertriglyceridemia
in 16%, compared to 4% and 7% respectively in control group. Dyslipidemia of LDL
was 26% in diabetics and 2% of controls while HDL was found low in 2% of diabetics
and none of controls.
Positive correlation was found between dyslipidemia and
glcosylated HbA1c, duration of diabetes and exercise.
In Conclusion: lipid abnormalities remain common in children with type 1
diabetes and need to be screened for.
-9-
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List of Tables
Page
Table. 1
Ethnic origin of the study group……………………
74
Table. 2
Father education…………………...……….
77
Table. 3
mother education…………….………...
77
Table. 4
father occupation…………………..….
78
Table. 5
mother occupation………………..…..
78
Table. 6
family history of the study group............
80
Table. 7
schooling level of the study group……………
81
Table. 8
school attendance of the study group……………
81
Table. 9
insulin dose…………………………………..
86
Table. 10 Distribution of glycosylated HbA1c……..
94
Table. 11 Correlation between exercise performance and
Dyslipidemia in patients and control group…………………103
Table. 12 Correlations between dyslipidemia and gender in
Patients and control group ………………………………105
Table. 13
Correlations between dyslipidemi and age group in
patient…………………………………….
Table. 14
107
Correlations between dyslipidemia and age group in
Control group………………………….
- 11 -
107
Table. 15 Correlations between dyslipidemia and blood pressure
In patient……………………………………...
110
Table. 16 Correlations between dyslipidemia and blood pressure
In control group……………………………………
110…
Table. 17 Correlations between dyslipidemia and sexual maturity
Rate in patients…………………………….
112
Table. 18 Correlations between dyslipidemia and sexual maturity
Rate in control group……………………
112
Table. 19 Correlation between dyslipidemia and family history of
coronary heart heart disease in patients…………………. 115
Table. 20 Correlation between dyslipidemia and family
history of coronary heart disease in control group…… 115
Table. 21
Table. 22
Correlations between dyslipidemia and family
history of obesity in Patients…. ………………
Correlations between dyslipidemia and family
history of obesity in control group………………
- 12 -
116
116
List of Figures
Page
Figure.1
Age group distribution of the study group ………
71
Figure.2
Gender distribution of the study group ……………
72
Figure.3
Distribution of parent consanguinity……………….
75
Figure.4
exercise performance of the study grouo………….
84
Figure.5
distribution of diabetes mellitus duration ………….
85
Figure.6
Weight centiles of the study group ………………
88
Figure.7
Height centiles of the study group………...
90
Figure.8
Blood pressure centiles of the study group
Figure.9
Sexual maturity rate of the study group……..
92
Figure.10
Prevalence of dyslipdemia of the study group……..
96
Figure.11 Prevalence of individual lipid profile dyslipidemia…
97
…………… 91
Figure.12 correlation between dyslipidemia and HbA1C ………… 99
Figure.13 correlation between dyslipidemia and diabetes duration….101
- 13 -
List of Abbreviations
AAP
American Academy of Pediatrics
ADA
American Diabetes Association
AGEs
Advanced Glycation End products
AHA
American Heart Association
CHD
Coronary Heart Disease
DCCT
Diabetes Control and Complications Trial
DKA
Diabetic ketoacidosis
DM
Diabetes Mellitus
FA
Fatty Acids
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
GAD
Glutamic Acid Decarboxylase
HDL
High Density Lipoprotein
HMG coA
3-hydroxy-3 methylgluteryl-CoA reductase
IAA
Insulin Auto- Antibodies
ICA
Islet Cell Antibodies
IDL
Intermediate Density Lipoprotein
LDL
Low Density Lipoproteins
MHC
Major Histocompatibility Complex
NCEP
National Cholesterol Education Program
- 14 -
NPH
Neutral Protamine Hagedorn
TC
Total Cholesterol
TG
Triglyceride
WHO
World Health Organization
- 15 -
CHAPTER ONE
INTRODUCTION AND LITREATURE
REVIEW
- 16 -
1. INTRODUCTION AND LITERATURE REVIEW
1.1 Historical Background and Definition of Diabetes
1.1.1. Historical background:
The name diabetes is derived from the Greek word diabeniein
which means excess. It was described in the first century AD by the
Greek physician Aretaeus, pointing to the polyuria which characterizes
the condition. Later in the fifth century Susruta recognized the
sweetness of urine of diabetic patients and the Latin word mellitus –
honey – was added.
Paul Langerhans a young German medical student described the
anatomy of islet cells in 1888 and their endocrine secretion was
summarized 4 years later by Langnese. The comprehensive theory of
diabetes mellitus was advanced by Nauny in 1898.The active agent
insulin was isolated by the collaborative work of the Toronto group in the
year 1921 and used in humans in the year 1922. The Toronto group was
awarded the Nobel Prize for this discovery in 1923 (1).
1.1.2. Definition:
The
term
(DM)
comprises
a
heterogeneous
group
of
hyperglycemic disorders as a result of relative or absolute deficiency of
insulin, along with varying degrees of peripheral resistance to the action
of insulin and a relative or absolute excess of glucagon (2)
- 17 -
1.1.3 New classification:
Every new year the diabetes community re-evaluates the current
recommendation for the classification, diagnosis and screening of
diabetes, reflecting new information from research and clinical practice.
New recommendations were announced at the American Diabetes
Association
(ADA)
meeting
in
Boston
in
June
1997
(3)
.
In this classification there is no distinction between primary and
secondary causes of diabetes. The terms type 1 and type 2 diabetes are
to be used, whereas, terms like insulin dependent, non insulin
dependent, juvenile onset, maturity onset, adult onset, and maturity
onset diabetes of the young (MODY) are to be eliminated. This change
reflects an attempt to classify diabetes according to etiologic differences
and to move away from describtions based upon age at onset or type of
treatment.
In type 1 diabetes the majority of patients have autoimmune
destruction of the pancreatic beta cells. This is termed type1A to
distinguish it from some rare cases in which an autoimmune etiology
cannot be determined i.e. idiopathic, which is termed type 1B. Type 1A
patients have an absolute requirement of insulin therapy and will
develop (DKA) if not given insulin. However, some patients with type 1
diabetes will not meet all of these criteria e.g. those who pass through a
transient non insulin dependent "Honey moon" period (2, 3).
- 18 -
Type 2 diabetes is by far the most common type of diabetes.
Patients don't have autoimmune destruction of beta cells, pancreatic
disease or other rare causes of hyperglycemia. They have sufficient
endogenous insulin production to prevent (DKA) and variable degrees of
insulin resistance, though some patients develop (DKA) under certain
circumstances and may require treatment with insulin (3, 4).
1.1.4 Diagnosis of diabetes mellitus:
1.1.4.1. Modalities of diagnosis:
• Fasting plasma glucose (FPG):
Fasting blood glucose is an elevated plasma glucose level after an
over night fast and is regarded as the gold standard for diagnosis. The
diagnostic value was 7.8 mmol/l or higher on at least two occasions in
the old criteria, but the ADA recommended a lower level of 7 mmol/l (2).
• Oral glucose tolerance test (OGTT):
This is performed in the morning after an over night fast by
taking plasma glucose sample as pretest. At 0 minute giving 1.75 g/kg
oral glucose and measuring blood glucose at 1 and 2 hour (2, 5).
Various
diagnostic
standards
for
diabetes
have
been
recommended. The most sensitive but not specific for diagnosis are
those of Mosenthal and Barry and the most specific diagnostic criteria
are those of the National Diabetes Data Group (NDDG) which was
previously known as the old criteria.
- 19 -
Glucose levels recommended as
diagnostic for diabetes by
OGTT are shown below (6):
Time after ingestion
Manthesal-Barry
Fajans-Conn
NDDG
1 hour
9.2 mmol/l
10.3 mmol/l
11.1 mmol/l
2 hours
6.4 mmol/l
7.8 mmol/l
11.1 mmol/l
Interpretation of the OGTT is as follows:
1- Fasting plasma glucose > 7 mmol/l or 2 hours concentration >11.1
mmol/l are diagnostic of diabetes.
2- Two hours plasma glucose > 7.8mmol/l and < 11 mmol/l suggests
impaired fasting glycemia.
3- Fasting plasma glucose > 6 but < 7 mmol/l suggests impaired fasting
glycemia.
Oral glucose tolerance test is indicated for confirmation of the
diagnosis of diabetes in uncertain cases with borderline blood glucose
concentration (e.g. in sibling of diabetic patient or in children with cystic
fibrosis prone to diabetes) and for diagnosis of impaired glucose
tolerance. When used for screening in large populations, the test
overestimates the prevalence of diabetes (1, 6).
• Glycated Hemoglobin (Hb A1C):
There had been interest in the use of HbA1c values for screening
and identification of impaired glucose tolerance and diabetes. An
increased level of Hb A1C constitutes presumptive evidence of diabetes,
- 20 -
though a normal HbA1c level doesn't exclude impaired glucose
tolerance or mild diabetes (1, 5). Hb A1c determinations correlate with the
fasting plasma glucose level, so their values may be considered in
combination. In one cross sectional analysis of two large data sets, 60%
of patients with diabetes diagnosed by the new fasting blood glucose
criteria had a normal HbA1c value as compared to 19% of those
diagnosed by the old criteria. Upon these findings diabetes should not
be diagnosed in patients with fasting blood glucose < 7.8 mmol/l unless
the Hb A1c was also high, and patients with normal HbA1c value and
fasting blood glucose between 6.1- 7.7 mmol/l
should be given the
diagnosis of impaired fasting glucose. However, there remain serious
problems in the standardization of HbA1c assays. Thus at the present
time the diagnosis of diabetes mellitus should not be made on basis of
HbA1c values alone (7, 8).
• Acute Insulin Response to glucose (AIRg):
In this test glucose is infused as 25%solution for 3 minutes at a total
load of 0.5g/kg; then plasma insulin is measured at 1 and 3 minutes, and
values above baseline are added. Sums below 48 micro unit/ml
are
predictive of diabetes, especially if the subject is islet cell cytoplasmic
antibody
positive (9).
- 21 -
1.1.4.2. New criteria:
The new criterion strongly suggest that the diagnosis of
diabetes be made on the basis of fasting blood glucose only .A
provisional report from the (WHO) agreed with the new definitions, but
suggests continued use of the (OGTT) for patients with blood glucose
values in the uncertain range (10). The following definitions have been
suggested (3, 10):
- Normal -- FPG < 6.1 mmol/L.
- Impaired -- FPG between 6.1- 6.9 mmol /l.
- Diabetes mellitus -- FBG above 7mmol/L or symptoms of diabetes and
random blood glucose at or above 11.1mmol/L confirmed on another
occasion.
The shift from using 2h value on an (OGTT) to (FPG) causes
change in the prevalence of (DM), depending on the population studied.
In one report the old criteria were more likely to diagnose diabetes
in
lean subjects, while the new criteria were more likely to identify it in
middle aged obese subjects. In another review almost twice as many
subjects were classified as diabetic by the new than the old fasting
criteria (11).
The prognostic impact of these changes in subjects at risk of
developing microvascular or macrovascular complications is not known,
although data are accumulating that the old criteria were better
- 22 -
predictors of cardiovascular risk and mortality. In a study over 25,000
patients followed for 7yrs, the 2 hour values of the (OGTT) were
predictive of high mortality while the fasting blood glucose was not (12).
1.2. Pathogenesis and Epidemiology of Type 1 Diabetes
1.2.1. Epidemiology:
1.2.1.1. Prevalence:
Type 1 diabetes mellitus is predominantly a disease of
whites and of populations with a substantial white genetic admixture,
including African American. In the United States the prevalence among
school aged children is about 1.9/1000 and 1 in 360 in children at 16
years. In Finland the prevalence is nearly 40 in 100.000 and 1 in
100,000 in Japan. These differences may not be entirely racial, because
there may be regional differences in prevalence within the country. An
environmental impact is also suggested by seasonal variations in rate of
appearance, and by the fact that fewer than half of identical twins are
concordant for IDDM (13).
1.2.1.2. Incidence:
Major world-wide variations in incidence exist. The United States
have intermediate incidence of about 12-15 new cases / 100,000. In
Korea, China and Mexico the incidence is 0.6/100,000 per year
compared to 38.4/100,000 per year in Finland. These observations have
implication for genetic counseling.
- 23 -
Incidence increases with age and peaks of presentation occur in
two age groups: at 5-7 years, the time of increased exposure to
infectious agents coincident with beginning of school and at puberty due
to increased pubertal growth hormone secretion which antagonizes
insulin action. A growing number of patients are presenting between 1
and 2 years, and about 25% of cases present after 35 years of age.
Incidence is not affected by sex since and there is no apparent
correlation with socioeconomic status. Seasonal distributions of newly
diagnosed cases exist with greater frequency in autumn and winter
months and this is more apparent in adolescent years (14).
There is a family history of type 1 (DM) in 10 % of cases. If a twin
develops type 1 (DM), the life time risk to a non affected monozygotic
twin is 60 % and for a dizygotic twin is 8 %. The risk of developing type 1
(DM) for an individual with an affected relative is as follow: in affected
siblings the risk is 8 %, if the mother affected is 2-3 %, 5-6 % if the father
is affected and if both parents are affected the risk will be 30 %(5, 15).
1.2.2 Pathogenesis:
Beta cells destruction occurs in genetically susceptible people.
At least 80% of the functional beta cells mass must be destroyed before
overt glucose intolerance occurs. The process in most cases is immune
mediated, probably takes months to years and may be initiated by
external environmental factors (16).
- 24 -
1.2.2.1 Genetics
Major histocompatibility complex (MHC) is important in diabetes
both because susceptibility of type 1 (DM) appears to be linked to
certain human leukocyte antigen (HLA) alleles and because this region
controls immune response. Approximately 95% of Caucasians with type
1 (DM) have either DR3 or DR4 antigens or 55 to 60% have both DR3
and DR4. Inheritance of one of these antigens confers a 3 to 5 fold risk
in developing type 1 DM and 10 fold risks if both are inherited.HLA DQ
beta chain alleles primarily determine susceptibility and resistance to
autoimmune destruction of beta cells. If aspartic acid residue occupies
position 57 in both alleles of that chain, autoimmune diabetes ordinarily
does not occur while full susceptibility requires absence of both alleles.
In addition higher risk is conferred by an arginine at position 52 of the
DQ alpha chain. It had been postulated that homozygous DR3 results in
a primary auto immune form of type 1 (DM), and that type 1 (DM) in
homozygous DR4 is caused by a primary environmental insult with a
secondary autoimmune response. The risk of developing type 1 diabetes
if one sibling is affected : Identical twins < 50%, HLA identical 1 in 5,
HLA haploidentical 1 in 20 and HLA non identical 1 in 100 (4,17) .
1.2.2.2. Environmental – genetic interactions:
Exposure to the environmental factors may be multiple, recurrent
and intermittent or continuous rather than a single triggering event.
- 25 -
These factors may precipitate beta cells destruction by direct damage or
by molecular mimicry refers to the immune response caused by similar
protein sequences in beta cell antigens and the offending agent (e.g.
viruses, bovine serum albumin)(18).
• Role of diet:
It has been suggested that a cell mediated response to a cow's
milk protein, casein, may be involved in the pathogenesis of type 1
diabetes. This suggestion was produced in an epidemiological study
from an epidemiological study of children from 10 countries.
(19)
.
Studies in Colorado (USA) and Yorkshire (UK) have shown that
incidence of type 1 (DM) correlates with the concentration of nitrates in
the drinking water. The incidence is 30% higher in areas with nitrate
concentration
above
14
–
18mg/l
compared
with
areas
with
concentration below 3.2 mg/l.
Dietary vitamin D supplementation also appears to correlate with risk
of type 1 DM. In a birth cohort study of 10,000 children, those who
regularly took vitamin D (2000 i.u daily) had a reduced incidence of type
1 DM compared to those who regularly took less (20) .
• Role of viruses:
The viral hypothesis would explain the increased incidence of
onset of type 1 (DM) in autumn, winter and colder climates.
Susceptibility to diabetes after viral infection appears to be genetically
- 26 -
determined. The onset of type 1 (DM) sometimes coincides with or
follows viral infection (such as mumps, rubella, CMV, measles, influenza,
EBV and poliovirus).
Coxackie B virus specific IgM responses have been found in 39%
of children with newly diagnosed type 1 DM, compared with only 6% of
normal children. Also antibody titres were significantly higher in pregnant
women whose children subsequently develope type 1 DM before 3 years
of age, compared with pregnant women whose children did not become
diabetic.
Enterovirus infections were almost two times more common in
siblings who developed type 1 DM than in siblings who remained non
diabetic (21).
In contrast to the above reports, there are data that refute the role
of viruses in the pathogenesis of type 1 DM. There is evidence that
viruses may protect against type 1 DM. In animal models of type 1 DM,
inoculation with lymphocytic choriomeningitis virus at an early age
reduced the incidence of diabetes and that raising the animal model in
pathogen free environment leads to an increased incidence of type 1
(DM) (22).
1.2.2.3. Autoimmunity:
An ongoing search has identified several auto antigens within
pancreatic beta cells that may play an important role in the initiation or
- 27 -
progression of autoimmune injury. It is not clear which of these auto
antigens is involved in the initiation of the injury and which are
secondary and released only after the injury (23).
• Islet antibodies:
• Cytoplasmic islet cell antibodies (ICAs):
In sections of fresh human pancreas, cytoplasmic islet cell
antibodies are present in the serum of 60 - 90% of newly diagnosed
patients with type 1 diabetes, compared to 0.5% of non diabetic controls.
The antibodies generally react with all four types of islet cells, although
in some patients antibodies are specific for beta cells. The later condition
is less predictive of future type 1 diabetes. These antibodies disappear
in most type 1 patient within 2-3 years after onset. The 10-15 % of
patients in whom these antibodies persist for longer than 2-3 years
exhibit high prevalence of thyroid autoantibodies, strong family history of
other autoimmune disorders, female preponderance, and reduced levels
of IgG antibodies to exogenous insulin(24).
• Glutamic Acid Decarboxylase antibodies (GAD).
This is the rate limiting enzyme for biosynthesis of the
inhibitory neurotransmitter gamma amino butyric acid (GABA), and is
expressed in several extra neural tissues including beta cells. It was
identified in 1990 as a major auto antigen in type 1 diabetes. Antibodies
to (GAD) are found in about 70% of patients with type 1 diabetes at the
- 28 -
time of diagnosis and may be positive 10 years before the onset of
clinical diabetes. Measurement of the (GAD) antibodies may be the
procedure of the choice for screening and confirmation of the diagnosis
of autoimmunity as the cause of diabetes. It is more reproducible,
fluctuates less with time, is simpler to perform and is predictive of
progression to hyperglycemia even in the absence of (ICAs) or (IAA) (25).
•
Insulin auto antibodies (IAAs):
Insulin auto-antibodies may be present in up to 50% of patients with
new onset type 1D developing before age 5years especially those with
DR4. Titers decline with age, in contrast to (ICAs).
1.2.3. Prediction of type 1 diabetes mellitus:
1.2.3.1. Use of genetic markers:
Genetic markers may be helpful in assessing the risk of diabetes
in close type 1 diabetic relatives. The risk is markedly increased,
averaging 6% in offspring and 5% in sibling (versus 0.4% in subject with
no family history).
The risk in siblings is influenced by the degree of genetic
similarity, falling from 33% in identical twins to 12.9 to 4.5 and to 1.8%,
respectively if the siblings share two, one or no haplotypes (26).
1.2.3.2. Use of immunological markers:
At least three islets antibodies are clinically useful (ICA), (IAA)
and (GAD). Humans may have any combination of these antibodies, as
- 29 -
an example incidence of type 1 diabetes is not increased with (IAA)
alone, but with the combination of (IAA) and (ICA) (27).
1.2.3.3. Use of metabolic markers:
Although glucose tolerance remains normal until close to the
onset of hyperglycemia, the acute insulin response to several
secretagogues
(glucose,
arginine,
glucagons
and
isoproternol)
decreases progressively during the pre clinical period. The most useful
test is the acute insulin response to glucose (AIRg). In first degree
relatives with type1 diabetes, an (AIRg) below the first percentile of
normal is a strong predictor of type 1 diabetes (27).
Simpler test that prove useful is to measure the fasting serum
concentration of
proinsulin. In normal subject
it accounts
for
approximately 15% of serum immunoreactive insulin. This proportion
rises as beta cells function declines (28).
1.3. Clinical Presentation and Management:
1.3.1. Clinical Presentation and course:
Most children with new onset type1 diabetes have symptoms of
less than one month duration, but some have had mild to moderate
symptoms for several months.
Most children present with the classic symptoms of polyuria,
polydipsia,
polyphagia,
weight
loss
and
lethargy.
Some
have
constipation, blurring of vision and infection especially candidal skin
- 30 -
infection. Although most school children will report polyuria, in young
children and infants this may be missed. So enquiry about bed wetting,
nocturia and number of diapers used is important because children at
this age are more likely to present with (DKA) with vomiting, abdominal
pain and symptoms of systemic infection. Type1 diabetes must be
considered in any child with clinical dehydration who continues to urinate
regularly
(29)
. At diagnosis most patients (approximately 75%) will not
have DKA.
Type1 diabetes usually proceeds through an ordered sequence;
prediabetes, impaired glucose tolerance, frank diabetes and non insulin
dependent period. After the initial presentation, most children with newly
diagnosed type1 diabetes undergo a honeymoon period or remission
phase. During this period the remaining functional beta cells regain the
ability to produce insulin and so requirements of exogenous insulin
dropped and hypoglycemia becomes a potential problem. This phase
usually begins within 1-3 months after diagnosis and continues for
several months, sometimes as long as 12-24months. Usually it occurs
gradually, but as in cases of acute infection it may be abrupt .As this
phase ends, requirements for exogenous insulin increase.
(30)
.
1.3.2. Management:
Normal growth in height and weight and normal timing of
adolescent pubertal development are important goals of long term
- 31 -
management. Chronically untreated children with poorly controlled type
1 diabetes often fail to grow normally and have delayed both skeletal
and sexual maturation. In contrast, children receiving excessive insulin
doses may gain weight too rapidly, have rebound hyperglycemia and
ketosis and similar degree of growth retardation.
Global view to all aspects needed for glycemic control is
warranted and integration of these parameters of treatment is essential.
These parameters are: Insulin therapy, diet therapy, exercise education
of the patient and his family and finally blood glucose monitoring.
Diabetes management is difficult during adolescence and metabolic
control often deteriorates. This is due to the hormonal changes and
increasing maturity and independence (1, 5)
1.3.2.1. Insulin therapy:
The therapeutic objectives of insulin therapy in type1 diabetes
include; elimination of the catabolic state and its symptoms, elimination
of glycosuria and achievement of pre-prandial and post-prandial
euoglycemia.
Effective use of insulin requires an understanding of its
pharmacokinetics. The major variables that affect glycemic control are;
insulin preparations, injection technique, site of injection, subcutaneous
blood flow and size of the subcutaneous depot (31).
- 32 -
• Insulin preparations:
Purified pork insulin and human insulin produced by recombinant
DNA technology are insulin preparations most commonly used .The
biologic effect of both is essentially identical but human insulin is less
antigenic and has a shorter duration of action. Many reports suggest an
increase in hypoglycemia unawareness with the use of human insulin.
Insulin lispro is superior to the regular insulin by the fact that it corrects
hyperglycemia more rapidly than regular insulin, very effective in use in
intensive therapy, has fewer episodes of hypoglycemia especially
nocturnal and it's action is not blunted by mixing with intermediate acting
insulin in comparison to the regular one (32) .
Although mixing of separate supplies of short and intermediate
acting insulin allows greater flexibility, there is little evidence that in
routine clinical practice this leads to better glycemic control than that
achieved by using premixed insulin. In fact, because of the variability in
peak effect it may be more difficult to achieve excellent glycemic control
with premixed insulin even though they are easier to use. Thus if near
normoglycemia is the goal, it is preferable to keep basal -intermediate or
long acting- insulin injections separate from pre-meal (regular) insulin
and to adjust them independently.
The absorption of insulin and hence the duration and peak of
activity vary among patients and from day to day by as much as 15-50 %
- 33 -
leading to unexplained fluctuation in glycemic control. This effect is
greater with longer acting insulin and least with regular one (33).
• Insulin regimens
There are two regimens used, the first is the conventional insulin therapy
(single and two daily regimens) and the second is the intensive insulin
therapy.
• Conventional insulin therapy:
- Single daily regimen:
It is preferred in newly diagnosed type 1 diabetics, those in honey moon period and those with type 2 DM who are not controlled with
maximum doses of drugs. The policy is to give intermediate acting
insulin before breakfast and if post prandial hyperglycemia occurs, short
acting insulin is added. Achieving control with a single daily injection is
nearly impossible (1, 13).
- Two daily regimen:
If the goal is to relief from hyperglycemic symptoms with a regimen
that is simple, then twice daily (NPH) or lente insulin will be effective in
many patients. If excessive post-prandial rise in blood glucose is a
concern, then regular insulin must be added. Using the later,
approximately 2/3 of the total dose is taken before breakfast and 1/3
before dinner. Doses usually divided as 1/3-1/2 short acting and 1/2 -2/3
intermediate acting. This regimen is based on the concept that each of
- 34 -
the four doses is covering 1/4 of the day and results in a single peak of
glucose absorption. This is also true for fixed insulin mixture and for the
new preparation of lispro- Mix 25 (4).
Most preadolescent children need approximately 0.7 -1 u/kg/d,
teenagers usually require 1-1.2 u/kg/d after the first few years of the
disease. On occasions it may be as great as 2 u/kg/d while in the honey
moon period the requirements may drop to less than 0.5 u/kg/d(4).
Complications of conventional therapy include: Hypoglycemia and
hyperglycemia in the morning whether or not preceded by hypoglycemia
(manifested clinically as Somogi and Dawn phenomenon). Also they
include Insulin allergy which may develop with initiation of therapy
usually within the first month or after insulin free period, (manifested as
cutanous or systemic reactions), Insulin resistance which is present in
the absence of obesity in type 1diabetes and recedes with good control
and finally lipodystrophy and lipoatrophy (34).
• Intensive insulin therapy
The diabetes control and complication trial (DCCT) demonstrates
that improved glycemic control with intensive insulin therapy in patient
with type 1 diabetes had led to graded reduction in microvascular
complications. The glycemic goals in the (DCCT) program were; 3.9- 6.7
mmol/L fasting and pre-prandial and less than 3.6 mmol/L at 3AM. Hb
A1c was to remain within 2 standard deviations of the non diabetic mean
- 35 -
level (35). Intensive insulin therapy can be accomplished in two ways: the
first is intensified multiple subcutaneous injections, and the use of
continuous subcutaneous insulin infusion.
- Multiple daily injections:
In general regular insulin is given before meal , and basal
coverage is provided either by intermediate acting insulin given before
bed time or by long acting insulin given together with regular insulin
before the evening dose . There is a choice for premeal insulin with
insulin lispro and inhaled insulin. The later causes very rapid rise in
serum insulin concentrations similar to lispro and faster than the regular
one, it is given as 1.5 units /kg 5 minutes before a meal. Food and drug
administration approval for its use is bending (36).
Long acting insulin analogue, insulin glargine, gives lower fasting
blood glucose concentrations with less nocturnal hypoglycemia as
compared to (NPH) insulin. Since the time action of it has virtually no
peak, this makes it the ideal basal insulin for intensive insulin therapy in
type 1 diabetes (37).
- Continuous subcutaneous insulin infusion pumps (CSII):
It provides meticulous regulation of blood glucose and greater
flexibility of life style especially in the timing of meals. Only fast acting
insulin is used with this therapy, the pump is programmed to deliver
boluses of regular insulin 30 minutes before meal and infuse insulin as a
- 36 -
constant basal rate (usually 0.5 -2 u/kg /d). The basal rate can be
programmed for up to 4 different basal rates in a 24hr period. The lower
rate to supply low nocturnal requirements and the higher rate to cope
with the early morning hypoglycemia.
Advantages of meticulous control are: 1- insulin absorption is less
variable from day to day, and therefore blood glucose profiles are more
predictable. 2- near normal levels of amino acids and lipid profile are
achieved. 3- Normal plasma glucagon levels and normal responses of
counter regulatory hormones.4-improvement of neuropathic components
of the diabetic syndrome, reversal of microalbuminuria and slowing the
progression of early retinopathy (38).
Disadvantages of meticulous control: 1- Retinopathy acceleration
2- Severe neuroglucopenia and hypoglycemia unawareness 3-obesity
(39)
.
1.3.2.2. Diet therapy:
For many years the (ADA) recommended standard diet in the
treatment of diabetes: Approximately 30% of dietary energy should be
derived from fat, 20 % from protein and 55 % from carbohydrates and
high fiber food with only modest amount of sucrose and refined sugars.
No particular food should be considered forbidden, and allowing diabetic
patients to consume up to 10% of their caloric intake as added sugars or
sweets doesn't appear to negatively impact metabolic control. The timing
- 37 -
of the meals must be carefully matched with that of insulin injections if
normoglycemia is to be achieved (40).
1.3.2.3. Exercise:
Physical fitness and regular exercise are important for all patients
with type 1 diabetes because insulin requirement may be lower and
metabolic control improves (41).
1.3.2.4. Monitoring glycemic control:
Two ways are available for monitoring glycemic control;
measuring blood glucose concentration and testing urine for glucose and
ketones.
• Mean blood glucose concentration:
The (ADA) recommends that patients with type 1D monitor their
blood glucose four times daily, before each major meal and at bed
time, more frequent testing ( up to seven times ), may be indicated if
the child is unwell, partaking in heavy activities or feel hypoglycemic.
The mean of these values is termed the mean blood glucose
concentration which is one of the useful measurements for defining
glycemic control (42).
The fasting blood glucose concentration is often used to monitor
progress since it correlates well with HbA1c value; although some
authors have argued that non fasting blood glucose is a better marker of
glycemic control than fasting values. The child should aim at a pre- 38 -
breakfast blood glucose of 6-8mmol/L, ( some recommend a lower range
to be 4mmol/L ), pre-lunch and pre-evening meal values of 4-8mmol/L,
pre-bed time level of 7-10 mmol/L and < 10 mmol/L two hours after
meal. In children less than five years of age acceptance of slightly higher
glucose concentrations may be necessary to avoid hypoglycemia which
may be a consequence of variable feeding patterns (43).
• Glycosylated HbA1c:
Glucose can attach to many proteins via a non-enzymatic process.
The average amount of HbA1c changes in a dynamic way and reflects
the mean blood glucose concentration over the previous 6-8 weeks.
Values are influenced by red blood cells (RBCs) survival, falsely high
values can be obtained when RBCs turnover is slow and vice versa. It is
recommended to be measured every 3-6 month. The (DCCT) aims for
HbA1c value of 7%; interpretation for its values is as follows
(44, 45, and 46)
,
5 - 5.9 % → within non-diabetic reference range with a possibility of
hypoglycemia, 6 - 6.9 % → ideal glycemic control, 7 -7.9 % → good
glycemic control in the absence of complications, 8 - 8.9 % →
associated with increased risk of microvascular complications, 9 -10.9 %
→ compliance likely to be a problem. Associated with high risk of
microvascular complications, > 11% → poor compliance.
- 39 -
• Fructoseamine:
Many proteins other than hemoglobin can also undergo nonenzymatic glycation leading to the formation of advanced glycosylation;
Fructoseamine is one of them. The disadvantages of fructoseamine are
that its turnover is more rapid than the hemoglobin (28 versus 120 days)
and its value must be adjusted to serum albumin (47).
•urine testing for glucose and ketones:
It has a potential errors that limits it's accuracy as a reflection of
glycemic control. Urine test may be negative in patient with normal, low
or
high
blood
glucose .For
these
reasons
blood
glucose
is
recommended for all diabetic patients aiming for strict glycemic control.
Testing for ketonuria is less subject to error because any positive
value suggests the presence of ketonemia (48).
1.4. Complications and Prevention:
1.4.1.
Potential
Mechanism
in
the
Pathogenesis
of
Complications:
The various diabetic complications don't necessarily have the
same pathologic mechanism. Three possible mechanisms have been
implicated in tissue changes, these include: 1- over glycation of proteins
2- increase in polyol pathway and 3- hemodynamic abnormality.
- 40 -
1.4.1.1. Glycation of proteins:
All proteins in the body can undergo glycation if exposed to
elevated glucose .Non-enzymaticaly glycated proteins slowly form
fluorescents cross-linked proteins called advanced glycation end
products or Ages. Receptors for these proteins are expressed on
endothelial
cells,
fibroblast,
mesangial
cells
and
macrophages.
Functional consequences of AGEs include cataract, limited joint mobility,
neuropathy and hyperlipidemia with its sequences (macro vascular
complications) (49).
1.4.1.2. Polyol pathway:
In this pathway glucose is reduced to sorbitol by the enzyme
Aldose reductase which is present in the retina, kidney papillae, lens,
schwan cells and aorta. It has been implicated in the pathogenesis of
cataract, retinopathy, nephropathy and aortic disease (50).
1.4.2. Complications:
Acute
complications
include
hypoglycemia
and
diabetic
ketoacidosis. Long term complications include; retinopathy, nephropathy
and neuropathy termed microvascular complications (develop in puberty
and early adulthood) and atherosclerosis and its sequel are termed
macrovascular complications (affect mainly older adults).
Other
complications include cardiomyopathy, dermopathy, joint dysfunction,
growth disturbances (growth failure and poor or excessive weight gain),
- 41 -
delayed puberty and autoimmune diseases. The risk of complications
may be increased by genetic factors, poor glycemic control, smoking
and duration of diabetes where complications increased with increased
duration (3, 5, 51).
1.4. 3. Prevention of type 1 diabetes mellitus:
The prevention of autoimmune diabetes is a realistic possibility.
The autoimmune process of type 1 diabetes begins years before beta
cell destruction becomes complete, there-by intervention is possible.
Potential prophylactic agents are:
• Insulin: Oral insulin is reported to reduce the severity of lymphocytic
infiltration in the pancreatic islets by acting as immunomodulator.
Aggressive insulin treatment of new onset type 1 diabetes in humans
increases the frequency and duration of insulin free remissions (52).
• Immunomodulation:
A- Azathioprine: is an immunosuppressive drug that inhibits or
prevents T-cell responses to antigens. Insulin could be discontinued with
its use in a number of patients but for no longer than one year (53).
B- Cyclosporine: A series of large scale trials in recently
diagnosed type 1 diabetes in Canada and France revealed that
remission were twice as common in the cyclosporine treated patients
compared with placebo. Although the remission lasted longer, almost all
patients required insulin again within 3 years.
- 42 -
C- Nicotinamide : A 20 nation international clinical trial ;the
European Nicotinamide Diabetes Intervention Trial (ENDIT) is underway
and the initial results suggest that the onset of type 1 diabetes can be
delayed by nicotinamide if it is started early enough (54) .
• Whole or partial pancreatic transplants have been successful in
treatment
with
type
1
diabetes,
but
they
require
life
long
immunosuppressant.
Further treatment is the use of specific immune therapy targeted at
the initiation of autoimmune process. In view of the success of
immunomodulation with bacillus Chalmette-Guerin (BCG) in mice, BCG
has been given to 17 newly diagnosed patients with type 1diabetes,
11(65%) went into remission for up to 10 months. This success rate was
significantly better than in control patients, and there were no side
effects (55).
1.5. Lipids of physiologic significance:
1.5.1 Definition:
Lipids are a heterogonous group of organic compounds that are
actually or potentially esters of fatty acids. They have the common
properties of being relatively insoluble in water and soluble in non-polar
compounds such as ether, Chloroform and benzene (56).
- 43 -
1.5.2 Biochemical importance:
Lipids are important dietary constituents because they are source
of high energy value, fat soluble vitamins and essential fatty acids. They
play many roles in the body eg in adipose tissue serves as storage form
of energy and serve as thermal insulator in subcutaneous tissues and
around certain organs. On the other hand, non-polar lipids act as
electrical insulators allowing rapid propagation of depolarization waves
along myelinated nerves and finally lipoproteins enter in the structure of
cell membranes and mitochondria (57) .
1.5.3. Classification:
1.5.3.1 Simple lipids :
Simple lipids are esters of fatty acids with various alcohols, divided
into:
• Fats (Acylglycerol): esters of one, two or three fatty acids with glycerol,
named as mono, di, and triacylglycerol respectively .Triacylglycerol in
the liquid state at room temperature is known as oil, while that in the
solid state is known as fat.
• Waxes: are esters of fatty acids with higher molecular weight
monohydric alcohols.
1.5.3.2. Complex lipids:
Complex lipids are esters of fatty acids containing groups in addition
to an alcohol and a fatty acid:
- 44 -
• Phospholipids: containing phosphoric acid residue such as glycerol in
glycerophospholipid and sphingosine in sphingophospholipids, are the
main lipid constituents of membranes.
• Glycolipids (glcophosphlipids): lipids containing Sphingosine, fatty
acids and carbohydrate –important in nerve tissues and cell membrane-.
• Other complex lipids: such as sulpholipids (containing sulphar), Aminolipids (containing amino acids) and lipoproteins (containing proteins) (58).
1.5.3.3. Precursors and derived lipids:
These include fatty acids, glycerol, steroids and fatty aldehydes.
Others include alcohol, lipid soluble vitamins, ketonbodies and
hormones.
• Neutral lipids: Are those which carry no charges and include
neutral fats (acylglcerols), Cholesterol and cholesteryl esters (59).
plasma lipids in humans are triglyceride(TG) 45%, total
phospholipids 35% , total cholesterol (TC) 15% and free fatty acids <
5%.
• Cholesterol:
Cholesterol is an alcohol that occurs in the circulation in two
forms; the free cholesterol accounting for about 30% and it is the form
that
exchange
readily
between
different
lipoproteins
and
cell
membranes. The other form is combined with a long chain FA as
cholesteryl ester accounting for the remainder 70% (storage form of
- 45 -
cholesterol). It is an amphipathic lipid (hydrophobic-hydrophilic) and as
such is an essential structural component of the outer layer of plasma
lipoproteins and of membranes in everybody cell especially adrenal
cortex, liver, kidney, brain and nervous tissues. It is the precursor of all
other steroids in the body such as corticosteroids, sex hormones, bile
acids and vitamin D (60).
A little more than half the cholesterol of the body arises by synthesis
(about 700 mg /day). The liver account of about 10% of total synthesis,
the intestine for about another 10%, other organs are the adrenal cortex
and reproductive tissues. All tissues containing nucleated cells are
capable of synthesizing cholesterol from acetyl coA derived from
glucose oxidation
(61)
. It is mainly a product of animal origin e.g. meet,
liver, butter fat, beef fat and brain, or in it's counterparts in plants named
phytosterl e.g. palm oils (56).
•Triglycerides:
Triglycerides are quantitatively the most significant lipids. They
constitute the majority of lipids in the body. They are important as a
major constituent of lipoproteins and as the storage form of lipids in
adipose tissues.
Triglyceride is the major portion (98-99%) of the animal lipids, the
remainder being cholesterol and other lipids. From animal sources e.g.
cod liver oil, butter lard, shark liver oils, it tends to solify at room
- 46 -
temperature, while those from plant source e.g. cotton seed, sesame,
olive and linseed oils remained liquid even at refrigerator temperature. In
the body (TG) are synthesized in most tissues from activated fatty acids
and phosphorylated C3 product of glucose catabolism (62).
•Fatty acids:
Non essential fatty acids can be synthesized in the body from
acetyl CoA derived from glucose oxidation or derived from external
sources such as vegetable oils.
• Lipoproteins:
Lipoproteins are a heterogeneous group of lipid-protein complexes
synthesized mainly in the intestine and liver and serve a wide variety of
functions in the blood; transporting lipids from tissues to tissues and
participating in lipid metabolism. In addition to free fatty acids four major
groups of lipoproteins have been identified in normal fasting human; very
low density lipoproteins (VLDL), low density lipoprotein (LDL),
intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and
a fifth type named chylomicron in the post absorptive period (63).
1- VLDL (pre-B-lipoprotein): Most of it is derived from the liver for the
export of triglycerol to extra hepatic tissues .In the plasma it is converted
to IDL and LDL.
2- LDL (B-lipoprotein): Represents the final stage of VLDL, is the major
transporter of cholesterol in the plasma (64).
- 47 -
3- HDL (α-lipoprotein): Involved in (VLDL) and chylomicron metabolism
and cholesterol transport from tissues to the liver a process known as
reverse cholesterol transport.
Triglyceride is the predominant lipid in chylomicron and (VLDL),
Phospholipids are the predominant lipid in HDL and Cholesterol is the
predominant lipid in (LDL). The purified protein component of a
lipoprotein particle is called apolipoprotein; each type of lipoprotein has a
characteristic apolipoprotein composition eg Apo A1 is prominent in
(HDL) (2, 4).
1.5.6 Lipid metabolism:
In general the incorporation of exogenous lipids occurs in three
phases: 1- digestion 2- absorption 3- transport.
• The digestive phase: In this phase; emulsification a process
by which lipid granules are broken up, started mechanically
in the mouth and completed in the small intestine by the
action of bile secreted from the gallbladder. Bile is composed
of lethicin and cholesterol and conjugated bile acids, the
highly amphipathic properties of the latter breaks up lipids
into smaller micelle units rendering them more vulnerable to
the action of digestive enzymes. Three hydrolytic enzymes
are produced by the pancreas and secreted into the
duodenum. These are the pancreatic lipase which acts on
- 48 -
TG to yield ( FAA), forming monoglyceride ,diglyceride and
glycerol, cholesterol esterases which cleaves the ester
linkages to release (FFA) and free cholesterol and the
phospholipase
A
which
hydrolysis
the
exogenous
phospholipids .
• The absorptive phase: In this phase the various micelle
components diffuse across the brush border into the mucosal
cells where the lipid content of the micelles are absorbed
while the bile salts passed down to the ileum. Inside the cell,
monoglyceride and (FA) are reesterified to (TG) and
cholesterol esters .
• Transport phase:
At this stage the nature of the lipid
transportation mechanism depends on the lipid molecules
being transported. The (TG) and other fat soluble molecules
eg cholesterol and phospholipids are incorporated into
chylomicron and released into the lymph of the thoracic duct,
in order to enter the circulation eventually. Short and medium
chains (TG) as well as small amount of long chain (FA) are
transported in the portal vein bound to albumin. Bile acids are
transported back to the liver through the enterohepatic
circulation (65).
- 49 -
Fat absorbed from diet and lipid synthesized by the liver and
adipose tissues must be transported between the various tissues for
utilization and storage. Since lipids are insoluble in water, the problem
arises of how to transport them in the blood .This is solved by
associating non-polar lipids (TG and cholesterol esters) with amphipathic
lipids (phospholipids and cholesterol) and lipoproteins to make water
miscible lipoproteins (57).
Chylomicrons are the largest of the lipoprotein fractions .In order to
pass through the endothelial cells of the capillaries, need to be
hydrolyzed first .they interact with (HDL) and activate lipoprotein lipase
which catalyzes the hydrolysis of triglycerides. Triglyceride is provided to
tissues as
monoglycerides, glycerol and free fatty acids; the later
quickly bind to albumin and taken up by the cells to be used for storage
as (TG) and for energy production .Having lost most of it's triglyceride
contents ,the chylomicrons interact with (HDL) again to became
chylomicron reminant
which contains
primarily cholesterol esters.
Receptors in the liver facilitate endocytosis of the reminant and its
hepatic degradation to release (TGs) and yield (VLDL) which again is
hydrolyzed to produce (IDL) and (LDL). LDL is rich in cholesterol and
has receptors on the membranes of hepatocytes and peripheral tissues
by which it is engulfed leading to deposition of cholesterol in the
cytoplasm (57, 66).
- 50 -
1.5.6.1 .Regulation of lipid metabolism:
• Hormonal regulation:
The rate of release of (FFA) from adipose tissues is affected by
many hormones that influence either the rate of estrificaton or the rate of
lipolysis. Several hormones promote lipolysis and accelerate the release
of
(FFA)
from
norepinephrine,
adipose
glucagons
tissues.
These
include
adrenocorticotrophic
epinephrine,
hormone,
thyroid
stimulating hormone, growth hormone and vasopressin.
Insulin inhibits release of (FFA) from adipose tissue leading to fall in
its concentration in the plasma. Hence in cases of insulin deficiency
sustained increase in plasma (FFA) levels occur. Insulin exerts its action
in two ways: First insulin enhances lipogenesis and synthesis of
acylglycerol by adipose tissue by several ways. And secondly, the
principal action of insulin in adipose tissue is to inhibit the activity of the
hormone sensitive lipase, which enhances FFAs release. Plasma (FFAs)
concentrations are more responsive than glucose to small changes in
circulating insulin levels due to greater insulin sensitivity of adipocytes
than most other insulin responsive tissues (67) .
• Dietary regulation:
When the amount of dietary cholesterol is reduced, cholesterol
synthesis increases to satisfy the needs of other tissues and organs .In
contrast, when the dietary cholesterol increases synthesis is almost
- 51 -
totally suppressed. This is achieved through the feed back inhibition of
the activity of 3-hydroxy-3 methylgluteryl-CoA reductase (HMG CoA)
which governs the rate limiting reaction in the pathway of cholesterol
biosynthesis (58, 64).
1.6. Clinical application:
Abnormalities of lipoprotein metabolism occur either at the sites of
production or utilization of lipoproteins causing various hypo (decreased)
or hyperlipidemias (increased). The most common cause of lipid
abnormality is (DM). Most other pathologic conditions affecting lipid
transport are primarily due to inherited defects (56).
• Hyperlipidemia:
Most of the hypercholesterolemia and hypertriglyceridemia in
children are secondary to exogenous or underlying clinical factors (68):
• Metabolic conditions; (DM), low (HDL), high 9LDL).
• Life style; smoking, physical inactivity, severe obesity.
• Hypertension/other underlying conditions: renal disease (renal
failure, transplant, nephritic syndrome), Liver disease (biliary tract
disease, cirrhosis and acute viral hepatitis).
• Endocrinopathy: hypothyroidism, Cushing syndrome.
• Drugs: cyclosporine A, thiazide and contraceptive pills.
- 52 -
• Storage diseases; Tay-sach, glycogen storage disease.
These conditions are relatively frequent in children and adolescents
and need to be searched for, because they can be influenced by
treatment of the underlying disorder (69,7o).
1.6.1. Screening of lipids in children:
1.6.1.1. Why to screen?
Interest in the study of plasma lipids has been at it's height in
the last one to two decades because of the close association between
hyperlipidemia and the development of atherosclerosis in children. This
fact poses the question of diagnosis and treatment of risk factors. There
was a controversy whether cholesterol should be searched for by
universal or by selective screening or by no screening at all (71, 72) .
In recent years cholesterol has been the third nationally
recommended health screening test in United State population and is
highly recommended by the national Heart, Lung and Blood institute for
both adult and children (73).
Lipid levels show differences in different populations and are
shown to be affected by age, sex, height, life style, infection and
genetics
(74, 75, 76)
. In addition levels may be affected by the type of food
ingested (77).
- 53 -
Several screening studies have been reported in non-diabetic
children of different ages and from different populations. In a study by
Knuiman and his group in 1983, plasma cholesterol levels in children
aged 8-9 yrs from different countries were compared. The results
showed variations in the cholesterol levels; the highest level was in
children from Finland while the lowest was in children from Ghana (78). In
a similar study on 13 yrs old children in which 15 countries were
compared, the highest cholesterol level was in children from Finland and
the lowest was in children from Nigeria (79).
Mohsen A.F.Elhazimi in the year (2001), studied the prevalence of
plasma lipid abnormalities in Saudi children aged 1-15 yrs and found
that the prevalence of lipid abnormality varied in the different age group
where the higher mean (TC) was in the 3-4 yrs olds and a significant
decrease occurred with age, with the lowest mean in those aged 1415yrs, while the highest level of (TG) was in the 2-3 yrs old and the
lowest in those aged 8-11 yrs (these changes in lipid may result from
sexual maturation and related hormonal levels). Cholesterol levels were
found to be lower than those reported in Finland, New Zealand and Italy
and similar to the Philippine population and higher than the population in
some of the African countries (79). Over 9% of all Saudi children and over
10% of those between 3-14 yrs of age fall in the high risk group for
(CHD) development when cholesterol levels are used (80).
- 54 -
As part of an epidemiological study on the cardiovascular risk
factors among children and adolescents in Navara; lipids and
lipoproteins were analyzed in 5829 children aged 4-17 yrs of both sex.
Results showed prevalence of hypercholesterolemia of about 21.07 %,
the lipid risk of LDL/HDL is very high 15-70 % and male adolescents turn
out to be the group with the highest risk (81).
Hyperlipidemia and atherosclerosis group in Canada analyzed the
relationship between Apo E phenotype and plasma lipid levels in 45
population samples from 17 different countries (1992). Results indicate a
consistent relationship between plasma (TG) level and Apo E phenotype
among different populations and that (TG) concentrations were
significantly higher in Apo E 2 than Apo E3 and that (HDL) is significantly
lower in Apo E4 than Apo E3(82) .
1.6.1.2. Whom to be screened?
Measurement of total cholesterol or lipid profile should be
performed only under certain defined circumstances .The American
Academy of Pediatrics (AAP), The American Heart Association (AHA)
and National Cholesterol Program (NCEP) don't recommend routine
total cholesterol screening in children.
- 55 -
Indications of cholesterol testing together with the recommended tests
are as follows (83, 84, and 85):
• In children as general (above the age of two years):
-Parent with (TC) of 240 mg /dl or more → measure (TC)
-Family history of premature coronary heart disease (CHD) →
measure fasting lipid profile
-Family history of dyslipidemia (abnormal lipid profile) → measure
fasting lipid profile
-Pediatric medical condition that predisposes patients to CHD of
dyslipidemia → measure fasting lipid profile.
- Family with unknown history (include situations in which parental
TC values are unknown) → measure (TC).
• In diabetic children:
Type 1:
- More than 12 yrs of age (assumed to be pubertal): screening
should be done at diagnosis but after glycemic control is achieved and
should be repeated after 5 yrs if the initial screen is normal.
- In those < 12 yrs of age (generally per pubertal): in the absence
of parental history of dyslipidemia or early (CHD), there is no clear
indication for screening.
- 56 -
Type 2:
- Screen at diagnosis regardless of age but after glycemic
control is achieved, if normal lipid values are obtained, screening
should be repeated every 2 yrs (84, 85).
Although universal screening would make it possible to identify all
those with high cholesterol levels, it has significant draw backs. The
panel decides not to recommend universal screening for the following
reasons: 1- quite a few children with high cholesterol levels will not have
high enough levels as adults to qualify for individualized treatment. 2Many young people will be labeled as patients with a disease, causing
unjustified anxiety for them and their families and 3- There is insufficient
evidence concerning the long term safety and efficacy of drug therapy in
childhood to reduce (CHD) morbidity and mortality in adulthood(85) .
1.6.2. Analytical procedures
In the past lipid profile was consisted of (TC), (TG) and the serum
appearance after standing in the refrigerator for several hours. Now
sophisticated methods are advanced to quantities the various lipoprotein
fractions .When TC, TG, HDL.C, and LDL.C are measured in a single
sample the test is termed lipid profile. Abnormalities in (TC) including
(HDL-C) and (LDL-C) with or without abnormal (TG) level is termed
dyslipidemia (61).
- 57 -
Children should be in their regular diet for 4-6 weeks before
testing .Recent changes in the diet or severe illness (eg hospitalization
within the last 4-8 weeks) is a contraindication for testing because
significant stress can lead to transient decrease in lipid levels or
transient lipid abnormalities( borderline or elevated levels) as in
hypertriglyceridemia following (DKA). Lipoproteins are acute phase
reactants and their concentration declines within 24 hours of acute
severe illness. Measurement of (TC) and (HDL.C) don't need to be
performed in the fasting state. Unlike (TG) in lipid profile which must
always follow an over night fast for at least 8 hours and preferably 12-14
hours. LDL.C can either be measured directly and so doesn't require a
fasting specimen or calculated as part of the lipid profile when (TG) are
less than 400 mg /dl using a Friedewald equation. LDL.C = TC– (HDL.C
+TG/5). TG/5 represents the VLDL.C (86).
Cholesterol level is influenced by 1- menstruation; level increases
before it, peaks at and then declines 2- haemolysis; dilutional effect may
occur with gross haemolysis
(87)
. Individualized specialized tests that
can be ordered if unexplained (CHD) is present in the family are the
apolipoproteins (2, 4).
The National cholesterol education program (NCEP) determined the
different plasma lipid levels in children in mg/dl as shown in the table
below (85, 88).
- 58 -
Table (1)
Children < 20
Borderline
Desirable level
years
Elevated level
level
TC
<170
170—199
> 200
LDL.C
<110
110---129
> 130
HDL.C
>45
35---45
*TG
<125
-
<35
> 125
* Not established by NCEP, 125 mg /dl approximates the mean 95th
percentile for (TG) in boys and girls during childhood and adolescence.
* Optimal lipid levels for diabetics are in accord with those of the Third
Adult Treatment Panel and (AHA):
LDL < 100mg/dl,
HDL > 35mg/dl
and TG < 150 mg/dl (84).
1.7. DIABETES AND LIPIDS:
Under normal conditions the reactions of the metabolism of various
nutrients proceed in a manner which would allow the maintenance of
constant levels of various intermediates. It is only when a certain
metabolite is accumulated in an unusual quantity the state of equilibrium
is shifted. One example of such a situation is (DM).
In diabetes utilization of glucose is decreased and as a result
most of the energy is obtained from oxidation of (FA) to acetyl CoA
through the citric acid cycle (CAC). For efficient glucose utilization an
- 59 -
adequate amount of oxaloacetate is required. Under normal conditions
this is met by its production from pyruvic acid, aspartic acid and glutamic
acid. In (DM) the formation of oxaloacetate is greatly reduced due to
lower rate of glycolysis so oxaloacetate is derived mainly from amino
acids thereby depleting the tissue proteins. Further more the function of
the (CAC) is diminished to a marked extent as the higher concentration
of long chain fatty acyl coA inhibits the first enzyme in the (CAC) and
leads to a small utilization of acetyl coA and ultimately generates less of
energy which would be one of the causes of weakness in diabetic
patients. Fatty acyl CoA also inhibits acetyl CoA carboxylase (the first
enzyme in FA synthesis). This is the probable explanation of depressed
lipogenesis and increased levels of (FFA) in the plasma (2).
1.7.1. Lipid Abnormalities in Diabetes:
Hypertriglyceridemia is common in diabetes both as a transient
component of poor metabolic control and as a persistent finding in some
relatively well controlled patients. In the later situation a genetic form of
hyperlipidemia may coexist with diabetes. Two mechanisms may be
operative for the hypertriglyceridemia: The decreased level of lipoprotein
produces a defect in lipolysis of TG and the increased level of (FFAs)
provides substrate for over production of hepatic (VLDL) and (TG).
- 60 -
Insulin therapy reverses both of these defects and restores TG levels to
normal.
In type 1 (DM) elevated levels of (LDL.C) result from several
factors: Insulin deficiency may reduce the activity of LDL receptors,
consumption of excess saturated (FAs) and cholesterol can suppress
the activity of (LDL) receptors and accentuates the rise in (LDL) levels
and the last that glycation and oxidation of LDL may reduce the affinity
of LDL to its receptors and thereby lower its clearance rate. The
incidence of elevated LDL .C in diabetic patient is not as high as that of
hypertriglyceridemia (89).
1.7.2. Shared Complications of lipids and diabetes:
1.7.2.1. Atherosclerosis:
Atherosclerosis is a disorder of the arterial wall characterized
by the accumulation of cholesterol and it's esters (referred to as fatty
streaks) in cells derived from monocots macrophage line in the subendothelium of large muscular arteries .This layer is then covered by
fibromuscular cap forming a fibrous plaque named atherosclerotic
plaque which narrows the blood vessel and serve as a site for
- 61 -
thrombus formation by promoting platelet aggregation. These changes
were found in children as young as 3 yrs. The condition is clinically
manifested as stroke, myocardial infarction and peripheral arterial
disease. (90).
Systemic epidemiological and pathological studies documented
the childhood origin of atherosclerosis and its progress slowly into
adulthood at which time it leads frequently to coronary heart disease,
one of the major causes of death (79, 91). Identified risk factors contributing
to the early onset of (CHD) in children and adolescents include (92):
• Metabolic: high LDL, HDL < 35 mg/dl and DM.
• Family history of premature (CHD) or peripheral vascular Disease
(before age 55 yrs).
• Life style: smoking, physical inactivity and obesity especially
abdominal (>95th Percentile weight for height on the national
Center for health Statistics)
• Hypertension.
Diabetes is a major risk factor contributing to the development
of atherosclerosis and
considered a coronary heart disease
equivalent (83).
- 62 -
Oxidation of elevated LDL levels is thought to be atherogenic. It's
uptake by monocytes /macrophage cells leads to the formation of
the foam cells the precursor of the atherosclerotic lesion. AGEs play
a role in lipoprotein oxidation and auto antibodies against glycated
LDL. Low levels of HDL in diabetic patient may result also from
glycation which accelerate its turnover or accelerate TG formation.
HDL protects against atherosclerosis by two mechanisms; first by
reversal of cholesterol transport and second by inhibition of LDL
oxidation. Increased platelet aggregation may contribute to diabetes
atherogenesis possibly as a result of elevated levels of Von
Willebrand factor and diminished level of prostacyclin (an inhibitor of
platelet aggregation) (2) .
To determine whether these risk factors are also associated with
atherosclerosis many studies were done in both diabetic and nondiabetic patients.
A longitudinal cohort over 15 yrs was identified from a
community study of the natural course of atherosclerosis including
1169 individuals aged 5-14 yrs. Results of lipoprotein variables in
childhood were associated with that in adulthood; more strongly for TC
and LDL.C than for TG and HDL.C. Adverse levels of LDL.C in
childhood persist overtime, progress to adult dyslipidemia and relate to
obesity and hypertension as well. This tracking of dyslipidemia
- 63 -
suggests that most but not all of children with dyslipidemia will have it
as adults, this is in part related to the dramatic decrease in total
cholesterol seen as children progress through puberty (93).
In the year 1994 arteries and tissues from approximately 3000
autopsied persons aged 15-34 yrs were examined in the Bogalusa Heart
study. The extent of both fatty streaks and fibrous plaques in the right
coronary artery and abdominal aorta associated positively with increase
in (TC), (LDL), hypertension, impaired glucose tolerance, smoking and
obesity. Age, sex and race were independent factors (91).
The pathological determinants of atherosclerosis in youth (PDAY)
study (1999) reported that LDL.C, severe obesity and elevated HbA1c
levels were significantly correlated with the postmortem diagnosis of
coronary atherosclerosis (94).
In the Muscatine study increased body mass index (BMI), blood
pressure (BP) and low (HDL.C) were correlated with the early
development of coronary calcification (considered a marker of
atherosclerosis). The prevalence of coronary calcium in adolescent with
familial hypercholesterolemia is 25% and the presence of calcium is
more likely with the highest (BMI) (95, 96).
Few data are available on which to base goal levels for two major
risk factors namely (BP) and lipid/ lipoproteins. To determine at which
levels of (LDL) , (HDL) ,(TG) and (BP) the relative risks of type 1(DM)
- 64 -
complications increased significantly; Orchard TJ
and his colleges in
the epidemiology of diabetes complication study followed up 589
diabetic patients over 10 yrs for incidence of mortality, (CHD) and
microvascular complications. The suggestive goal levels were; LDL.C<
100 mg /dl, HDL>45 mg/dl, TG < 150 mg /dl, systolic BP < 120mmHg
and diastolic one < 80 mmHg and complications was found to be
associated with levels above these. Age, sex and glycemic control had
little influence on these goals .The conclusion was that vigorous control
of BP and lipid abnormalities is needed (79).
1.4.2.2. Retinopathy and nephropathy.
The association of dyslipidemia with microvascular complications
has been less investigated. It may cause or exacerbate diabetic
retinopathy and nephropathy by alteration of the coagulation fibrinolytic
system, changes in membrane permeability, damage to endothelial cells
and increased atherosclerosis .Hyperlipidemia is associated with faster
decline in glomerular filtration rate and progression of albuminuria and
nephropathy. Recent evidence also suggests a role of lipoprotein (a) in
progression of retinopathy and nephropathy (98).
There is some evidence to implicate serum lipids in exudative
maculopathy. Cross sectional studies suggest that higher serum lipids
are found in patients with macular exudates. Lipid lowering therapy may
significantly benefit diabetic retinopathy and nephropathy. However,
- 65 -
most of the data are based on short term studies and need to be
ascertained (98).
1.8. Management of dyslipidemia:
Prevention of (CHD) is the goal of lipid abnormalities treatment.
The risk increases with increasing plasma cholesterol and (LDL). High
(TG) although not an independent risk factor for (CHD), is generally
accompanied by low (HDL) which may predispose to it. Lowering LDL and
increasing HDL are thus goals in prevention. (86).
Patients with borderline or elevated levels of lipids should be
subjected either to dietary or both dietary and pharmacological treatment
according to the (NCEP) recommendations (85).
• LDL.C and TC:
Acceptable levels → provide education on eating pattern
recommended and provide (CHD) risk factors advice including
measurement of (BP) regularly, anti-tobacco counseling, encouragement
of physical activity and management of obesity. Repeat lipoprotein
analysis in 5 yrs.
Borderline levels → provide risk factor advice, initiate step one
diet therapy and other risk factors intervention. Re-evaluate the patient
status in one year duration.
With lipid values greater than the optimal levels:
- 66 -
- Blood glucose control should be maximized and dietary
counseling should be provided.
- Follow up of fasting lipid profiles should be performed at 3 month
and then at 6 month to determine the effect of the above measures. If
treatment goals are achieved lipid profile should be repeated yearly,
but if failed further intervention is warranted based on (LDL) levels
shown below:
-Borderline levels → maximize non pharmacologic treatment.
- LDL level 130--159 mg/dl→ consider medications, basing the
treatment decision on the child (CHD) risk factors.
- LDL levels > 160 mg/dl and TC > 200 mg/dl → start medications.
B.Triglycerides:
Elevated levels are not directly managed with medications. If >
150 mg /dl → maximize blood glucose control and achieve desirable
weight. If > 1000 mg /dl (increased risk of pancreatitis is present) → start
medications. Serum LDL levels can be lowered by reducing saturated fat
and cholesterol intake and reducing weight. Serum TG can be lowered
by substitution of starch for sugar and weight reduction while Serum
HDL can be raised by decreasing cigarette smoking, increasing physical
activity and good control of diabetes (99).
- 67 -
1.8.1. Diet therapy:
Dietary modifications are the bases of treatment in children. The
NCEP recommends management of lipid disorders as shown in table
2(85, 99).
Table (2):
Nutrient
recommended intake
Step one
Total fat
step two
no more than 30% of
total calories
saturated FA
polyunsaturated FA
<10 % of total calories
up to 10%
<7%
same
monounsaturated FA
remaining fat calories
same
cholesterol
> 300 mg/day
>200
carbohydrates
55% of total calories
same
proteins
15-20 % of total calories
same
calories
to promote normal growth
same
and development.
- 68 -
The international society of pediatric and adolescent diabetes
(ISPAD) recommendations for dietary fat intake in type 1 diabetics is
same as those shown above
(100)
. The (ADA) recommends an
individualized diet with intake similar to other children, as comparable to
(ISPAD) recommendations (101).
In patients with severe hypercholesterolemia dietary cholesterol
intake should not exceed 150 mg/day in children and 250- 300 mg /day in
adolescents. Even more important is the reduction of the intake of
saturated fats eg butters fat, beef fat, palm oil and their replacement by
monounsaturated and polyunsaturated fat such as natural oils. Some
additional lowering of (LDL) may be achieved by the preferential use of
vegetables over animal proteins and of complex carbohydrates over sugar
since sucrose and fructose have a greater effect in raising blood levels
than do other carbohydrates (69).
The reason for cholesterol lowering effect of polyunsaturated FAs is
still not clear .However, several hypotheses have been advanced
including the stimulation of cholesterol excretion into the intestine and it's
oxidation to bile acids .Other hypotheses is the shift in distribution of
cholesterol from the plasma into the tissues (58) .
1.8.2. Drug therapy
There are no major long term studies demonstrating harm or
benefits of lipid lowering drugs. In general it should be restricted to children
- 69 -
with genetic disorders of lipid metabolism. Indications of drug therapy
according to the (NCEP) program in children 10 yrs of age or older (after
adequate trial of dietary therapy) include (85, 88):
1- LDL.C > 190mg/dl in patient with no CHD risk factor.
2- LDL.C >160mg/dl and a positive family history of premature (CHD) or
two or more of its risk factors after vigorous attempt had been made to
control them .The goal is LDL.C <130 mg/dl in general and < 100 mg /dl in
diabetics. Medical therapies for the common pediatric dyslipidemias are
listed below (102):
Table (3)
Predominant Fredrickson
lipid
phenotype 1st Choice
elevation
Bile acid
LDL.C
II A
binding
resins
Niacin
LDL.C + TG
II B
Niacin
TG
IV
Medications
2 Choice
3rd Choice
nd
Niacin
Fibric acid
derivatives
/atorvastatin
Fibric acid
derivatives
HMG –COA
reductase
inhibitor
--------
--------
1.8.2.1. Bile acids resins:
The (NCEP) recommends acid binding resins as the drugs of
choice in treating high (LDL) in children. They block bile reabsorption
from the gut resulting in bile excretion in stool. Compensatory
hepatocytes bile synthesis increased which leads to increased
- 70 -
hepatocytes LDL-R expression and hence (LDL) clearance resulting in
drop in its concentration.
The powder resin cholestyramine and cholestipole are insoluble in
water and must be mixed with water or juice to avoid development of
intestinal obstruction .The resins are divided between breakfast and
dinner and are dosed in scoops or packets of 4-5g each. Typical dosing
in children is to begin with 1-2 packets per day and increase every
month to achieve (LDL) level < 130 mg/dl or until maximum is reached,
24g in cholestyramine and 30 g in cholestipol. These drugs can lead to
hypertriglyceridemia and therefore indicated for treating type IIA but not
routinely type IIB (103).
1.8.2.2. Niacin:
Niacin is the second line drug. It is effective in patients with
combined
hyperlipidemia
and
in
those
with
isolated
hypertriglyceridemia resulting from elevated (VLDL) level. It appears to
decrease lipoprotein production and increase its clearance.
Starting dose is 50 mg/day and increased gradually every 4 weeks
or often less until (LDL) is < 160 mg/dl or (TG) is < 300mg/dl or until a
dose of 1500 -2000mg /day is reached without liver toxicity. Splitting the
dose should be attempted as soon as a dose of 100 mg/day is reached.
Once (LDL) < 160mg/dl and (TG) < 300/dl no need to increase the dose.
When (LDL) is < 130 mg/dl and (TG) < 125 mg/dl niacin dose can be
- 71 -
reduced or a trial period off medications can be attempted.
It has
potentially significant systemic toxicity that include ;liver disease, GI tract
upset and facial flushing .liver enzymes need to be measured every 3
month in these patients
(104)
.
1.8.2.3.. HMG – COA redductase inhibitor:
Consider use of this drug if the above two drugs failed or not
tolerated. HMG-COA redductase catalyzes the conversion of HMGCOA to mevalonate which is the rate limiting step in the synthesis of
cholesterol. Inhibition blocks hepatocytes synthesis of cholesterol
which stimulates hepatocytes to produce more (LDL) receptors leading
to (LDL) clearance from the circulation .Food And Drug Administration
(FDA) approved that statin is available since the year 2000. Examples
of this group are lovostatin, pravastatin, simvastatin, fluvastatin and
atorvastatin .Major complications are liver toxicity and rhabdomyolysis
leading to renal failure (105).
1.8.2.4. Fibric acid derivatives
This class inhibits lipoprotein production and increases its
clearance. It is useful for treatment of a variety of dyslipidemias
including type IIA, IIB IV and type V. usually given after the above
mentioned drugs in treating type IIA but can be used after niacin in
treating hypertriglyceridemias .No data exist on it's use in children
- 72 -
because safety and effectiveness are not established yet. Examples
are Gemfibrozil and Fenofibrate (98).
1.9. Studies Done on Lipid Profile:
Less is known about lipid abnormalities in diabetic children. Some
studies have shown normal values two years after diagnosis while many
others have shown different results (106).
LDL and TC are higher in children with type1diabetes than their
siblings
(107)
.This was proved by Tores M and his colleges in their study of
141(58 males and 83 females) diabetic children and adolescents and their
first degree relatives (1997). They found that mean concentration of (TC),
(LDL) and ApoA1 were significantly higher in diabetic boys compared to their
siblings (108). However, the Pittsburgh Diabetes clinic study found a difference
between diabetic patients and their siblings in HDL.C sub-fraction but other
lipid levels were not significantly different (109).
Lipid abnormalities are also common in diabetics than their controls
(110)
. This was approved by some and rejected by other studies: The
prevalence of dyslipidemia in children with type 1(DM) and it's relation to
glycemic control was studied by K Azad, J M Parkin, M F court and M F laker
in a group of 51 children and adolescents and a control population of 132
school children. The prevalence of dyslipidemia in the diabetic group was
39 % compared with 17% in the control group. Serum cholesterol alone was
- 73 -
raised in 25% of the diabetics and together with (TG) raised in 14%
compared with 16% and 0.7 % respectively in control subject .Age has no
effect in (TC) and (TG)
concentrations in children within the age range
studied and there is a positive correlation between (TC), (TG) and (HbA1c)
in diabetic children .This confirm that glycemic control is a major factor
affecting serum lipid concentration since that patients with good control have
glycated (Hb A1c) similar to the control group
(111)
. Another study agreed
upon these results where Plasma lipoproteins and lipoprotein lipase activity
in 15 newly diagnosed diabetics 7-23 yrs old and their healthy control of the
same age were evaluated in the year 1985 by Rubba P, Capaldo B and
Caprio S. They found that (TG), (VLDL) and (TC) were higher than in the
control group and are inversely related to lipoprotein lipase activity.
Decreased activity of the enzyme had been found to be associated with
hypertriglceridemia and reduced (HDL) in young diabetic patients with
ketonuria (112).
During a four weeks summer camp, A.Pollak .K, Widhalm, and
E.Schober (1980) studied plasma lipoproteins and (HbA1c) in 19(8
females and 11males) diabetics aged 2-12 years with a duration of 1-10
yrs in comparison to 64 non diabetic control of similar age . All children
took part in daily physical activities and received a modified diet. The
mean (TG) was found to be significantly high in diabetic children on
admission to the camp than the control. This difference is no longer
- 74 -
apparent at the end of the study .The mean (TC) and lipoproteins were
similar in both groups though (TC) was significantly higher in diabetic
females compared to diabetic males. HDL level; which did not differ
from control values, at the end of the study had increased significantly in
diabetics to levels similar to those in the control group. No relationship
was found between (HbA1c) estimates and (TG) or (TC) or between
males and females
(113)
. Similar results were shown when Serum
lipoproteins and apolipoproteins were followed up in 34 children during a
period of 5 yrs from diabetes onset in Sweden children (1997). Diabetics
didn't differ from their control group in these respects but serum (TG)
and (VLDL) were high in some diabetic patients and correlate
significantly to subcutaneous fats and there was no correlation between
any serum lipid and (HbA1c) (114).
Lipid abnormalities relate to metabolic control in some
all studies
(115)
(107)
but not
. The effect of glycemic control in lipid profile in type
1(DM) was studied by Ercigas F, Arslan B and Uslu Y. Results showed
that (TC) and (TG) were significantly higher than the control group and
significantly increased in poorly controlled in relation to metabolically
well controlled diabetics (116).
The correlation between glycemic control and lipid metabolism
in respect of possible risks for the development of macrovascular
disease were studied by Thomer J and Klinghammer A (1993) in 78
- 75 -
diabetic children. There was no association between the quality of
glycemic control and (LDL) or (HDL) and a week association with
cholesterol .In nearly all patients (HDL) was estimated to be in the upper
normal range (117).
Familial and dietary factors are important parameters in
determining the lipid abnormalities. To determine whether abnormal lipid
levels in children with type1diabetes are the result of poor metabolic
control or genetic factors; Abraha A, James T
and their colleges
conducted a study in 141 diabetics aged 7.7-19 yrs and 192 of their
parents (1999). Nearly 15.3% had hypercholesterolemia, 17.9 % had
hypertriglyceridemia and both were high in 5.6 %. Cholesterol, (TG) and
(VLDL) were significantly related to glycemic control and familial factors
may be important determinants of lipid levels in young diabetic people
(118)
. This was not agreed upon in Adelaide at Australia where Esko J
Wiltshire D, Craig H and Jennifer studied the relative influence of diet,
metabolic control and familial factors on lipid in 79 diabetic children aged
8 yrs and more and 61 age and sex matched control .Results showed
that (TC), (LDL), (HDL) and Apo B were significantly higher in diabetics
than in their control. cholesterol, (LDL) and Apo B show no difference
between subjects with or without family history of premature (CHD) or
lipid disorder and correlate independently with (HbA1c) but not with
dietary control. Patients with high (LDL) >130 mg/dl had significantly
- 76 -
higher (HbA1c). They conclude that lipid abnormalities remain common
in children with type1diabetes and were related to metabolic control but
not dietary intake and can occur even in children who adhere to current
dietary recommendations (119).
Lipid levels are shown to be affected by age and sex
M, Souchan PF and Benali K (2000 ) studied
(120)
. Polka
the relation between
metabolic control , pubertal status and plasma lipoprotein levels in 126
diabetic children with a mean duration of about 7-8 yrs
and their
controls. Cholestrol of diabetics was higher in both sex and at each age
than their control with a prevalence of 16% and was not correlated with
the degree of metabolic control. The prevalence of hypertriglyceridemia
was 5% in diabetics and was weekly positively correlated with the
duration of (DM) and metabolic control. They conclude that plasma
cholesterol levels are higher in diabetic children and don't follow the
usual decreasing pattern during puberty (121).
Physical activity is one of the important risk factors controlling lipid
levels. For this fact Lipman
and his colleges conduct a study to
determine the prevalence and predictors of hypercholesterolemia and to
examine the distribution and inter-relationship of risk factors for (CHD) in
67 sub samples .They found that frequency of dyslipidemia was more
than expected in the total sample and
(TC) – (CHD) risk factor
associations were not observed. However, diabetes control and physical
- 77 -
activity were correlated with (TC). They conclude that assessing lipid
profile in type 1diabetics and monitoring (CHD) risk factors in
hyperlipidemic children is important (122).
Although most studies of lipids in children with type 1 diabetes
have shown increased (TC) and (TG)
(107)
, results for (HDL) have been
conflicting some had found lower levels as Chase H (123) or normal levels
(113)
. Whereas others found higher levels as RH Eckel, JJ alber and his
colleges in their study of the components of (HDL) in diabetic patients
and their control. HDL level was slightly higher than in the control
(124)
.
Another supporting study was that done by Anderson GE, and colleges
on serum lipids and lipoproteins in 157 diabetics and 350 healthy
reference individuals and it's relation to obesity. TG was lower while (TC)
and (HDL) were higher in diabetics than their controls. Serum lipids and
lipoproteins didn't correlate with obesity (113,125).
- 78 -
CHAPTER TWO
JUSTIFICATION AND OBJECTIVES
- 79 -
2. JUSTIFICATION AND OBJECTIVES
2.1 Justification
■ Diabetes mellitus is one of the major risk factors of lipid
disorders.
■ Early identification of lipid abnormalities aids in early management
and prevention of complications.
■No similar study was done in Sudanese diabetic children.
- 80 -
2.2 Objectives
■ To determine the prevalence of dyslipidemia in children with
type 1 diabetes.
■ To study the correlation between dyslipidemia and some risk
factors.
- 81 -
CHAPTER THREE
PATIENTS AND METHODS
- 82 -
3. PATIENTS AND METHODS
3.1. STUDY DESIGN:
This is a cross- sectional, prospective, case control hospital based
study.
3.2. STUDY AREA:
The study was conducted in Khartoum State at diabetic clinics of:
• Gaffer Ibn Auf Children Emergency Hospital, (Khartoum).
• Ahmed Gasim Teaching Hospital, (Khartoum North).
• Gaber Abu Eleiz Diabetes Center, (khartoum).
3.3. STUDY PERIOD:
The study was conducted during a period of 6 months, from
September 2004 January 2005.
3.4 STUDY POPULATION:
Children diagnosed as type 1 diabetes aged < 18 years and their
control groups were included.
3.5. INCLUSION CRIETRIA:
• All children with type 1 diabetes < 18 yrs who came for follow up
in the above mentioned referral clinics were enrolled in the study.
• Non-diabetic children matched according to age group and sex
were selected from schools as the control group.
- 83 -
3.6. EXCLUSION CRITERIA:
Diabetic patients and /or control were excluded in the following
conditions:
• Presence of acute illness 4-6 weeks prior to enrollment in the study
including DKA.
• Refusal of the child and /or their guardians to participate in the study.
3.7. SAMPLE SIZE:
The sample size was calculated according to the equation:
N = Z2
PQ
2
d
Where
N = sample size.
Z = 1.96 (at 95th level of confidence).
P = probability of the problem under study =o.95% .
Q = 1- P = 0.05%.
d = desired margin of error (o.1).
At the 95th level of confidence N= 86. The total number of patients
Studied were 100 ( total number of control is 100).
3.8. ETHICAL APPROVAL:
• Written approval of the study was obtained from the above
mentioned hospital administrators.
• Informed consent was taken from children and /or their guardians.
- 84 -
3.9. STUDY TOOLS:
3.9.1. Questionnaire:
A standardized questionnaire was designed which Included:
Personal characteristics of the patient such as name, gender and
ethnic group (125). Developmental history including schooling and
exercise diabetes related variables such as duration of diabetes ,insulin
dose and socio- demographic characteristics of parents. Family history
of DM, obesity, CHD and hypertension were also included. The last
section contains clinical examination data and investigation results.
3.9.2. Clinical examination:
Every child was subjected to a clinical examination with emphasis
on weight using stand on scale, height using unstretchable tape, blood
pressure using Mercury sphygmomanometer with different cuff sizes and
presence or absence of hepatomegaly and joint immobility.
3.9.3. Investigations:
3.9.3.1. Sample collection and storage:
All patients were requested to fast for at least 8 hours. After
sterilization using 70% alcohol, 3 ml of blood were withdrawn in a
disposable syringe without applying tourniquet. One ml of whole blood was
collected in (EDTA) labeled container for HbA1c testing. The remaining 2
ml were centrifuged for 3 hours to extract plasma and then collected in a
plane container for lipid profile testing. Both tubes were coded with serial
- 85 -
numbers and stored in the refrigerator at 2—8 C° to be analyzed within 7
days.
3.9.3.2. Laboratory investigations:
HbA1c was preformed only to patients and determined on whole
blood using colorimteric ion exchange column. The cut-off points used were
those established by the (DCCT)as shown in (appendix 1). Specimens for
testing lipid profile were analyzed using enzymatic colorimetric method
in which two control materials were used ; control level 1(normal) and
control level 2 (abnormal)as shown in (appendix 2).
3.10 STATISTICAL METHODES:
Data was entered in computer using the Statistical Package of
Social Science (SPSS). Frequencies were obtained for all variables and
Chi square tests were computed for selected variables. The level of
significance was taken as p < 0.05 and fissure exact test was used in
frequencies of less than 5.
3.11. POTENTIAL DIFFICULTIES:
• Transport of samples to be centrifuged and stored.
• Two referral clinics were conducted in the same day.
3.12. INPUT OF THE AUTHOR:
The task of questionnaires completion, performing the clinical
examination, collection of blood samples and entering the data in the
computer were conducted by the author.
- 86 -
3.13. OTHER PARTICIPANTS IN THE STUDY:
Laboratory technicians in Gaber Abu Aleiz Diabetes Center
participated a lot in this study together with colleagues in pediatrics.
3.14. FUNDS AND GRANTS:
The research was done with self resources with no external funds.
- 87 -
CHAPTER FOUR
RESULTS
- 88 -
4. RESULTS
A total number of 200 children were enrolled in the study .one
hundred diabetic and the same number for control matched according to
age group and sex.
4.1. DEMOGRAPHIC CHARACTERISTICS OF THE STUDY
GROUP.
4.1.1. Age group:
The mean age of the study group was (12.1 yrs ± 2.5. SD for
diabetics and 12.0 yrs ± 3.5.SD for control) and ranged from (3.5-18 yrs).
The majority of children, 53 patients (53%), were in the age group 10 –
14 yrs, in comparison to 77 controls (77%). While in the age group 15 –
18 yrs were 25 diabetic (25%) and 12 controls (12%). In the age group
5-9 yrs there were 17 patients (17%) with their counterpart 9 (9%)
controls. Only 5 diabetics (5%) and 2 (2%) of control were in the age
group 1-4 yrs. The difference in age group distribution between the two
groups was statistically insignificant,(P <0.5) as shown in (Fig 1).
4.1.2. Gender:
Female gender constitutes about 56 of the study group (56%) while
males constitute 44(44%) as shown in (Fig 2)
- 89 -
study group. Fig 1. Age group of the
(n=200)
77%
80%
70%
60%
53%
Percentage
50%
40%
30%
25%
17%
20%
12%
9%
10%
5%
0%
2%
0%
0%
<1
1--4
5--9
10--14
Age group
Patient
Control
P.value= 0.5
- 90 -
15--18
Figure 2. Gender distribution of the study group.
(n=200)
Male
44.0%
Female
56.0%
- 91 -
4.1.3. Ethnic group:
Arab ethnic group constituted the majority of the study group 69
patients (69%) while the controls were 68 (68%). Ten of the patients
(10%) and 9 of the controls (9%) were Nubians. Kordofanian and
Darforian descendants were 9 patients (9%) and 16 controls (16%). Five
patients (5%) and 3 controls (3%) were Bija, while 2 diabetics (2%) and
3 controls (3%) were Nuba. Only one patient was from the Nilotic group,
while 4 patients (4%) and one control were Equatorials. The difference in
ethnicity was not statistically significant, (P=0.4) as shown in (Table 1).
4.2. FAMILY AND SOCIAL HISTORY:
4.2.1. Consanguinity.
In 39 patients (39%) there was no consanguinity between parents,
compared to 50 controls (50%). First degree cousins were (35) 35% and
(36) 36% for patients and controls respectively. Second degree
consanguinity was found in 24% of the patients and only in 5 controls
(5%). In two patients (2%) parents are far cousins compared to 9
controls (9%). The overall difference between the two groups was
statistically significant. (P=0.01) as shown in (Fig 3).
- 92 -
Table 1. Ethnic origin of the study group.
Ethnic group origin
Patient
N
%
Control
N
%
Arab
69
(69)
68
( 68)
Nubian
10
(10)
09
( 09)
Kordofanian and Darforian
09
(09)
16
(16)
Nilotic
01
(01)
00
( 00)
Bija
05
(05)
03
( 03)
Nuba
02
(02)
03
(03)
Equatorial
04
(04)
01
(01)
Total
100
100
100
- 93 -
100
Figure 3. Parent consanguinity.
(n=200)
50
50
45
39
40
35
36
35
30
24
Percentage
25
20
15
9
10
5
5
2
0
1st degree relative
2nd degree relative
Far relative
Consanguinity
Cases
Control
P.value< 0.0 1
- 94 -
No consanguinity
4.2.2. Parents education:
Father education (university and high school) was 41% and 46% in
patients and controls respectively. Those who had basic and
intermediate schooling were 43(43%) in the diabetic group and 38(38%)
in the control group. Illiterate fathers were 16(16%) in each group.
Illiterate mothers were 25 (25%) in patients and 28% in control. Only 4
mothers (4%) had postgraduate education in diabetic group compared to
7 mothers (7%) in the control group. The difference in education
between the two groups was not statistically significant, (P = 0.6 and 0.1
for father and mother education respectively), as shown in (Table 2, 3).
4.2.3. Parents occupation:
The majority of parents were labourers 68 (68%) and 72 (72%) for
both patients and controls respectively. Government employee and
businessmen were 29% in the patients group and 26% in the control
group. The least were the unemployed parents; 3% for patients and 2%
for control group. Most mothers were housewives, 92% in the patient
group and 89% in the control group. Six mothers (6%) were government
employee in both groups while only 2 mothers of diabetics and 4 of the
controls were labourers. The difference was statistically insignificant,
(P= 0.2 and 0.7 respectively), as shown in (Table 4, 5).
- 95 -
Table 2. Father education.
Level of education
Patient
Control
Not educated
N
16
%
(16)
N
16
%
( 16)
Basic school
25
( 25)
25
( 25)
Intermediate school
18
(18)
13
( 13)
Secondary school
29
(29)
27
( 27)
University level
12
(12)
19
( 19)
Total
100
100
100
100
p.value= 0.6
Table 3. Mother education.
Level of education
Patient
Control
Not educated
N
25
%
( 25)
N
28
%
(28)
Basic level
32
(32)
25
(25)
Intermediate level
14
(14)
24
(24)
Secondary level
25
(25)
15
(15)
University level
04
(04)
07
(07)
Total
100
100
*99
P. value= 0.1
* One mother died.
- 96 -
99
Table 4. Father occupation.
Occupation
Patient
N
%
Control
N
%
Businessmen & professionals 12
(12)
16
( 16)
Government employee
17
(17)
10
(10)
Skilled laborer
41
(41)
39
(39)
Unskilled laborer
27
(27)
33
(33)
Unemployed or retired
03
(03)
02
(02)
Total
100
100
100
100
P. value= 0.2
Table 5. Mother occupation.
Occupation
Patient
Control
N
%
N
%
Government
employee
Housewife
06
(06)
06
( 06)
92
(92)
89
(89)
laborers
02
(02)
04
(04)
Total
100
100
*99
99
P. valu= 0.7
* One mother died
- 97 -
4.2.4. Family history:
Family history of diabetes mellitus was 51 (51%) and 55 (55%) in
the patients and control group respectively. The difference was
statistically not significant,(P=0.5). Family history of hypertension was
41% in the patients group and 43% in the control group. Statistically the
difference was not significant,(P=0.7). Seven patients had family history
of (CHD) in comparison to 5 in the control group. The difference was
statistically not significant,(P=0.5). History of obesity was found in 18%
of the patients group and only in 7% of the control group. Statistically
the difference was significant,(P=0.01)as shown in (Table 6).
4.3. CHILD EDUCATION:
4.3.1 Level of schooling:
The majority of children were at basic school level, 63 patients (63%)
and 72 control (72%), followed by secondary school ,26 patients (26%)
and 25 control (25%). Five patients (5%) and 3 in the control group (3%)
were at kinder-garden while 6 patients (6%) and none of the control
group were not educated. Statistically the difference was not significant,
(P= 0.4), as illustrated in (Table 7).
- 98 -
Table 6. Family history of the study group.
Study group
Case
Control
P. value
No.
%
No.
%
Diabetes mellitus
51
(51)
55
(55)
0.50
Coronary heart disease
07
(07)
05
(05)
0.50
Obesity
18
(18)
07
(07)
0.01
Hypertension
41
(41)
43
(43)
0.70
Family history
- 99 -
Table 7. Schooling level of the study group
Study group
Patient
Control
Schooling
No.
%
No.
%
Not educated
06
(06)
00
(00)
Kinder garden
05
(05)
03
(03)
Basic
63
(63)
72
(72)
Secondary
26
(26)
25
(25)
Total
100
100
100
100
P value= 0.4
Table. 8. School attendance of the study group.
Patient
N
%
School attendance
Control
N
Regular
69
(64.8)
Interrupted
12
(11.2)
000
000
Stopped
13
( 12.2)
000
000
94
100
100
Total
94
p.value< 0.05
- 100 -
100
%
( 100)
4.3.2. School attendance:
Of the 94 diabetics attending school, twelve diabetics (11.28%) had
interrupted schooling, 13(12.2%) stopped compared to none of the
children in the control group. Regular attendance was found in 69(64.8%)
diabetics and 100(100%) in the control group. This was statistically
significant, (P <0.05) as demonstrated in (Table 8)
- 101 -
4.4. EXERCISE:
Most of the children in both groups were physically active, 62% of
patients and 55% of the control. This was not statistically significant,
(P= 0.3), as illustrated in (Fig 4 ).
4.5. DIABETES MELLITUS VARIABLES.
4.5.1. Duration of diabetes:
Newly diagnosed diabetics of <1years were 23%. The majority of
patients 45% had diabetes for 1-5 years while 24% had it for 5-9 years.
Duration of > 9years was found in only 8% of patients(Fig 5).
4.5.2. Type of insulin:
Only two patients (2%) use soluble insulin alone. A dose of 0.05-1
U/kg/d was used by 66% of diabetics. Those who require a dose <0.05
were 13% while 21% use a dose of 1-2 U/kg/d(Table 9).
- 102 -
Figure 4. Exercise performance of the study group (DM).
(n= 200)
62%
70%
55%
60%
45%
50%
38%
40%
30%
20%
10%
0%
Patients
Control
Yes
No
P.value = 0.3
- 103 -
5 Figure. Duration of diabetes.
08%
23%
24%
45%
< 1year
5-9years
1-4 years
> 9years
5 Figure. Duration of diabetes.
(n =100)
- 104 -
Table 9. Insulin dose.
Insulin dose
No.
%
<0.5 U/Kg
13
(13)
0.5-1 U/Kg
66
(66)
1-2 U/Kg
21
(21)
100
100
Total
- 105 -
4.6. ANTHROPOMWTWRIC MEASURES:
4.6.1. Weight
Twenty nine diabetics (29%) and 25 controls (25%) were at < 3rd
centile. Nine diabetics (9%) and 4 of the control group (4%) were at <
5th centile, 6(6%) diabetics and 11(11%)of the control group were at <
10th centile and 25(25%) diabetics and19 of the control group (19%)
were at < 25th centile. At < 50th centile there were 22(22%) diabetics and
15(15%)of the control group while 5(5%) diabetics and 14(14%) of the
control group were at < 75th centile. Three diabetics (3%) and 10 in the
control group (10%) were at < 90th centile while none and 1 (1%) of
diabetics were at < 95th and 97th centiles compared to 1(1%) of the
control group at each centile respectively.
None of diabetics or the
control were at > 97th centile. The difference was statistically insignificant,
(P = 0.4) as shown in (Fig 6).
4.6.2. Height.
In both groups 18 children (18%) were at < 5th centile while 7
children (7%) were at the 5th centile. Ten in control group (10%) and 13
diabetics (13%) were at < 10th centile while 20(20%) diabetics and
18(18%)of control group were at < 25th centile. Diabetics at < 50th and
75th centiles were 21(21%) and 11(11%) compared to control group
18(18%) and 16(16%) in the same centiles respectively. Six diabetics
- 106 -
Figure 6. Weight centile of the study group.
(n =200)
50%
45%
40%
Percentage
35%
30%
25%
29%
25%
25%
22%
19%
20%
15%
14%
15%
11%
10%
9%
10%
6%
5%
4%
5%
3%
1% 1%1%
0%
0%
< 3rd
<5th
< 10th
< 25th
< 50th
< 75th
Weight centile
Patients
Control
P.value = 0.4
- 107 -
< 90th
< 95th
< 97th
(6%) and 7 controls (7%) were at < 90th centile while 4 diabetics (4%)
and 6(6%) controls were at < 95th centile. The difference was statistically
insignificant, (P= 0.9) as demonstrated in ( Fig 7).
4.6.3. Blood pressure:
In both groups 50 children (50%) had BP <50th centile, while 34
patients (34%) and 28 controls (28%) were at the 50th centile. Eleven
patients (11%) and 17(17%)of the control group were at the 75th centile.
Three patients (3%) and 5(5%) of the control group had BP at the 90th
centile and only two diabetics and none of the control group fall in the
95th centile. There was no statistically significant difference,(P= 0.3) as
shown in( Fig 8).
4.6.4. Sexual Maturity Rate (SMR).
Fifty (50%) of the diabetics were in stage1 compared to 48(48%) of
the control group. At stage 2 and 3 there were 9(9%) and 14(14%)
diabetics respectively compared to 22(22%) and 7(7%)of the control
group. At stage IV there were 8 (8%) patients and 8(8%)of the control
group while those at stage v were 20 patients (20%) and 15 of the
control group (15%). The difference was not statistically significant, (P =
0.08) as shown in (Fig 9)
- 108 -
Figure 7. Height centiles of the study group graph.
(n = 200)
25%
25%
25%
21%
20%
20%
18%
18%
16%
Percentage
15%
13%
11%
10%
10%
7%
6%
5%
6%
4%
0%
<5
< 10th
< 25th
< 50th
< 75th
Height centiles
Patient
P.value= 0.9
- 109 -
Control
< 90th
< 95th
Figure 8. Blood pressure of the study group.
(n = 200)
50%
50% 50%
45%
40%
34%
35%
28%
Percentage
30%
25%
20%
17%
15%
11%
10%
5%
5%
3%
2%
0%
0%
<50
50
75
40
95
Blood pressure
Patients
Control
P.value = 0.3
- 110 -
Figure 9. Sexual maturity rate of the study group.
( n= 200)
50
50
48
45
40
35
Percentage
30
25
25
22
20
20
14
15
9
10
7
7
8
5
0
Stage I
Stage II
Stage III
Stage IV
Sexual m aturity rate
Case
P.value= 0.08
- 111 -
Control
Stage V
4.7. INVESTIGATIONS:
4.7.1. Glycosylated HbA1c:
Good glycemic control (HbA1c) was found in 43 (43%) of
patients and distributed as, non diabetic level (4.4- 6 %) was found in 8
diabetics (8%). Four (4%) had a goal level (6- < 6.5%) and 31(31%) had
good control (6.5- 8%), While diabetics with action suggested levels (> 8)
were 57(57%)as shown in(Table 10).
4.7.2. Prevalence of dyslipidemia:
Dyslipidemia was found in 43% in the diabetic group and 21% in
the control group. This difference was statistically significant, (P <0.001),
as shown in (fig 10).
Cholesterol was abnormal (border line and elevated) in 37% of the
diabetics; it was elevated in 10 patients (10%) and borderline in 27
(27%), compared to 4 elevated levels and 13 borderline levels in the
control group. The difference was statistically significant, (P= 0.01).
Triglyceride level was high in 16 patients (16%) compared to 7 (7%)
of the control. The difference was statistically significant (P< 0.04).
LDL was elevated in 28 diabetics (28%) while only 2 (2%) of the
control had elevated levels. The difference was statistically significant,
(P< 0.00).
- 112 -
- 113 -
HDL was low in 7 diabetics (7%) and none of the controls. The
difference was statistically significant,(0.007), as shown in (Fig11).
- 114 -
Figure10. Prevalence of dyslipidemia of the study group.
(n =200)
79
80
70
percentage
60
57
50
43
40
21
30
20
10
0
normal
patients
control
abnormal
P.value < 0.00
- 115 -
Fig 11. Prevalence of individual dyslipidemia of the study group.
(n =200)
40%
37%
35%
30%
28%
25%
20%
17%
16%
15%
10%
7%
5%
2%
2%
0%
0%
TC
TG
LDL
Patient
P.value< 0.01
P.value< 0.04
HDL
Control
P.value< 0.00
- 116 -
P.value< 0.007
4.8. CORRELATION BETWEEN LIPID ABNORMALITIES AND RISK
FACTORS.
4.8.1. Glycosylated HbA1c:
Patients with good glycemic control and abnormal cholesterol level
were 15(25.4%) compared to 21(53.8%) with poor glycemic control and
abnormal lipids. This difference was statistically significant,(p<.0.01).
Four patients (6.8%) with elevated (TG) had good glycemic control
in comparison to 12(30.8%) with poor control. The difference was
statistically significant, (p <0.05).
Patients with abnormal (LDL) and low (HDL) with good glycemic
control were 12 (20.3%) and 2 (3.4%) respectively compared to 15
(38.5%) and 5 (12.8%) with bad glycaemic control. The difference was
statistically insignificant,(p= 0.1) for both as shown in (Fig 12).
- 117 -
Figure 12. Correlation between dyslipidemia and glycosylated
HBAIC/patient.
(n =98)
60.00%
53.80%
50.00%
38.50%
Percentage
40.00%
30.80%
30.00%
25.40%
20.30%
20.00%
12.80%
10.00%
6.80%
3.70%
0.00%
TC
TG
LDL
Dyslipidemia glycosylated
Good control
TC
TG
LDL
HDL
Poor control
P.value < 0.01
P.value < 0.05
P.value = 0.1
P.value = 0.1
- 118 -
HDL
4.8.2. Duration of diabetes mellitus:
Patients with diabetes duration < 1 yr and abnormal cholesterol
were 8 (34.8%) compared to 10(22.2%) with 1-5 yr duration. Diabetes
duration of 5-9 yrs and abnormal cholesterol was found in 14(58.3%)
while in only 5(5%) patients with abnormal cholesterol had diabetes for >
9yrs.statistically, the difference was significant,(p<0.01). Diabetes
duration of < 1yr and abnormal (LDL) was found in 5 patients (21.7%)
compared to 9 diabetics (20%) with 1-5 yrs duration. Eight patients
(33.3%) had a duration of 5-9 yrs and 6(75%) had it for > 9yrs. This
difference was statistically insignificant (p= 0.1).
Patients with diabetes duration < 1 yr and elevated triglycerides
were 4 (17.4%) compared to 6 (13.3%) with 1-5 yr duration. Diabetes
duration of 5-9 yrs and elevated (TG) was found in 6 (25%) while none
of the diabetics with > 9yrs duration had elevated (TG).statistically the
difference was not significant,(p=0.3). None had diabetes duration of <
1yr and low (HDL). Four patients (8.9%) with low (HDL) had diabetics for
1-5 yrs duration compared to 2 patients (8.3%) and only 1 (12.5%) with
diabetes duration of 5-9 yrs and > 9 yrs respectively. This difference was
statistically insignificant,(p=0.4)as shown in (Fig 13).
- 119 -
Fig 13. correlation between dyslipidemia and duration of diabetes.
(n =100)
80.00%
75%
70.00%
62.50%
60.00%
58.30%
Percentage
50.00%
40.00%
35.80%
33.30%
30.00%
25%
22.20%
21.70%
20%
20.00%
17.40%
13.30%
12.50%
8.90%
8.30%
10.00%
0.30%
0%
0.00%
TC
TG
LDL
Dyslipidem ia-duration
<1yr
1-4yr
5-9yr
TC P.value < 0.01
TG P.vale = 0.3
LDL P.value =0.1
HDL P.value= 0.4
- 120 -
>9yr
HDL
4.8.3. Exercise:
• Cholesrtol
level: patients
with abnormal
cholesterol
who
performed exercise were 20(32.3%) in comparison to 17 (44.7%)
who didn't, while 6controls (10.9%) performed exercise and
11(24.4%) didn't. The difference was not statistically significant for
both groups,(p=0.2) for patients and (p=0.07) for control.
• Triglyceride level: seven diabetics (11.3%) with elevated TG
exercised compared to 9 (23.7%) didn't. while the 7 (12.7%) of the
control with elevated TG performed exercise. The difference was
insignificant(p=0.1).
• LDL level: Diabetics with elevated LDL and performed exercise
were 12(19.4%) in comparison to 16(42.1%) with no exercise. Only
2 (3.6%)of the control group with elevated LDL exercised. The
difference was statistically significant for diabetics(p<0.01) and not
for the control group (p=0.1).
• HDL level: Three diabetics (4.8%) with low HDL performed
exercise compared to 4 (10.5%) with no exercise and none of the
controls, the difference was statistically insignificant, (p=0.2) as
shown in (Table 11 &12)
- 121 -
- 122 -
4.8.4. Gender:
Cholesterol: Male diabetics who had abnormal cholesterol were
15(34.1%) compared to 22 diabetic females (39.3%), while only 7 of the
control group (15.9%) were males and 10 females (17.9%). The
difference was statistically insignificant for both patients(p=0.5) and the
control group (p=0.7).
Triglycerides: Four diabetic males (9.1%) compared to 12 females
(21.4%) had elevated TG, while 3 males (6.8%) in the control group and
4 females (7.1%) had elevated TG. The difference was statistically
insignificant.
LDL level: Ten males (22.7%) and 18 females (32.1%) had
elevated (LDL) compared to 2 male of the control group (3.6%). The
difference was statistically insignificant,(p=0.2) for both groups.
HDL level: Two Males (4.5%) had low (HDL) compared to 5
females (8.9%), while none of the control group had low (HDL) This
difference was statistically insignificant(p=0.3). As shown in (Table 13,
14)
4.8.5. Age group:
Cholesterol level: Three diabetics (60%) with abnormal cholesterol
were at age group 1-4 yrs compared to none of the control group. Six
diabetics (35.3%) and only one(11.1%)of the control group were at age
- 123 -
- 124 -
group 5-9 years. At age group
10 -14, there were 17 diabetics
(32.1%) and 13 of the control group (16.9%) while, 11 patients (44%)
and 3 of the control group (25%) were at age group 15-18 yrs. The
difference was not statistically significant (p=0.5 ) for patients and (p=0.7)
for the control group.
Triglyceride level: One diabetic (20%) at age 1- 4yrs had elevated
TG compared to none of controls. Two diabetics (11.8%) and one
control (11.1%) were at age group 5-9yrs while, 6 diabetics (11.3%) and
6 controls (7.8%) were at age group 10-14yrs. Those aged 15-18yrs
were 11 patients with none of controls. The difference was
insignificant,(p=0.2, p=0.7) for patients and control respectively.
LDL level: Two diabetics (40%) at age group 1-4 yrs, 3 (17.6%) at
age 5- 9 yrs had abnormal LDL compared to none of their controls.
Fifteen diabetics(28.6%) and 2 controls (2.6%) were at age group 10 -14
yrs while eight diabetics (32%) and none of controls were at age group
15-18yrs. The difference was statistically insignificant,(p=0.6 , p=0.8) for
patients and control respectively.
HDL level: Two diabetics (11.8%) at age group 5-9 yrs, 1(1.9%) at
10-14yrs age group and 4 (16%) at 15-18yrs group had low HDL
compared to none of the controls. Statistically the difference was
insignificant,(p=0.1). (Table 15.16)
- 125 -
Table 13. correlation between dyslipidemia and age group in years
In the Patients.z
Age group
1-4yr
5-9 yr
10-14 yr
15-18 yr
Dyslipidemia
No
%
No
No
%
No
%
TC
03
(60)
06
(35.3) 17
(32.1)
11
(44)
0.5
TG
01
(20)
02
(11.8) 06
(11.3)
07
(28)
0.2
LDL
02
(40)
03
(17.6) 15
(28.3) 08
(32)
0.6
HDL
00
(00)
02
(11.8) 01
(01.9)
(16)
0.1
%
04
p.value
Table 14. correlation between dyslipidemia and age group in
years in the Control group.
Age group
Dyslipidemia
1-4yr
No
%
5-9 yr
No
%
10-14 yr
No
%
15-18 yr
p.value
No
%
TC
00
(00)
01
(11.1)
13
(16.9)
03
(25)
0.7
TG
00
(00)
01
(11.1) 06
(07.8)
00
(00)
0.7
LDL
00
(00)
00
(00.0) 02
(02.6) 00
(00)
0.8
HDL
00
(00)
00
(00.0) 00
(00.0) 00
(00)
-
- 126 -
4.8.6. Blood pressure
• Cholesterol: Seventeen diabetics (34%) and 12 (24%) of
the
control group with blood pressure < 50thcentile had abnormal
cholesterol. Three of the control group (10.7%) and 14 diabetics
(41.2%) with abnormal cholesterol were at 50th centile. Three
diabetics (27.3%)
where at the 75th and 3 (100%) at the 90th
centile had abnormal cholesterol in comparison to none of the
control. The difference was statistically insignificant
• Elevated TG: In both groups 5 children (10%) had BP < 50th
centile while, 8 diabetics (23.5%) and 2 of the control group (7.1%)
were at the 50th centile. One patient at each of the 75th (9.1%), 90th
(33.3%) and 95th (50%) had elevated TG compared to none of the
control. The difference was statistically not significant.
• Abnormal LDL: Eleven diabetics (22%) and only two of the
control group (3%) with abnormal LDL were at < the 50th centile
compared to 12 diabetics (35.3%) and only one of the control
group (3%) at the 50th. Two diabetics (18.2%) and (66.7%) at each
of the 75th and 90th centile had abnormal LDL compared to none of
control. At the 95th centile there was one patient (50%) compared
to none among the control. Statistically this difference was not
significant
- 127 -
• Low HDL: Two diabetics (41%) were at < 50th centile compared to
4 (11.8%) at the 50th and only one (33%) at the 90th centile and
none of the control group had low HDL as shown in(Table 17, 18) .
The difference was statistically insignificant.
4.8.7. Sexual Maturity Rate (SMR).
• Abnormal cholesterol level: Eighteen diabetics (36%) and 7
of the control group were at stage 1. Four diabetics (44.4%)
and 4 of the control group (18.2%) were at stage II. Five
diabetics (35.7%) and 2 of the control group (25%) were at
stage III. In stage IV and V there were 2(28.6%) and 8(40%)
diabetics respectively and two for stage IV (25%) and V
(14.3%) of the control group.
• Elevated TG: Six diabetics (12%) and 3 of the control (6.3%)
were at stage I compared to only one diabetic (11.1%) and 2
of the control (9.1%) at stage II. Four diabetics (28.6%) were
at stage III while only one of the control group (12.5%) was in
the same stage. Diabetics in stage IV and V were 3(42.9%)
and 2(10%) respectively compared to none in stage IV and
only one of
the control
group (7.1%) in stage V. The
difference was statistically insignificant.
- 128 -
Table 15. correlation between dyslipidemia and blood pressure in
The patients.
Blood
pressure
Lipid
<50th
No
50th
75th
% No
90th
%
No
%
No
95th
p.value
% No
%
17
(34)
14
(41.2)
03
(23.7)
03 (100) 00
(00)
0.1
05
(10)
08
(23.5) 01
(09.1)
01 (33.3) 01
(50)
0.2
11
(22)
12
(35.3) 02
(18.2) 02 (66.7) 01
(50)
0.2
02
(04)
04
(11.8) 00
(00.0) 01
(00)
0.1
TC
TG
LDL
(50) 00
HDL
Table 16. Correlation between Dyslipidemia and Blood pressure in
The Control group.
Blood
pressure
Lipid
<50th
No
50th
% No
75th
%
No
90th
%
12
(24)
03
(10.7)
02 (11.8)
05
(10)
02
(07.1) 00
(00.0)
01
(02)
01
00
(00)
00
No
95th
% No
p.value
%
00 (00)
00
(00)
0.2
00 (00)
00
(00)
0.5
(03.0) 00
(00.0) 00 (00)
00
(00)
0.8
(00.0) 00
(00.0) 00
(00) 00
(00)
--
TC
TG
LDL
HDL
- 129 -
• Abnormal LDL:
Diabetics at stage I were 12(24%)
compared to none of the control. Three diabetics (33.3%) and
only one of control (4.5%) were at stage II. Four diabetics
(28.6%) and only one of the control group(12.5%) were at
stage III. One (14.3%) and 8 (40%) diabetics were at stage IV
and V respectively compared to none of the control group.
The difference was statistically insignificant.
• Low HDL level: Two diabetics (4%) and (14.3%) were at
stage I and III respectively. One diabetic at each of stage II
(11.1%), stage IV (14.3%) and stage V (5%) compared to
none of the control group as shown
difference was statistically insignificant.
- 130 -
in(Table 19,20). The
Table 17. Dyslipidemia- Sexual Maturity Rate (SMR) correlation in
Patients.
SMR
Lipid
Stage I
No
Stage II
% No
%
Stage III
No
%
17 (36.6) 04
(44.4)
05 (35.7)
05 (12.0) 01
(11.1) 04
(28.6)
11 (24.0) 03
02 (04.0) 01
Stage IV
No
Stage V
% No
p.value
%
02 (28.6) 08
(40.3)
0.9
03 (42.9) 02
(10.0)
0.1
(33.3) 04
(28.6) 01 (14.3) 08
(40.0)
0.6
(11.1) 02
(14.3) 01 (14.3) 01
(05.0)
0.5
TC
TG
LDL
HDL
Table 18. Dyslipidemia - sexual maturity rate (SMR) correlation in
Control group.
Blood
pressure
Lipid
<50th
No
50th
% No
75th
%
07 (14.6) 40 (18.2)
No
90th
%
No
95th
% No
p.value
%
02 (25.0)
02 (25)
02
(14.3)
0.9
03 (6.30) 02
(09.1) 01 (12.5)
00 (00)
01
(7.10)
0.8
00 (00.0) 01
(04.5) 01
(12.5) 00 (00)
00
(00)
0.1
00
(00.0) 00
(00.0) 00
(00) 00
(00)
--
TC
TG
LDL
(00)
00
HDL
- 131 -
4.8.8. Family history:
Correlation between lipid profile and family history of (CHD) and
obesity as risk factors were as follows:
• Abnormal cholesterol:
• Three diabetics (42.9%) had family history of (CHD) compared to
none of the control group. Thirty four diabetics (36.6%) and 17 of
the control group (17.9%) had no family history of (CHD.
Statistically this difference was not significant(p=0.7) and (p=0.2)
for patients and control respectively.
• Six diabetics (33.3%) compared to none of the control had family
history of obesity. Thirty one diabetic (37.8%) and 17 of the control
(17.9%) had no family history of obesity. The difference was not
statistically significant, (p=0.7) for the patients and (p=0.2) for the
control group.
• Elevated TG: All children in the study with elevated TG had no
family history of (CHD). One diabetic (5.6%) and only 1 control
(6.14.3%) had a positive family history of obesity compared to 15
diabetics (18.3%) and 6 of the control (6.5%) with negative history.
The difference was statistically not significant.
• Abnormal LDL level: Two patients (28.6%) and none of the
control had family history of (CHD) compared to 26 patients (28%)
and 2 of the control (2.1%) had not, with statistically insignificant
- 132 -
difference. Six diabetics (33.3%) and none of the controls with
abnormal (LDL) had family history of obesity compared to 22
diabetics (26.8%) and 2 of the control (2.2%) who hadn’t,
Statistically the difference was not significant.
• Low HDL level: One diabetic (5.6%) had low (HDL) and family
history of obesity compared to none of the control. The difference
was statistically insignificant, as shown in (Table 21, 22, 23, 24).
- 133 -
Table 19. Correlation between dyslipidemia and family history
Of coronary heart disease in patients.
Family history of CHD
positive
No
%
Dyslipidemia
negative
No
%
p.value
03
(42.9)
34
(36.6)
0.7
00
(00.0)
16
(17.2)
0.2
02
(28.6)
26
(28.0)
0.9
00
(00.0)
07
(07.5)
0.4
TC
TG
LDL
HDL
Table 20. Correlation between dyslipidemia and family history of
Of coronary heart disease in control group.
Family history of CHD
positive
%
No
Dyslipidemia
negative
No
%
p.value
00
(00)
17
(17.9)
0.2
00
(00)
07
(07.4)
0.4
00
(00)
02
(02.1)
0.7
00
(00)
00
(00.0)
--
TC
TG
LDL
HDL
- 134 -
Table 21. Correlation between dyslipidemia and family history of
Obesity in patients.
Family history of obesity
Dyslipidemia
positive
No
%
negative
No
%
06
(33.3)
31 (37.8)
0.7
01
(05.6)
15
(18.3)
0.1
06
(33.3)
22
(26.8)
0.5
01
(05.6)
06
(07.3)
0.7
P.value
TC
TG
LDL
HDL
Table 22. Correlation between dyslipidemia and family history of
Obesity in control group.
Family history of obesity
Dyslipidemia
positive
No
%
negative
No
%
00
(00.0)
17
(18.3)
0.2
01
(14.3)
06
(06.5)
0.4
00
(00.0)
02
(02.2)
0.6
00
(00.0)
00
(00.0)
--
P.value
TC
TG
LDL
HDL
- 135 -
CHAPTER FIVE
DISSCUSSION
- 136 -
DISCUSSION
5.1. DEMOGRAPHIC CHARACTERISTICS:
5.1.1. Age group:
The age of children in the study ranged from 3.5 - 18 yrs
covering most of the childhood period, the same as in studies done in
diabetic children in Australia and in none diabetic Saudi children
Other studies covered only certain age group
(78, 79)
(80,113).
. Two groups
dominated; first the age group 10-14yrs (53%) and 15-18yrs comprising
(25%) representing pubertal years and the second was the age group 59yrs ( 17%) mostly school children, a result which coincides with the
literature which described two peak age of childhood diabetes (14)
5.1.2. Gender:
Females outnumbered males in this study, F: M was 1.27: 1.0,
a result that goes with other studies and contradicts the study done by
P o l lak K in i n wh ic h ma les o utn u mbe r ed fe mal es ( 1 0 8 , 1 2 7 , 1 1 3 ) .
5.1.3. Ethnic group:
There was a wide variation in different ethnic group origin with
the predominance of Arab in both groups. This finding may reflect the
multi-ethnic community and the population structure of
the national
capital Khartoum, where the study was conducted. it may also indicate
ethnic differences in the prevalence of type 1 diabetes (13,126).
- 137 -
5.2. FAMILY AND SOCIAL HISTORY:
4.2.1. Consanguinity:
Consanguinity was observed among the majority of parents in
both groups constituting 61%. In the diabetic group this may raise the
point of genetic factors as a risk factor. This
should be taken with
caution since a consanguineous marriage is a common practice in our
community (4, 17,118).
5.2.2. Parent education:
The majority of parents were educated, 84% of fathers and 77% of
mothers. This finding has an important impact on parent's knowledge
and communication with the sources of information and management of
their diabetic children (4,5) .
5.2.3. Parent occupation:
The majority of fathers were either skilled or unskilled laborers
giving reflection of their poor monthly income. The same findings were
reported in a study done by Zaki, while the majority of mothers were
housewives adding no more to the family income. On the other hand,
this can be taken as an advantage by the more time available to look
after their children (128).
- 138 -
5.3. CHILD EDUCATION
4.3.1. Level of schooling:
Only six diabetics (6%) hadn't attended the school and this was
attributed to over protection for them by their parents since diagnosis.
Similar results (7%) were encountered by Mohammed A in his study of
knowledge, attitude and practice among diabetic children (129)
5.3.2. School attendance:
Diabetics in the study had irregular
school attendance in
13% while 12% stopped schooling. Similar results were reported by
Mohammed A, 14% stopped schooling while 38% had irregular
attendance(129). The importance of child education is a major issue since
higher education level of the diabetic patients was found to be
associated with better knowledge regarding diabetes as reported in the
above mentioned study.
5.4. EXERCISE
Most of children perform physical activity, a required practice
to maintain acceptable blood glucose and lipid levels according to the
National Cholesterol Education Program(NCEP) guidelines and other
studies (5, 41, 85, 122).
- 139 -
5.5. DIBATES MELLITUS VARIABLES
5.5.1. Duration of diabetes:
Duration of diabetes in this study was < 1 yr - > 9yrs (maximum
13 years), a similar duration was found in the study done by Pollak K (113).
Diabetics with duration > 9yrs were 8% in our study and they were the
group who needs special attention looking after complications. Since
long diabetes duration and social background were found to be well
related to the development of complications as demonstrated by Daoud
in his study and mentioned in the literature (5,130).
5.5.2. Insulin dose:
A dose of 0.5-1 u/kg/ d was used by 2/3 of diabetics while 1/5
used a dose of 1-2 u/kg/d reflecting the metabolic control of the diabetics
in the study. These results were in line with both the literature on insulin
dose in preadolescents and teenagers (4).
- 140 -
5.6. ANTHROPOMETRIC MEASURES
5.6.1. Weight:
The weight centile distribution of both groups showed no
difference which can be attributed to their similar social class. No cases
of overweight were detected reflecting the absence of weight effect on
lipid profile abnormalities as reported by Anderson GE (125).
5.6.2. Height:
In both groups 18% were below the 5th centile (stunted) with no
difference in other height centiles. Similarities in both groups may refute
the role of diabetes on height in this study, since the effect of diabetes
on height leading to growth failure is well recognized in the literature. In
this study these percentages were lower than those reported by Zaki,
40% in diabetic children and may point to improvement in diabetes
control (5, 128).
5.6.3. Blood pressure:
The majority of children had normal blood pressure. Five
children in the Control group and 3 diabetics (3%) were at the 90th
centile and 2 diabetics were at the 95th centile. This result demonstrated
the importance of regular blood pressure monitoring as recommended
by[NCEP] and vigorous control of BP and lipid abnormalities as
concluded by Orchad TJ (79).
- 141 -
5.6.4. Sexual maturity rate:
Most of children were preadolescents and there was no
difference in the two groups regarding the stages of puberty to point to
diabetes role since diabetes can cause delayed puberty as mentioned in
the literature (5).
5.7. INVESTIGATIONS
5.7.1. Glycosylated HbA1c:
Diabetics
with
good
glycemic
control
were
59%
in
contradistinction to the findings of Zaki who found poor glycemic control
in 58.8% of the diabetics studied. This can be explained in part with the
exclusion criteria in our study of patients with (DKA) who were included
in her study (128).
5.7.2. Prevalence of dyslipidemia:
Prevalence of dyslipidemia was found to be 43% in diabetics
and 21% in the control group. This was higher than the prevalence found
by K Azad 39% in diabetics and 17% in control and lower than that of
Saudi non diabetic children of 9%
(80,111)
. These results demonstrated
that dyslipidemia was common in diabetics than their controls and were
similarly common in many studies
(108,112,116,119,122)
and not in line with
others (109,113,114).
Prevalence of hypercholesterolemia was 10% in diabetics which
was lower than the results found by Abraha A (15.3%) and Polka M
- 142 -
(16%)
(118,121)
. Prevalence of hypercholesterolemia in controls was 4%
which was lower than the results of Navars study (21.7%) and higher
than that of Saudi children (1.55%) (80, 81).
Prevalence of hypertriglyceridemia was16% which was lower
than the prevalence found by Abraha A (17.9%) and Pollka M (5%)(118)
(121)
. In the control group the prevalence of 4% was higher than that of
Saudi children (1.96%)
(80) .
In this study HDL was found to be lower in
diabetics than their controls, the same result was reported by Chase H
(123)
while others reported either high or normal levels of HDL
(117,119,124,125)
.
Results of this study demonstrated increased prevalence of
dyslipidemia in Sudanese diabetics and non diabetics. Explanations for
this can be: first due to the fact that diet is an important operative factor
causing hyperlipidemia was not addressed in this study. Secondly race
and geographical distribution may play a role, since they affect lipid
profile as reported in the literature and finally this study included all lipid
profle variables in comparison to other studies which concentrated
mainly on the levels of(TC) and( TG).
- 143 -
5.8. CORRELATION BETWEEN LIPID PROFILE AND RISK
FACTORS
5.8.1. Glycosylated HbA1c:
Both (TC) abnormalities and hypertriglyceridaemia were positively
correlated with metabolic control using (HbA1c); same results were
reported in many studies
(111,113,116,118)
. Both (LDL) abnormalities and low
(HDL) had no association with HbA1c in this study, similar results were
reported by Thomer J
(117,119)
. The effect of( HbA1c) on the development
of lipid disorders is well known in the literature (49).
5.8.2. Duration of diabetes:
Both (TC) and ( LDL) dyslipidemias were positively correlated with
the duration of diabetes mellitus with increasing abnormalities with
increased duration. Similar results were reported by Polka M
(121)
. Part
of this can be explained by the increased metabolic derangements and
complications ( hyperlipidemia is one of them) with increased duration
(3,51).
5.8.3. Exercise:
In this study there was positive correlation between exercise and (LDL)
level. while Lipman found a positive correlation with TC (122). The effect of
exercise on lowering blood lipid levels was addressed by many studies
(5, 68, 85)
.
- 144 -
5.8.4. Gender:
Female gender showed positive correlation with (TG)level.
Although there was no association with other lipid profile, the percentage
of lipid abnormalities increased in females compared to males. These
were similar to Polka M results and in contradiction to those of Plolak K
(121) (113)
.
5.8.5. Age group:
Age had no effect on lipid profile; similar results were reported by K
Azad and Orchad TJ,This in contradistinction to findings of the study on
Saudi children where the highest mean of (TC) was in the age 3-4 years
old and a significant decrease occurred with age , with lowest mean in
those 14-15 yrs old (79) (80) .
5.8.6. Blood pressure:
Although blood pressure had no effect on lipid profile in the
study, Orchad TJ, in his study ,concluded the importance of vigorous
blood pressure control. He also reported that complications of diabetes
and hyperlipidemia were more with systolic blood pressure > 120
mmHg and diastolic blood pressure of > 80mmHg ( 79).
5.8.7. Sexual maturity rate:
Puberty had no effect on lipid profile and there was loss of the
decreasing lipid abnormality with puberty. Similar results were reported
- 145 -
by Polka M and conflicting results were found in the Navara study and
the study of Saudi children. The effect of puberty can be related to the
sexual maturation and related hormone levels in this period as stated by
Al-Hazemi in his study (121, 81, 80).
5.8.8. Family history:
Lipid profile showed no difference between children with or without
family history of (CHD) or obesity, a result similar to those found by Esko
J, while Abraha A found significant relation between familial factors and
lipid profile (118) (119).
- 146 -
CONCLUSION
- 147 -
CONCLUSION
Prevalence of dyslipidemia was found to be higher in
diabetics than their control.
Prevalence of hypertriglyceridemia was observed to be the
highest in relation to other lipid profile variables and showed
higher percentages in female gender.
Dyslipidemia of total cholesterol and (LDL) have positive
correlation with (HbA1c) and increased with poor glycemic
control.
Risk factors positively correlated with lipid profile are
duration of diabetes mellitus, metabolic control and exercise.
Both Sexual maturity rate and blood pressure have no effect
on lipid profile. However, there is increasing percentage of
hypercholesterolemia with increasing blood pressure and
advance in (SMR) in the patient group.
Family history of obesity and coronary hear disease has no
effect on lipid profile.
- 148 -
RECOMMENDATIONS
- 149 -
RECOMMENDATIONS
It is extremely important to develop a national diabetes
program for lipid screening.
Education of children and their families about the dietary
guidelines is recommended for all children. Addressing
its role in both diabetes and hyperlipidemia management,
together with encouragement of exercise.
Routine follow up of weight, height and blood pressure.
Metabolic control assessment by HbA 1c every 3-6
month and plan for complication detection is needed.
The
association
of
hyperlipidemia
with
complications can be addressed in another study
- 150 -
diabetes
REFERANCES
- 151 -
REFERANCES
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Diabetes, 13th ed. London: Oxford Blackwell scientific publications; 1991.p.243-5.
2- Jean D, Daniel W, Henry M, P.Reed L. Diabetes Mellitus. In: Roger H, Daniel W,
(editors). William's Text Book of Endocrinology, 9th ed. Philadelphia:
W.B.Saunders; 1998.p.973-1039.
3- Report of the Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care 1997; 20:1183-90.
4- Leslie P. Diabetes Mellitus. In: Julia A, Catherine D, Ralph D, (editors). OSki's
Pediatrics. Principles and Practice, 3rd ed. Philadelphia: Lippincott William's and
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APPENDIX
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