Retinol Binding Protein-4 in Type 2 Diabetic Patients with and without Liver Cirrhosis


Master's Thesis, 2017

128 Pages, Grade: C


Free online reading

2
Acknowledgement
First and foremost, I am thankful to Allah, for without His grace, this work
would have never been accomplished as we feel his great care, support and guidance
in every step in our life.
I am genuinely and deeply indebted to Dr. Nehad Shokry Shoeib Professor of
Internal Medicine and Endocrinology, Faculty of Medicine, Ain shams University for her
constant guidance, gentle encouragement, foresight and faith in me. Thank you for your
help and unfailing support pushing me forward all the time, to overcome every obstacle in
the way.
I would like to express my deepest appreciations to Dr. Salwa Seddik Hosny
Assistant professor of Internal Medicine and Endocrinology, Faculty of Medicine, Ain
Shams University for her keen supervision, and valuable advice that guided me all the
way through the various phases of this work, and for teaching me through her
tremendous experience.
My special thanks and cardinal appreciations to Dr. Maram Mohamed Maher
Mahdy Lecturer of Internal Medicine and Endocrinology, Faculty of medicine, Ain
Shams University for her continuous interest, precious suggestions and inexhaustible
patience.Really,I owe to her much more than can be expressed. God blessing all of her
faithful efforts.

3
Content
ListofAbbreviations
3
Introduction
6
DiabetesMellitus
8
Classificationofdiabetesmellitus:
10
Diagnosisofdiabetesmellitus:
17
Criteriafordiabetesmellitusdiagnosis:
18
Prediabetes
23
Type2diabetesmellitus:
25
Riskfactorsoftype2diabetesmellitus:
26
Pathogenesisoftype2diabetes:
28
Type2DiabetesMellitusandInsulinResistance:
28
KineticofInsulinSecretion
29
Mechanismsofglucoseinducedinsulinsecretion:
31
Alterationsofinsulinsecretion:
32
InsulinActionattheCellularLevel:
33
RoleofinsulinsignalingsystemsinInsulinResistance:
34
Themetabolicsyndrome
35
Type2diabetesmellitusandtheliver
38
TheRoleoftheLiverinGlucoseHomeostasis:
38
Spectrumofliverdiseaseindiabetics:
39
Nonalcoholicfattyliverdiseases(NAFLD)
39
PathogenesisofNAFLD
41
Diabetesmellitusandhepatocellulacarcinoma:
42
Livercirrhosis
44
Definition:
44
Classificationoflivercirrhosis:
45
Retinolbindingprotein4
53
Adiposetissueinhealthanddisease
53
RetinoidReceptors:
56
RetinolBindingProtein4andInsulinResistance:
57
Defectsintheabilityoffatcellstotransportglucosearelinkedtoinsulinresistanceinmuscle
andlivers:
58
SubjectsandMethods
59
Specimencollectionandpreparation:
61
Statisticalanalysis
63
Results
64
Discussion
98
Summary
106
Recommendations
109
References
110
L
ISTOF
A
BBREVIATIONS
ADAG
AlC-derived average glucose
ALB
Albumin

4
ALT
Alanine amino transferase
AST
Aspartate amino transferase
ATP Adenosine triphosphate
BMI Body mass index
CGM Continuous glucose monitor
CHOL
Cholesterol
CVD
Cardiovascular disease
DCCT Diabetes control and complication trial
DM
Diabetes mellitus
DPP
Diabetes prevention program
DSME Diabetes self management education
FPG
Fasting plasma glucose
GDM Gestational diabetes mellitus
HAPO
Hyperglycemia and adverse pregnancy outcomes
HbA1c Haemoglobin A1c
HCV Hepatitis C virus
HDL High density lipoprotein
HNF
Hepatic nuclear factor
IDDM
Insulin - dependent diabetes mellitus
IFC
International federation of clinical chemistry

5
IFG
Impaired fasting glucose
IGT
Impaired glucose tolerance
IRSI
Insulin Receptor substrate I
LADA
Latent autoimmune diabetes in adults
LDL
Low density lipoprotein
MODY
Maturity onset diabetes in the young
NAFLD
Non alcohol fatty liver disease
NASH
Non Alcohol steato hepatitis
NGSP
National glycol hemoglobin standarzation
program
NHANES
National health and nutrition examination
survey
OGTT
Oral glucose tolerance test
PPG
Postprandial plasma glucose
PT
Prothrombin time
RBP4
Retinol binding protein 4
SMBG
Self monitoring of blood glucose
TG
Triglycerides
UKPDS
United kingdom prospective diabetes study

6
I
NTRODUCTIONI
Diabetes mellitus is a common disease despite the fact that only half or two
thirds are diagnosed, the figure is around 189 million people in 2003, and this
may reach
324
million by 2025 (Helen and John., 2009).
Diabetes mellitus result from a lack or diminished effectiveness of endogenous
insulin. Hyperglycemia is just one aspect of a far reaching metabolic
derangement, which may cause
serious
microvascular and macrovascular
complications (Murry., 2007). Etiological wise diabetes mellitus is classified
into type 1, type 2 and other causes, with type 2 accounting for 90% of cases
globally (Henry and Shalomo., 2008).
The prevalence of type 2 diabetes continues to rise at alarming rate, significant
defect in glucose homeostasis and
fuel
metabolism are detectable long before
overt diabetes occurs. One of the earliest derangements in metabolism is insulin
resistance.It is defined as impaired glucose disposal in a hyperinsulinemic ­
euglycemic study (Mokdad., 2003).
Fasting hyperinsulinemia, a compensatory mechanism to maintain euglycemia
in setting of insulin resistance, is also present before overt diabetes occurs
(Storlien et al., 2004).
Integrated fuel homeostasis relies among interactions among numerous tissues
in widely varying states, including the fed state, fasting, and exercise. This
harmony in various tissues is maintained
by
communication between them, and
is signaled by glucose and its various metabolites. When this communication
between tissues (mainly pancreas, adipose tissues, and liver) is lost insulin
resistance and diabetes mellitus occurs (Von Eynatten and Humpert., 2007).
Retinol binding protein 4 (RBP4) a 21-KDa protein synthesized in the liver and
adipose tissues, formerly recognized for its role as a specific transport for
vitamin A, now it is known that it plays a crucial role in insulin resistance and

7
diabetes mellitus. Adipose RBP4 expression and serum RBP4 level are elevated
in mouse model of insulin resistance, elevated circulating RBP4 increase blood
glucose by inhibiting insulin signaling in skeletal muscle and upregulating
hepatic gluconeogenesis (Koch et al., 2010).
Recent finding also showed that RBP4 is an independent risk factor in type 2
diabetes, impaired glucose
tolerance
, and in healthy individuals with strong
family history of diabetes. Hyperinsulinemia and insulin resistance are found in
nearly all patient with liver cirrhosis, and insulin resistance is a risk factor for
both survival and disease progression in patient with liver cirrhosis (Bugianesi et
al., 2007).
Approximately 70% of persons with type 2 diabetes
mellitus have a fatty liver
and the disease follows a more aggressive course with necroinflammtions and
fibrosis. This
potentially
severe complication is frequently over looked, and
patients may benefit from it's early diagnosis and management (Kenneth., 2009).
Aim of
the
work
To assess the level of Retinol Binding Protein 4 in type 2 diabetic
patients
with
and without liver cirrhosis.

8
D
IABETES
M
ELLITUS
Diabetes mellitus is a group of metabolic diseases characterized by
hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
The chronic hyperglycemia of diabetes is associated with long term damage,
dysfunction and failure of various organs especially the eyes, kidneys, nerves,
heart and blood vessels. Several pathogenic processes are involved in the
development of diabetes. These range from autoimmune destruction of the
-
cells of the pancreas with consequent insulin deficiency to abnormalities that
result in resistance to insulin action. The basis of the abnormalities in
carbohydrate, fat and protein metabolism in diabetes is deficient action of
insulin on target tissues (American Diabetes Association., 2009).
Diabetes mellitus (DM) comprises a group of common metabolic disorders
sharing the phenotype of hyperglycemia. Several distinct types of DM exist
caused by interaction of genetics, environmental factors, and life style choices.
Factors contributing to hyperglycemia may include reduced insulin secretion,
decreased glucose utilization, and increase glucose production (Larry., 2006).
The resulting hyperglycemia is associated with disorder of carbohydrate, fat, and
protein metabolism and can lead to long term organ dysfunction (Michael.,
2009).
Diabetes is a chronic illness that requires continuing medical care and ongoing
patient self management education and support to prevent acute complications
and to reduce the risk of long-term complications (American Diabetes
Association., 2010).
Epidemiology of Diabetes Mellitus:
Diabetes mellitus is one of the most common endocrine disorders, the

9
prevalence of this chronic metabolic disease is increasing (Townsend., 2000).
In 1985, 30 million people around the world were diagnosed with diabetes; in
2000, that figure rose to over 150 million (Vincent., 2008).
In 2006, according to the world health organization, at least 171 million people
suffered from diabetes, and it is estimated that by the year 2030, this number
will double (Jones et al., 2006).
The International Diabetes Federation states "every ten seconds two people are
diagnosed with diabetes somewhere in this world" (Vincent., 2008).
Type 2 DM is the predominant form of diabetes worldwide accounting for 90-
95% of cases globally. The prevalence of type 2 DM is expected to rise more
rapidly in the future because of increasing obesity and reduced activity levels
(Kasper and Fuaci., 2005)

10
ighest number of estimated cases of diabetes
List of countries with h
Table (1):
for 2030.
Country
People with diabetes (Million)
India
79.4
China
42.3
United states
30.3
Indonesia
21.3
Pakistan
13.9
Brazil
11.3
Bangladesh
11.1
Japan
8.9
Philippines
7.8
Egypt
6.7
(Roglic., 2004)
C
LASSIFICATIONOFDIABETESMELLITUS
:
There is increasing interest in the classification of sub types of diabetes,
which is assisting in the personalization of treatment for affected individuals.

11
This classification has now replaced the earlier, clinical classification into
`insulin- dependent diabetes mellitus' (IDDM) and `non- insulin dependent
diabetes mellitus' (NIDDM), which was based on the need for insulin treatment
at diagnosis. IDDM is broadly to type 1 diabetes and NIDDM to type 2 diabetes
(Bious and Donnelly., 2010).
Calssification of diabetes mellitus:
Table (2):
I. Type 1 diabetes (Beta-cell destruction, usually leading to absolute insulin
deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with
relative insulin deficiency to a predominantly insulin secretory defect with
insulin resistance).
III. Other specific types of diabetes
A. Genetic defects of Beta-cell function characterized by mutations in:
1. Hepatocyte nuclear transcription factor (HNF) 4
(MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1
(MODY 3)
4. Insulin promoter factor-1 (IPF-1) (MODY 4)
5. HNF-1 (MODY 5)
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA

12
8. Subunits of ATP-sensitive potassium channel
9. Proinsulin or insulin conversion
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes
C. Diseases of the exocrine pancreas--pancreatitis, pancreatectomy, neoplasia,
cysticfibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in
carboxyl ester lipase
D. Endocrinopathies--acromegaly, Cushing's syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma.
E. Drug- or chemical-induced--Vacor, pentamidine, nicotinic acid,
glucocorticoids, thyroid hormone, diazoxide, B-adrenergic agonists, thiazides,
phenytoin, -interferon, protease inhibitors, clozapine.
F. Infections--congenital rubella, cytomegalovirus, coxsackie.
G. Uncommon forms of immune-mediated diabetes--"stiff-person" syndrome,
anti-insulin receptor antibodies
H. Other genetic syndromes sometimes associated with diabetes--Down's
syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome,
Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome,
myotonic dystrophy, porphyria, Prader-Willi syndrome.
IV. Gestational diabetes mellitus (GDM).
(Bious and Donnelly., 2010)

13
Type I DM: result from destruction of the beta cells of the pancreas due to
autoimmunity and associated with genetic susceptibility, and poorly understood
environmental
factors that initiate the disease process. It is believed that this
process starts along time before the disease actually begins. This may allow
future prevention of the disease. Autoimmune antibodies like islet cell
antibodies antiglutamate decarboxylase and anti inhibitor of apoptosis protein's
are present (Tim and Sudhesh., 2010).
Type I DM is divided into:
Autoimmune diabetes:
-
A
It was previous called type 1 diabetes, (IDDM) or juvenile onset diabetes. It
commonly occurs in childhood and adolescence, but it can occur at any age,
even in the 8
th
and 9
th
decades of life. It accounts for only 5-10% of those with
diabetes. It results from a cellular-mediated autoimmune destruction of the
-
cells of the pancreas. Markers of the immune destruction of the
-cell include
islet cell auto-antibodies (ICAs), auto-antibodies to insulin, auto-antibodies to
glutamic acid decarboxylase (GAD), and auto-antibodies to the tyrosine
phosphatase IA-2 and IA-2
. The rate of -cell destruction is quite variable,
being rapid in some individuals (mainly infants and children) and slow in others
(mainly adults) (David and Dolores., 2007).
Idiopathic diabetes:
-
B
This form of diabetes is strongly inherited, lacks immunological evidence
for
-cell autoimmunity and is not HLA associated. Only a minority of patients
with type-1 diabetes falls into this category. Individuals with this form of
diabetes suffer from episodic ketoacidosis and exhibit varying degree of insulin
deficiency between episodes, so an absolute requirement for insulin replacement
therapy in the affected patients may be needed (American Diabetes Association.,
2009).

14
1- Type 2 DM: Is a complex heterogeneous condition and recent genetic
studies revealed many subtypes, up to 50% of children presenting with DM
are now presenting with type 2 DM in some areas due to increasing
prevalence of obesity. Latent autoimmune diabetes in adults (LADA)
comprise about 5% of patients with type 2 DM and have auto antibodies,
but their presentation is some what like type 2 DM. (Tim and Sudhesh.,
2010).
2- Specific types of diabetes:
3- Monogenic diabetes (previously referred to as maturity onset diabetes in the
young, (MODY). This is a collection of autosomal dominant conditions
resulting from single gene mutations usually presenting before 25 years of
age.
4- MODY I: Due to mutation in hepatocytes nuclear transcription factor(
HNF)4. These patients display a progressive decline in B cell function and
develop chronic complications of diabetes comparable to type 2 diabetes,
and fair better with insulin.
MODY 2: Due to reduction of glucokinase activity leading to reduced insulin
secretion. Homozygotes developed insulin deficiency at birth,
while heterozygotes have a bengin course that respond well to diet
or oral therapy.
MODY 3: This is the most common type Due to mutation in hepatocytes nuclear
transcription factor( HNF)1. The course is similar to type 2
diabetes but no insulin resistance.
MODY 4: Due to mutation in hepatocytes nuclear transcription factors(
HNF)1. In this type homozygotes develop agenesis of the
pancneas, while heterozygotes develop a mild late onset disease
(median age 35 years).

15
MODY 5: A moderately severe form with congenital kidney defects and
nephropathy.
MODY 6: A milder form similar to mody 4.
(David and Dolores., 2007)
Gestational Diabetes Mellitus (GDM):
For many years, GDM was defined as any degree of glucose intolerance
with onset or first recognition during pregnancy, whether or not the condition
persisted after pregnancy, and not excluding the possibility that unrecognized
glucose Intolerance may have antedated or begun concomitantly with the
pregnancy. This definition facilitated a uniform strategy for detection and
classification of GDM, but its limitations were recognized for many years. As
the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in
women of childbearing age, the number of pregnant women with undiagnosed
type 2 diabetes has increased (Lawrence et al., 2008).
GDM carries risks for the mother and neonate. The Hyperglycemia and
Adverse Pregnancy Outcomes (HAPO) study, a large-scale (~25,000 pregnant
women) multinational epidemiologic study, demonstrated that risk of adverse
maternal, fetal, and neonatal outcomes continuously increased as a function of
maternal glycemia at 24-28 weeks, even within ranges previously considered
normal for pregnancy. These results have led to careful reconsideration of the
diagnostic criteria for GDM. (International Association of Diabetes., 2010).

16
Screening for and diagnosis of GDM.
Table (3):
Perform a 75-g OGTT, with plasma glucose measurement
fasting and at 1 and 2 h, at 24-28 weeks of gestation in women
not previously diagnosed with overt diabetes.
The OGTT should be performed in the morning after an
overnight fast of at least 8 h.
The diagnosis of GDM is made when any of the following
plasma glucose values are exceeded:
Fasting >92 mg/dl (5.1 mmol/1)
1 h > 180 mg/dl (10.0 mmol/1)
2 h >153 mg/dl (8.5 mmol/1)
(Diabetes care., 2011)
These new criteria will significantly increase the prevalence of GDM,
primarily because only one abnormal value, not two, is sufficient to make the
diagnosis (Diabetes care., 2011).
It is important to note that 80-90% of women in both of the mild GDM
studies (whose glucose values overlapped with the thresholds recommended
herein) could be managed with lifestyle therapy alone (Landon et al., 2009).
Women with a history of GDM have a greatly increased subsequent risk for
diabetes and should be followed up with subsequent screening for the
development of diabetes or prediabetes, as outlined in testing for diabetes (Kim
and Choi., 2002)

17
Clinical features of type 1 and type 2 diabetes.
Table (4):
Type 1 diabetes
Type 2 diabetes
Sudden onset with severe symptoms of
thirst and ketoacidosis (vomiting,
hyperventilation, dehydration.
Usually insidious onset of
tiredness, thirst, polyuria,
nocturia.
Spontaneous ketosis.
No ketoacidosis.
Recent, marked weight loss. Usually lean. Usually overweight or obese;
often no recent weight loss.
Life-threatening; needs urgent insulin
replacement.
Frequent infections, e.g. urine,
skin, chest.
Absent C ­ peptide.
C - peptide detectable
Markers of autoimmunity present (e.g.
islet cell antibodies).
Often other features of
`metabolic syndrome', e.g.
hypertension.
Symptoms may be minimal
and/or ignored by patient.
(Bious and Donnelly., 2010)
D
IAGNOSISOFDIABETESMELLITUS
:
The diagnosis of diabetes rests on the measurement of plasma glucose level.
Because plasma glucose concentration range as a continuum, the criteria are
based on the threshold for complications of diabetes.
The primary end point used to evaluate the relationship between glucose level
and complications was retinopathy. There is also association between fasting
plasma glucose (FPG) and 2 hours plasma glucose and risk of macrovascular
and cardiovascular disease. Undiagnosed type 2 DM is common, with estimated

18
lag of 5 to 7 years between the onset of diabetes and diagnosis. It is estimated
that up to 30% of patients are undiagnosed, coupled with greater like hood of
having dyslipidemia, hypertension and obesity, it is important for the clinician to
screen for diabetes in a cost effective manner in subjects who demonstrate major
risk factors for diabetes (Henry and Shalomo., 2008).
C
RITERIAFORDIABETESMELLITUSDIAGNOSIS
:
A) Normal glucose tolerance
Fasting glucose 100 mg/dl.
Random glucose 140 mg/dl.
2 hours post 75g glucose load 140 mg/dl.
B) Impaired fasting glucose
Fasting glucose 100 mg/dl- 126 mg/dl .
C) Impaired glucose tolerance
2 hours post 75 gram load glucose 140mg- 200mg/dl
D) Diabetes (Non pregnant adult)
Fasting glucose 126 mg/ dl
2 hours post 75 glucose load 200 mg/dl.
Diagnosis requires confirmatory test on separate day.
(American Diabetes Association., 2010)
Recent research suggest that non-invasive spectroscopic measurements of
advanced glycation end products in the skin may be useful, accurate, and less
invasive. Advanced glycation end products are biomarkers for diabetes and are
closely associated with and predictive of diabetes complications specially
retinopathy and nephropathy and are more sensitive at diagnosing diabetes than
fasting glucose or HbA (Trisha and Glenn., 2008).
The use of HbA1c for the diagnosis of diabetes was not recommended due
to lack of uniformity of the assay world wide. There was world wide effort for

19
international standerdization suggesting the use of international federation of
clinical chemistry reference system. In June 2009 the international committee of
expert announced their consensus that the HbA1c assay is an accurate way to
diagnose diabetes mellitus in adult and children but not in pregnant women. The
international committee advices that anyone with reading of 6.5% or greater
should be considered to have diabetes, waiting for major diabetes groups to
agree (Leonid., 2009).
Epidemiologic datasets show a similar relationship between A1C and risk
of retinopathy as has been shown for the corresponding FPG and 2-h plasma glu-
cose thresholds. The A1C has several advantages to the FPG and OGTT,
including greater convenience, since fasting is not required; evidence to suggest
greater pre-analytical stability; and less day-to-day perturbations during periods
of stress and illness. These advantages must be balanced by greater cost, the
limited availability of A1C testing in certain regions of the developing world,
and the incomplete correlation between A1C and average glucose in certain
individuals. In addition, A1C levels can vary with patients' ethnicity as well as
with certain anemias and hemoglobinopathies. For patients with an abnormal
hemoglobin but normal red cell turnover, such as sickle cell trait, an A1C assay
without interference from abnormal hemoglobins should be used. For conditions
with abnormal red cell turnover, such as pregnancy, recent blood loss or
transfusion, or some anemias, the diagnosis of diabetes must employ glucose
criteria exclusively (Ziemer et al., 2010).
The established glucose criteria for the diagnosis of diabetes (FPG and 2-h
PG) remain valid as well. Just as there is less than 100% concordance between
the FPG and 2-h PG tests, there is not perfect concordance between A1C and
either glucose-based test. Analyses of National Health and Nutrition Examina-
tion Survey (NHANES) data indicate that, assuming universal screening of the
undiagnosed, the A1C cut point of 6.5% identifies one-third fewer cases of

20
126 rng/dl (7.0
undiagnosed diabetes than a fasting glucose cut point of
mmol/1) (Cowie et al., 2010).
e diagnosis of diabetes.
Criteria for th
Table (5):
6.5%. The test should be performed in a laboratory
A1C
using a method that is NGSP certified and standardized to the
DCCT assay.*
or
126 mg/dl (7.0 mmol/1). Fasting is defined as no caloric
FPG
intake for at least 8h.*
or
200 mg/dl (11.1 mmol/1) during an
sma glucose
h pla
-
2
OGTT. The test should be performed as described by the
World Health Organization, using a glucose load containing
the equivalent of 75 g anhydrous glucose dissolved in water.
or
In a patient with classic symptoms of hyperglycemia or
200 mg/dl
hyperglycemic crisis, a random plasma glucose
(11.1 mmol/1).
* In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.
(Diabetes care., 2011)
As with most diagnostic tests, a test result diagnostic of diabetes should be
repeated to rule out laboratory error, unless the diagnosis is clear on clinical
grounds, such as a patient with a hyperglycemic crisis or classic symptoms of

21
preferable that
200 mg/dl. It is
mia and a random plasma glucose
hyperglyce
the same test be repeated for confirmation,
since there will be a greater likelihood of concurrence in this case. For
example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of
diabetes is confirmed. However, if two different tests (such as A1C and FPG)
are both above the diagnostic thresholds, the diagnosis of diabetes is also
confirmed (Diabetes care., 2011).
On the other hand, if two different tests are available in an individual and
the results are discordant, the test whose result is above the diagnostic cut point
should be repeated, and the diagnosis is made on the basis of the confirmed test.
6.5%)
terion of the A1C (two results
That is, if a patient meets the diabetes cri
but not the FPG (126 mg/dl or 7.0 mmol/1), or vice versa, that person should
be considered to have diabetes) (Sacks et al., 2002).
Because A1C is thought to reflect average glycemia over several months
and has strong predictive value for diabetes complications (Staratton et al.,
2000), A1C testing should be performed routinely in all patients with diabetes,
at initial assessment and then as part of continuing care. Measurement
approximately every 3 months determines whether a patient's glycemic targets
have been reached and maintained. Some patients with stable glycemia well
within target may do well with testing only twice per year, while unstable or
highly intensively managed patients (e.g., pregnant type 1 women)
may be tested more frequently than every 3 months.
The availability of the A1C result at the time that the patient is seen (point-
of-care testing) has been reported to result in increased intensification of therapy
and improvement in glycemic control (Miller et al., 2003).
The A
1
C test is subject to certain limitations. Conditions that affect
erythrocyte turnover (hemolysis, blood loss) and hemoglobin variants must be

22
considered, particularly when the A1C result does not correlate with the patient's
clinical situation. In addition, A1C does not provide a measure of glycemic
variability or hypoglycemia. For patients prone to glycemic variability
(especially type 1 patients, or type 2 patients with severe insulin deficiency),
glycemic control is best judged by the combination of results of self monitoring
of blood glucose (SMBG) testing and the A1C. The A1C may also serve as a
check on the accuracy of the patient's meter (or the patient's reported SMBG
results) and the adequacy of the SMBG testing schedule (Sacks et al., 2002).
Table 5 contains the correlation between A1C levels and mean plasma glu-
cose levels based on data from the international AlC-Derived Average Glucose
(ADAG) trial utilizing frequent (SMBG) and continuous glucose monitor
(CGM) in 507 adults (83 % Caucasian) with type 1, type 2, and no diabetes
(Nathan et al., 2008).
Correlation of A1C with average glucose.
Table (6):
Mean plasma glucose
AIC (%)
Mg/dI
MmoI/I
6
126
7.0
7
154
8.6
8
183
10.2
9
212
11.8
10
240
13.4

23
11
269
14.9
12
298
16.5
(Nathan., 2008)
For patients in whom AlC/estimated average glucose (eAG) and measured
blood glucose appear discrepant, clinicians should consider the possibilities of
hemoglobinopathy or altered red cell turnover, and the options of more frequent
and/or different timing of SMBG or use of continuos glucose monitor CGM.
Other measures of chronic glycemia such as fructosamine are available, but their
linkage to average glucose and their prognostic significance are not as clear as is
the case for A1C (Diabetes care., 2011).
P
REDIABETES
In 1997, The Expert Committee on Diagnosis and Classification of Diabe-
tes Mellitus recognized an intermediate group of individuals whose glucose
levels, although not meeting criteria for diabetes, are nevertheless too high to be
considered normal. These persons were defined as having impaired fasting glu-
cose (1FG) (FPG levels 100-125 mg/dl [5.6-6.9 mmol/1]) or impaired glucose
tolerance (IGT) (2-h PG values in the OGTT of 140-199 mg/dl [7.8-11.0
mmol/1]) (Diabetes care., 1997).
Individuals with IFG and/or IGT have been referred to as having
prediabetes, indicating the relatively high risk for the future development of
diabetes, IFG and IGT should not be viewed as clinical entities in their own
right but rather risk factors for diabetes as well as cardiovascular disease (CVD).
IFG and IGT are associated with obesity (especially abdominal or visceral
obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and
hypertension
(Genuth et al., 2003).

24
In a systematic review of 44, 203 individuals from 16 cohort studies with a
follow-up interval averaging 5,6 years (range 2.8-12 years), those with an A1C
between 5.5 and 6.0% had a substantially increased risk of diabetes with 5-year
incidences ranging from 9-25%. An A1C range of 6.0-6.5% had a 5-year risk of
developing diabetes between 25-50% and relative risk 20 times higher compared
with an A1C of 5.0%
(Zhang et al., 2010).
Diagnosis of prediabetes:
Table (7):
FPG 100-125 mg/dl (5.6-6.9 mmol/1): IFG
or
2-h plasma glucose in the 75-g OGTT 140-199 mg/dl (7.8-11.0 mmol/1):
IGT
or
A1C 5.7-6.4%
*For all three tests, risk is continuous, extending below the lower limit of the range and becoming
disproportionately greater at higher ends of the range.
(Diabetes care., 2011)
As is the case for individuals found to have IFG and IGT, individuals with
an A1C of 5.7-6.4% should be informed of their increased risk for diabetes as
well as CVD and counseled about effective strategies to lower their risks. As
with glucose measurements, the continuum of risk is curvilinear--as A1C rises,
the risk of diabetes rises disproportionately (American Diabetes Associatio.,
2009).
Criteria for testing for diabetes in asymptomatic adult individuals
1. Testing should be considered in all adults who are overweight (BMI
25kg/m2) and
have additional risk factors:

25
Physical inactivity.
First-degree relative with diabetes.
Women who delivered a baby weighing 4kg.
Hypertension (140/90mmHg or on therapy for hypertension).
HDL cholesterol level 35mg/dl (0.9mmol/l) and/or a triglyceride level
250mg/dl (2.82mmol/l)
Women with polycystic ovary syndrome.
HbA1c 5.7%, IGT, or IFG on previous testing.
Other clinical condition associated with insulin resistance (e.g., severe
obesity, acanthosis nigricans).
History of cardiovascular disease.
2. In absence of the above criteria, testing diabetes should begin at age 45 years.
3. If results are normal, testing should be repeated at least at 3-year intervals.
(American Diabetes Association., 2010)
T
YPE
2
DIABETESMELLITUS
:
It is the commonest type of diabetes, various clinical risk factors are
associated with the disease such as obesity, increasing age, family history of
diabetes and ethnic and geographical variations in its frequency give clues to the
etiology and pathophysiology of type 2 diabetes (Abo Romia., 2004).
It was previously called (NIDDM) or adult-onset diabetes this form of
diabetes accounts for 90-95% of those with diabetes. It is characterized by
disorder of insulin action and insulin secretions either of which may be
predominant feature (American Diabetes Association., 2009).
Type 2 diabetes is currently thought to occur in genetically predisposed
individuals who are exposed to series of environmental influences that
precipitate the onset of the clinical disease. Type 2 diabetes has a strong genetic

26
component, although the major genes that predispose to this disorder have not
yet identified
(Kasper and Fuaci., 2001).
Type 2 frequently goes undiagnosed for many years because the
hyperglycemia develops gradually and at earlier stages is often not severe
enough for the patient to notice any of the classic symptoms of diabetes.
Ketoacidosis seldom occurs spontaneously in this form of diabetes when seen it
usually arises in association with the stress of another illness such as infection
(Diabetes Care., 2003).
Most patients with this form of diabetes are obese, and obesity itself causes
some degree of insulin resistance. Patients who are not obese by traditional
weight criteria may have an increased percentage of body fat distributed
predominantly in the abdominal region (Buse and Polonsky., 2003).
The principle siqnaling pathway involves sequential acivation of the insulin
receptor, insulin receptor substrates (IRS), phosphatidiinositol -3- kinase (PI3K),
AKT and prtien kinase C isoform (Youssef et al., 2011).
R
ISKFACTORSOFTYPE
2
DIABETESMELLITUS
:
The greater the number of risk factors in an individual the greater the
chance of developing diabetes (Kriska et al., 2003).
Age 45 years.
Overweight (BMI 25kg/m
2
).
Family history of diabetes (i.e., parents or siblings with diabetes).
Habitual physical inactivity.
Race/ethnicity (e.g., African-Americans, Hispanic-Americans, Asian-
Americans, and pacific Islanders).
Previously identified Impaired Fasting Glucose or Impaired Glucose
Tolerance

27
History of Gestational diabetes or delivery of an overweight baby weighting
4kg.
Hypertension (140/90mmHg in adults).
HDL cholesterol 35mg/dl or triglyceride level 250mg/dl.
Polycystic ovary syndrome.
History of vascular disease
(Kriska et al., 2003)
Tim and Sudhesh.,
d 10 lean men fare on the Journey through life (Joslin, 1941) (
How 10 obese men an
Fig. (1):
2010).

28
P
ATHOGENESISOFTYPE
2
DIABETES
:
The key hormonal defects responsible for hyperglycemia in type 2 diabetes
are decreased insulin secretion and elevated glucagon secretion but also the
secretion and action of the gut incretin hormones, glucagon-like peptide-1 and
glucose-dependent insulinotropic polypeptide are altered in type 2 diabetes
(Farech et al., 2009).
Persons with type 2 diabetes consistently demonstrate three cardinal
abnormalities:
I. Resistance to the action of insulin in peripheral tissues particularly muscle, fat
and also the liver.
II. Defective insulin secretion, particularly in response to glucose stimulus.
III. Increased glucose production by the liver.
(Powers., 2001)
T
YPE
2
D
IABETES
M
ELLITUSAND
I
NSULIN
R
ESISTANCE
:
Insulin is a protien consisting of 51 amino acids contained within an Alpha
chain (21 amino acid) and Beta chain (30 amino acid) joined by disulfide
bridges. Insulin is secreted by Beta cells of islets of pancreas which comprises
about 1- 1.5% of pancreatic volume. A precursor molecule, preproinsulin is
cleaved to proinsulin and then to insulin by microsomal enzymes, 50% of
secreted insulin is degraded in a single pass through the liver (David and
Dolores., 2007).

29
(Leclercq et al., 2007).
Insulin signaling
Fig. (2):
Insulin is an anabolic hormone secreted by pancreatic -cells that is
required for the maintenance of glucose homeostasis.
It
inhibits hepatic glucose
production and increases peripheral glucose uptake and glycogen synthesis
(Leclercq et al., 2007).
K
INETICOF
I
NSULIN
S
ECRETION
Glucose and other secretagogues affect insulin release by acting on multiple ionic
and metabolic mechanisms. Beta-cells are sensitive to the rate of change as well
as the actual concentration of a secretagouge. Characteristics of insulin
release in
response to a rapid-onset stimulation by glucose are as follows:
First phase:
Initial response is a transient, rapid rise in release (firstphase), which
terminates in 5-10 minutes. The -cells release their contents in an all-or-none

30
fashion when their thresholds are exceeded by the ambient glucose (Bokvist et
al., 1995).
Impaired first-phase release predicts impending development of type 1
diabetes and is an early feature of impaired ß-cell function in type 2 diabetes.
This lack of first-phase response, or acute insulin response (AIR), in persons
with type 2 diabetes has been observed by many investigators (DeFronzo and
Ferrannini., 1982).
Second phase:
This is followed by a progressively increasing (second phase) in which glucose
continually amplifies its own signal.
It is produced by a potentiating factor (P), which in response to constant
glucose, gradually increases. In contrast to first-phase release, P is not depleted
during insulin secretion, but is degraded gradually with a half-life of 20-60
minutes. These characteristics of P metabolism create the memory (priming) in
the -cell (Grodsky., 1996).
Third phase:
If the islets are exposed to elevated glucose levels for periods 15
minutes, they become primed or potentiated so that, after a brief rest period,
their response to the same stimulus is greater than seen initially. This memory
component can persist for 1 hour and is referred to as time-dependent
potentiation (Byrne et al., 1995).
If the islets are further stimulated by glucose beyond 1-3 hours, insulin
release spontaneously declines to a low level, which can be maintained for up
to 48 hours (thirdphase) (Bolaffl et al., 1990).

31
Chronic exposure of ß -cells to glucose (hyperglycemic environment) for
1-3 hours results in spontaneous decreased insulin secretion. This phenomenon
has been referred to as glucose toxicity (Weir and Leahy., 1994).
The mechanisms responsible for these changes have still not yet been
defined, but several biochemical alterations have emerged. Perhaps the most
striking abnormality is the profound reduction in the Beta-cells glucose
transporter GLUT-2 found in cases of hyperglycemia (Ogawa et al., 1995).
Glucokinase plays a critical role in regulating the rate of insulin secretion
and changes in the intrinsic activity of this enzyme are found in hyperglycemic
states (Chen et al., 1994).
M
ECHANISMSOFGLUCOSE
INDUCEDINSULINSECRETION
:
(1) Ion Flux:
Glucose inhibits ATP-sensitive K
+
channels (presumably through its
stimulation of ATP production), thereby causing membrane depolarization;
depolarization activates the L-type voltage-dependent Ca
++
channels resulting
in Ca
++
entry (influx) and an increase in cytosolic Ca
++
. It was found that the
predominant effect of ion flux is on first-phase release (Ammala et al., 1993).
(2) cAMP:
Glucose stimulates adenyl cyclase and cAMP levels that mediate protein
kinase A activity and phsphorylation of intracellular proteins. Although an
increase in cAMP alone elicits only a small nonphasic insulin release, it
enhances both phases in the presence of glucose. An effect on first-phase
release is consistent with observations that cAMP facilitates flux and Ca
++
uptake into the -cell (Ma et al., 1993).

32
(3) Phosphoinositol Metabolism:
Activation of phospholipase C results in phosphoinositol hydrolysis,
causing production of both diacylglycerol and inositol phosphates.
Diacylglycerol phosphate, in turn, activates protein kinase C and
phosphorylation of protein substrates different from those
phosphorylated by cAMP. The current evidence indicates that this
pathway is an important positive contributor to the regulation of second-phase
insulin secretion (Kelley et al., 1994).
A
LTERATIONSOFINSULINSECRETION
:
(1) Obesity:
Hypersecretion of insulin is an early feature in nondiabetic obese subjects.
This hypersecretion is necessary to compensate for metabolic insulin resistance
secondary to obesity and overeating. Primary hypersecretion of insulin as the
cause of insulin resistance and obesity has been proposed, but never proven.
(Vaag et al., 1995).
The expression of both the GLUT-2 gene and the glucokinase gene is
increased in obese persons, which may explain why hyperinsulinemia may
develop despite normal or near-normal plasma glucose values (Chen et al., 1994).
It was found that insulin deficiency developed years before hyperglycemia
in genetically predisposed subjects. This may indicate that, for genetic reasons,
the -cells in obese diabetics may be unable to compensate for insulin resistance
in the long term (Vaag et al., 1995).
In the general population, peripheral insulin resistance, IGT and
hyperinsulinemia are metabolic changes observed
with aging. Physical inactivity
and obesity appear to be important factors in causing the reduction in insulin
sensitivity in the elderly population. On completion of exercise training

33
programs, elderly subjects demonstrated marked improvements in insulin
sensitivity from baseline, which was associated with a corresponding reduction
in Beta-cell secretory responses to glucose (Muller et al., 1996).
I
NSULIN
A
CTIONATTHE
C
ELLULAR
L
EVEL
:
Circulating insulin rapidly reaches the target tissues, where it interacts
with its receptor. The insulin receptor (IR) is a transmembrane tyrosine kinase
that is expressed as a tetramer in an 2 2 configuration (Ullrich et al., 1985).
Insulin binding to specific regions of the
-subunit leads to a rapid
configurational change in the receptor that eventuates in autophosphorylation
of specific tyrosine residues of the intracellular region of the -subunits
resulting in activation of the tyrosine kinase activity of the receptor (Lee et al.,
1997).
In the inactive state, the catalytic site of the tyrosine kinase is occluded
by the activation-loop preventing access of ATP. Autophosphorylation of
tyrosine residues in the activation-loop causes a conformational change that
allows ATP to reach the catalytic site (Hubbard., 1997).
The activated insulin receptor kinase phosphorylates substrate proteins on
tyrosine residues and these phosphorylated tyrosine residues serve as docking
sites for downstream effectors (White., 1998).
Insulin-receptor signaling involves two major pathways: the mitogen-
activated protein (MAP) kinase and the phosphatidylinositol 3-kinase (PI3-K).
When the MAP kinase pathway is activated, it mediates the growth-promoting
effects of insulin by phosphorylating transcription factors leading to the
induction of genes (Marshall., 1995).
The metabolic response to insulin is primarily mediated via the PI3-K
pathway. When the PI3-K pathway is activated, it results in production of

34
phospatidylinositol 3,4,5 phosphate which activates the PI3-K dependent kinase
which has been implicated in regulating the translocation of GLUT 4, an insulin-
sensitive glucose transporter expressed by muscle and fat cells, to the cell
surface (Czech and Corvera., 1999).
Stimulation of glycogen synthesis is another key metabolic effect of
insulin. Glycogen synthase kinase-3 (GSK-3) mediates the activation of
glycogen synthase in response to insulin. Insulin induces the phsphorylation and
inactivation of GSK-3, rendering it incapable of inhibiting glycogen synthase
activity, thereby enhancing protein synthesis. Insulin can also activate protein
synthesis at the translational level (Cross et al., 1995).
R
OLEOFINSULINSIGNALINGSYSTEMSIN
I
NSULIN
R
ESISTANCE
:
Insulin resistance is a common pathologic state in which target cells fail to
respond to ordinary levels of circulating insulin. It is frequently associated with
a number of diseases, including obesity and type 2 diabetes (Virkamaki et al.,
1999).
At the molecular level, impaired insulin signaling results from mutations
or post-translation modifications of the insulin receptor itself or any of its
downstream effector molecules (Taylor and Arioglu., 1998).
In some cases, insulin resistance could be accounted for by a defect in
insulin binding to its receptor; however, insulin resistance is most often
attributed to a post binding defect (Roach et al., 1994).
A marked reduction in the receptor kinase activity was observed in patients
with extreme insulin resistance, but with normal insulin binding. However, these
events are rare and do not play an important role in the pathophysioloy of typical
type 2 diabetes or obesity (Krook and O'Rahilly., 1996).

35
Glycogen synthesis is markedly reduced in the muscle of type 2 diabetic
patients. Recent studies, using nuclear
magnetic resonance, demonstrated that
one of the defects resulting in these changes was a reduction in glucose
transport, as evidenced by reduced intracellular levels of glucose and glucose-6
phosphate (Krook et al., 2000).
Insulin resistance is present in the majority of patients with type 2 diabetes,
their first degree relatives, individuals with impaired glucose tolerance and
obesity. For years debates raged about whether insulin resistance or insulin
secretion was more important in the pathogenesis of diabetes (Golin et al.,
1996).
An important concept was the nature of the relationship between insulin
resistance and insulin secretion in maintaining normal glucose tolerance, thus
mismatches of Beta-cell function relative to insulin requirements were predicted
to result in hyperglycemia and the development of diabetes (Hermanns et al.,
2005).
Insulin resistance has been associated with multiple metabolic
abnormalities, several of which are traditional cardiovascular risk factors (high
LDL cholesterol, hypertension, obesity and diabetes), while others are known as
non traditional risk factors like increase reactive proteins, interleukin 6, increase
fibrinogen, plasminogen activator inhibitor, increase homocysteine, uric acid
and presence of microalbuminurea. Because of the link between insulin
resistance and these cardiovascular risk factors, it has been attractive that
insulin resistance is the underlying pathophysiological cause of increase
cardiovascular disease in diabetes and obesity (
Maheux et al., 1997).
T
HEMETABOLICSYNDROME

36
A constellation of metabolic derangements in patient with insulin resistance
and diabetes millitus are associated with increase risk of cardiovascular disease,
and has been called the metabolic syndrome (Henry and Shalomo., 2008).
Individuals with this syndrome has significantly increase risk for
cardiovascular disorders, for example men with this syndrome are 3-4 times
more likely to die of cardiovascular disease (Pamela et al., 2005).
The metabolic syndrome strongly predict diabetes mellitus type 2. Indeed,
metabolic syndrome accounts for up to half of new case of diabetes in the
Framingham offspring study among those who did not have diabetes as base line
and were followed for 8 years (
Ford et al., 2008).
In 2008 expert recommended that metabolic syndrome could be used to
identify an early likehood of developing cardiovascular disease. The presence of
any of metabolic syndrome parameter should raise the awareness to determine
10 years absolute risk for cardiovascular disease and treatment initiated based on
this (
Rosenzweig et al., 2008)
.
Diabetes mellitus increase the death from myocardial infraction, stroke, and
non ischemic cardiovascular disease. Its estimated that 80% of diabetes mellitus
die of cardiovascular disease, and has synergistic effect with other factor such as
smoking, hypertension, dyslipidemia and insulin resistance as measured by
elevated fasting insulin level (Henry and Shalomo., 2008).
In 2005, the International Diabetes Foundation proposed a new definition
for metabolic syndrome for clinical use (set out in Table 9) that avoids the
technical difficulties associated with insulin measurement.

37
iabetes Federation definition of metabolic
International D
Table (8):
syndrome
.
Parameter
Qualification
Central obesity (waist
circumference
In all cases:
Central obesity (Waist
circumference)
In men:
94cm in Europids, Sub-Saharan
Africans and Arabs.
90cm in South Asians and Chinese
85cm in Japanese
In women:
80cm in all populations, except
90cm in Japanese
Any 2 of the following 4:
Raised triglyceride level
1.7mmol/l
OR
Specific treatment for this lipid
abnormality
Reduced HDL-C levels
0.9 mmol/l in males or _1.1 mmol/l
in female
OR
Specific treatment for this lipid
abnormality
Raised blood pressure
Systolic 130mmHg
or diastoiic 80 mmHg
OR
treatment of previously diagnosed
hypertension

38
Raised fasting plasma glucose
5.6 mmol/l
(OGTT recommended to confirm
diabetes)
OR
previously diagnosed type 2 diabetes
(Steven and Richard., 2008)
Insulin resistance is accompanied by many other alterations that are not
included in the diagnostic criteria for the metabolic syndrome. Increases in apo
B and C-III, uric acid, prothrombotic factors (fibrinogen, plasminogen activator
inhibitor 1), serum viscosity, asymmetric dimethylarginine, homocysteine, white
blood cell count, pro-inflammatory cytokines, the presence of microalbuminuria,
non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis, obstructive
sleep apnoea, and polycystic ovarian disease are all associated with insulin
resistance (Eckel and Grundysun., 2005).
T
YPE
2
DIABETESMELLITUSANDTHELIVER
T
HE
R
OLEOFTHE
L
IVERIN
G
LUCOSE
H
OMEOSTASIS
:
The liver plays important roles in the homeostasis of glucose metabolism since it
acts as a major target organ for insulin and a site for gluconeogenesis and
glycogen storage. Diabetes mellitus, commonly develops in patients with liver
cirrhosis as the result of hepatocyte dysfunction, is known as hepatogenous
diabetes mellitus (Kim and Choi., 2006).
An appreciation of the role of the liver in the regulation of carbohydrate
homeostasis is essential to understanding the many physical and biochemical
alterations that occur in the liver in the presence of diabetes and to
understanding how liver disease may affect glucose metabolism. The liver uses
glucose as a fuel and also has the ability to store it as glycogen and synthesize it
from non-carbohydrate precursors (gluconeo-genesis) (Levinthal and Tavill.,
1999).

39
Glucose absorbed from the intestinal tract is transported via the portal vein to
the liver. Although the absolute fate of this glucose is still controversial, some
authors suggest that most of the absorbed glucose is retained by the liver so that
the rise in peripheral glucose concentration reflects only a minor component of
postprandial absorbed glucose. Therefore, it is possible that the liver plays a
more significant role than does peripheral tissue in the regulation of systemic
blood glucose levels following a meal (Bjorntorp and sjostrom., 1978).
While Katz et al. (1983) suggested that
most
absorbed glucose is not taken up by
the liver but is rather metabolized via glycolysis in the peripheral tissues.
Insulin is metabolized by insulinase in the liver, kidney, and placenta. About 50%
of insulin secreted by the pancreas is removed by first-pass extraction in the liver.
Insulin promotes glycogen synthesis (glyco-genesis) in the liver and inhibits its
breakdown (glyco-genolysis).It promotes protein, cholesterol, and triglyceride
synthesis and stimulates formation of very-low-density lipoprotein cholesterol. It
also inhibits hepatic gluconeogenesis, stimulates glycolysis, and inhibits
ketogenesis. The liver is the primary target organ for glucagon action, where it
promotes glyco-genolysis, gluconeogenesis, and ketogenesis (Karem and
Forsham., 1994).
In type 2 diabetes, excessive hepatic glucose output contributes to the fasting
hyperglycemia. Increased gluconeogenesis is the predominant mechanism
responsible for this increased glucose
output
, while glycogenolysis has not been
shown to be increased in patients with type 2 diabetes. Hyper-glucagonemia has
been shown to augment increased rates of hepatic glucose output, probably
through enhanced gluconeogenesis (Consoli et al., 1989).
Liver disease is an important cause of death in type 2 diabetes.
In the population-
based Verona Diabetes Study, cirrhosis
was the fourth leading cause of death
and accounted for 4.4%
of diabetes-
related
deaths. The standardized mortality
ratio, i.e., the relative rate of an event compared with the
background rate, for
cirrhosis was 2.52 compared with 1.34 for
cardiovascular disease (CVD). In
another prospective cohort
study, cirrhosis accounted for 12.5% of deaths in
patients
with diabetes (Tolman et al., 2007).
S
PECTRUMOFLIVERDISEASEINDIABETICS
:
N
ONALCOHOLICFATTYLIVERDISEASES
(NAFLD)
Nonalcoholic fatty liver disease is a chronic liver condition characterized by
insulin resistance and
hepatic
fat accumulation, in the absence of other

40
identifiable causes of fat accumulation, such as alcohol abuse, viral hepatitis,
autoimmune hepatitis, alpha-1 antitrypsin deficiency, medications like
corticosteroids and estrogens, and other conditions (Ali and Cusi., 2009).
The perception of nonalcoholic fatty liver disease as an uncommon and benign
condition is rapidly
changing
. Approximately 70% of persons with type 2 diabetes
mellitus have a fatty liver and the disease follows a more aggressive course with
necroinflammation and fibrosis (i.e. nonalcoholic steatohepatitis) in diabetes.
New evidence suggests that it is not steatosis per se but the development of
lipotoxicity induced mitochondrial dysfunction and activation of inflammatory
pathways that leads to progressive liver damage. Nonalcoholic steatohepatitis is
a leading cause of end-stage liver disease and contributes to cardiovascular
disease in patients with type 2 diabetes mellitus (Kenneth., 2009).
Diabetes, dyslipidemia, hypertension, and cardiovascular disease (CVD) occur
more frequently in individuals with NAFLD (Targher et al., 2008).
This is of concern as the prevalence of NAFLD is rapidly increasing in children
and adolescents, particularly in Hispanics. As with adults, metabolic syndrome
(MetS) is common in children with NAFLD (Schwimmer et al., 2008).
Obesity and type 2 DM share a `metabolic soil' that promotes hepatocyte
lipotoxicity: adipose tissue insulin resistance, subclinical inflammation,
hyperinsulinemia, and abnormal glucose metabolism (Cusi., 2008). Bland
steatosis has a relatively benign course. Follow up of patients with hepatic
steatosis alone has revealed that 3% will eventually develop Cirhosis overtime.
NASH in contrast has a progressive course, where a sizable subset of patients
will develop fibrosis and cirrhosis (Matteoni et al., 1999).
Patients with NASH who develop cirrhosis have 30-40% liver related mortality
over 10 years follow up period similar to patients with chronic hepatitis C
related cirrhosis and there is an even higher mortality rate in obese patients.
Patients who present with cryptogenic cirrhosis, which is a possible presentation
of end stage NAFLD, can also develop hepatocellular carcinoma (Ratziu et al.,
2002).
The vast majority of patients with cryptogenic cirrhosis have features of
metabolic syndrome in particular obesity and type 2 diabetes, leading to the
belief that these patients in effect have end stage NAFLD.
Type 2 diabetes is an independent risk factor for the development of NAFLD.
The prevalence of type 2 diabetes is 30- 50% in patients with NAFLD, and 62%
of type 2 diabetes met ultrasound criteria for NAFLD (Jimba et al., 2005).

41
Furthermore, type 2 diabetes is an independent risk factor for increase liver
related mortality in a case- cohort study of patients with NAFLD (Younossi et
al., 2004).
More advanced liver disease was seen in those patients with morbid obesity with
type 2 diabetes as compared to those with normal glucose level (Papadia et al.,
2004). The presence of obesity and type 2 diabetes in patients with metabolic
syndrome has an additive effect on the prevalence and severity of chronic liver
disease (Marchesini et al., 2004).
P
ATHOGENESISOF
NAFLD
patitis C infection and in
Potential role of RBP4 in mediating the progression of chronic he
Fig. (3):
the metabolic pathway to NASH. RBP4 was suggested as a novel circulating marker for HCV-induced
steatosis and could in addition play a
role
in the metabolic pathway from visceral obesity to insulin
resistance and fatty liver disease (Matthias et al., 2008).
The most commonly accepted hypotheses of the pathogenesis of NASH is two-
hit hypothesis (
Day and James, 1998)
. The first hit is insulin resistance, which
leads to accumulation of fat in the liver
(Li et al., 2002).
There is a second hit possible in the form of endotoxin or another insult to the
hepatic steatosis triggering oxidative stress, which generates reactive oxygen
species resulting in lipid peroxidation and cytokines relies ultimately leading to
inflammation and hepatic fibrosis (
Yang
et al., 1997).

42
Tumor necrosis factor is increased in obese patients. This cytokines along with
interleukin-6 is believed to result in insulin resistance by producing the up
regulation of suppressor of cytokines signaling proteins (Katsuki et al., 1998).
Central obesity along with increase lipolysis of visceral tissue result in increase
delivery of free fatty acids to the liver leading to hepatic steatosis, the first hit in
the development of NAFLD. Insulin resistance decreases the uptake of glucose
to muscle and increase lipolysis of visceral fat, resulting in increased delivery of
free fatty acids to the liver (
Nielsen
et al., 2004).
There is also increase hepatic lipogenesis and decrease export of lipid from the
liver despite increased beta oxidation of fat, with net accumulation of fat in the
liver (
Diraison
et al., 2003).
Free fatty acids, besides increasing free fatty acid oxidation and lipid
peroxidation, can directly increase tumor necrosis factor this leads to and
further promoting insulin resistance leading to a higher prevalence of type 2
diabetes in NAFLD associated cirrhosis (Feldstein et al., 2004).
The most accurate means of diagnosing NAFLD is a liver biopsy specially in
patients with the metabolic syndrome (
Nugent
and Younossi., 2007) abdominal
imaging studies like abdominal ultrasound, computed tomography and magnetic
resonance imaging cannot differentiate between benign hepatic steatosis and
NASH (
Saadeh
et al., 2002).
Because nonalcoholic steatohepatitis may develop even in the presence of
normal liver transaminases, a liver biopsy is still necessary for a definitive
diagnosis. However, new imaging methods and plasma biomarkers are emerging
as alternative diagnostic tools (Kenneth., 2009).
Raised serum leptin and resistin and decreased adiponectin levels, may
differentiate between bland hepatic steatosis and NASH and may render the
biopsy obsolete (Gawrieh et al., 2004).
D
IABETESMELLITUSANDHEPATOCELLULACARCINOMA
:
Most diabetic patients are non-insulin dependent and are characterized by
hyperinsulinemia. High insulin level or its precursors may interact with liver
cells to stimulate mitogenesis or carcinogenesis (Moore et al., 1998).
Alternatively, the metabolic effects of diabetes may increase the risk of
hepatocellular carcinoma through non Alcoholic steato hepatitis and
Cryptogenic cirrhosis (Marceau et al., 1999).

43
Patients
with diabetes have a high prevalence of liver disease and patients
with
liver disease have a high prevalence of diabetes (Trombetta et al., 2005).
The negative impact of diabetes on the retina, renal, nervous and cardiovascular
system is well recognized, yet little is known about it's effect on the liver
(Liane., 2010).
Existing guidelines do not advocate screening for liver related complications
among persons with diabetes, making the liver a potentially neglected target
organ. Although diabetic hepatopathy is potentially less common, it may be
appropriate for addition to the list of target- organ conditions related to diabetes.
When the liver fail, there is no equivalent form of management, such as
haemodialysis or photocoagulation. Annual screening for liver disease might be
accomplished by means of a simple biochemical analysis such as alanine amino
transferase (Goessling et al., 2008).
Individual with type 2 diabetes have an increased prevalence of cirrhosis, and a
proportion of patients with acute and chronic liver disease develop diabetes
mellitus (Petrides., 1994).
Recent evidence has even suggested that elevated level of aminotransferase may
be a marker of future risk of diabetes (Orasanu and Plutzky., 2009)
Virtually the entire spectrum of liver disease is seen in patients with type 2
diabetes. This includes abnormal liver enzymes, nonalcoholic
fatty liver disease
(NAFLD), cirrhosis, hepatocellular carcinoma,
and acute liver failure. In
addition, there is an unexplained
association of diabetes with hepatitis C
(Trombetta et al., 2005).
Also, Patients with various forms of liver disease can be predisposed to impaired
glucose tolerance because of corticosteroid and hydrochlorothiazide therapy or
haemo-chromatosis (Niedereau et al., 1985).
The management of diabetes in patients with liver disease is
theoretically
complicated by liver-related alterations in drug
metabolism, potential
interactions between the drugs, and a
low, albeit real, incidence of hepatotoxicity
(Tolman et al., 2007).

44
L
IVERCIRRHOSIS
D
EFINITION
:
Cirrhosis is defined as the histological development of regenerative nodules
surrounded by fibrous bands in response to chronic liver injury which lead to
portal hypertension and end-stage liver disease (Schuppan and Afdhal., 2008).
It is an irreversible alteration of the liver architecture and consist of diffuse
fibrosis of the hepatic parenchyma resulting in nodule formation (Friedmann
and Keeffe., 1998).
Fibrosis is not synonymous with cirrhosis, fibrosis may be in acinar zone 3 in
heart failure or in zone 1 in bile duct obstruction and congenital hepatic fibrosis
or interlobular in granulomatous liver disease but without a true cirrhosis.
Nodule formation without fibrosis as in partial nodular transformation is not
cirrhosis (Sherlok and Dooly., 2002a).
Cirrhosis has followed hepatic cellular necrosis. Although the causes are
multiple the end result is the same. In all cirrhotic patients the triad of necrosis,
regeneration and scarring is present (Conn and Atterbury., 1987).
World Health Organization definition of cirrhosis is a diffuse process
characterized by fibrosis and the conversion of normal liver architecture into
structurally abnormal nodules that lack normal lobular organization. This
definition distinguishes cirrhosis from other types of liver disease that have
either nodule formation or fibrosis, but not both. These hepatic disorders
may be characterized by portal hypertension in the absence of cirrhosis.
Nodular regenerative hyperplasia, for example, is characterized by diffuse
nodularity without fibrosis, whereas chronic schistosomiasis is characterized
by Symmers' pipestem fibrosis with no nodularity (Lowarence and Emmet.,
2012).
The consequence of cirrhosis includes vascular disturbances such as intrahepatic
shunting of blood, obstruction to portal venous blood flow (resulting in portal
venous hypertension) and impaired parenchymal function including protein
synthesis, hormone metabolism and excretion of bile (Millward and Wright.,
1979).
Structural changes in the liver may cause impairment of hepatic function
manifested as (Jaundice, portal hypertension and varices, ascites, hepatorenal
syndrome, spontaneous bacterial peritonitis, hepatic encephalopathy and
progressive hepatic failure) (Lowarence and Emmet., 2012).

45
C
LASSIFICATIONOFLIVERCIRRHOSIS
:
A- Morphological classification:
1.
Micronodular cirrhosis: Characterized by thick, regular septa, regenerating
small nodules less than 3mm in diameter, uniform and by involvement of every
lobule (Sherlock and Dooley., 2002a).
Micronodular liver may represent impaired capacity for growth as in: alcoholism,
hemochromatosis, biliary obstruction, hepatic venous outflow obstruction and
Indian childhood cirrhosis (Friedmann and Keeffe., 1998).
Macronodular cirrhosis: Is characterized by septa and nodules of variable
sizes more than 3mm in diameter. Regeneration is reflected by large cells with
large nuclei and by cell plates of varying thickness (Sherlock and Dooley.,
2002a), such as in chronic hepatitis C, chronic hepatitis B, alpha-1-antitrypsin
deficiency and primary biliary cirrhosis (Friedmann and Keeffe., 1998).
Mixed cirrhosis [Micronodular and Macronodular cirrhosis]: It is a
compromise term used when both macro and micronodules are present with
equal frequency (Anthony et al., 1978).
Regeneration in micronodular cirrhosis often converts to macronodular
(Sherlock and Dooley, 2002a).
B- Histological classification:
It confirms the morphologic diagnosis and subdivides it into histological and
sometimes etiological categories. According to histological classification, liver
cirrhosis is classified in to the following types:
Portal cirrhosis.
Post-hepatic cirrhosis.
Post-necrotic cirrhosis.
Biliary cirrhosis.
Cardiac cirrhosis.
(Conns and Atterbury., 1987)
C- Functional classification:
In any case of cirrhosis the following should be considered:
Degree of development of cirrhosis:

46
Activity: indicating tendency towards progression which depends mostly on the
activity of the attendant chronic hepatitis as reflected by
hypergammaglobulinemia and by inflammation and cell necrosis.
Degree of hepatocyte alteration: (steatosis, hepatic cholestasis) as a basis of
presenting hepatic symptoms indicated by liver function testes.
Presence of complications: as portal hypertension and its sequelae.
Liver biopsy is required for the evaluation of the first three considerations
(Winkel et al., 1976).
D- Aetiological classification:
.
cirrhosis according to etiology
of
sification
Clas
Table (9) :
(Anand., 1999)
1.
delta; C viral hepatitis with extensive necrosis
types B;
:
Viral hepatitis
can progress directly to post necrotic cirrhosis and chronic active hepatitis may
progress to cirrhosis but it is not clear how often does this sequence of events
occur (Schalm., 1997).
Hepatitis B, C and D represent the major viral agents currently shown to cause
chronic hepatitis. Long term complications are cirrhosis with attendant problems
resulting from hepatic synthetic failure, portal hypertension and hepatocellular
carcinoma (Sherlok and Dooly., 2002a).
The World Health Organization has declared hepatitis C a global health
problem, with approximately 3% of the world's population (roughly 170-200
million people) infected with HCV. In the United States , approximately 3
million people are chronically infected, many of whom are still undiagnosed. In

47
Egypt the situation is quite worse. Egypt has a population of 81 million and
contains the highest prevalence of hepatitis C in the world. The national
prevalence rate of HCV antibody positivity has been estimated to be between
10-13% (Mohamed., 2004).
Chronic hepatitis C infection may lead to cirrhosis and hepatocellular carcinoma
and is a leading cause of liver transplantation in the United States (Alter et al.,
1992).
In addition to these known risk factors, there is now emerging evidence to
suggest that hepatitis C virus (HCV) infection may also contribute to the
development of diabetes for example, glucose intolerance is observed more
often in patients with hepatitis C virus infection compared with controls with
liver disease (Allison et al., 1994).
There is also increase frequency of genotype 2a among diabetic patients with
hepatitis C infection in contrast to genotype 1 which is the most common form
of infection in the general population (Andrew., 1999).
Experimental data are compatible with direct interference of HCV with the
insulin signaling cascade. This was first suggested by a study in which liver
specimens obtained from 42 non-obese, non-diabetic, HCV-infected individuals
and 10 non-HCV-infected subjects matched for age and BMI were exposed in
vivo to insulin, and examined for the contents and phosphorylation/activation
status of some insulin signaling molecules (Aytug et al., 2003).
Insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by two-fold in
HCV-infected patients compared to non-HCV-infected ones, and this was
paralleled by significant reductions in IRS-1/p85 phosphatidylinositol 3-kinase
association, IRS-1-associated phosphatidylinositol 3-kinase enzymatic activity
and insulin-stimulated Akt phosphorylation (Aytug et al., 2003).
-
2
Alcoholic liver cirrhosis is serious sequale of the chronic abuse
Alcohol:
of ethanol. The development of liver damage is related to the amount and
duration of alcohol abuse (Boyer., 1985).
Recent study done on sixteen European countries showed that alcohol
consumption has negative impact on health in terms of liver cirrhosis mortality,
also no difference was found between different types of alcohol. Indeed beer has
the most serious consequences on health than other types (Jan and Valdmer.,
2010).

48
3-Biliary cirrhosis:
Due to long standing intermittent or partial biliary obstruction. It may be
primary or secondary:
a) Primary biliary cirrhosis: (PBC).
It has been called chronic non suppurative destructive cholangitis (Burroughs
and Westaby, 2002).
It is the most common autoimmune liver disease affecting up to 1 in 1000
women over 40 years of age (Kaplan and Gershwin, 2005).
It is characterized by destruction of intrahepatic bile ducts and high titers of
antimitochondrial antibodies in patients sera (Akiyoshi and Murri, 1998).
The granulomatous destruction of interlobular bile ducts that characterized PBC
is almost always associated with antimitochondrial antibodies specific for the E2
subunit of the pyruvate dehydrogenase complex (Gershwin and Mackay, 2008).
b) Secondary biliary cirrhosis:
It is a sequal of long standing obstruction of the biliary tract for more than one
year before cirrhosis develops (Tartakovsky and Hagg, 1995).
4) Wilson's disease:
Wilson disease (WD) is an autosomal recessive disorder of copper transport that
results in accumulation of copper primarily in the liver, brain and cornea. WD is
the most common inherited liver disease with the prevalence of 1: 37,000 in the
pediatric population in Korea. Mutations in the ATP7B gene cause failure of
copper excretion in to the bile and a defective incorporation of copper into
ceruloplasmin (Seo, 2006).
It is a rare inherited disease predominantly of young people that is characterized
by cirrhosis of the liver, bilateral softening degeneration of basal ganglia and
greenish brownish pigmented rings in the periphery of the cornea (Kayser

49
Fleischer rings) (Sherlock and Dooley, 2002a).
It should be suspected in any individuals between ages 3-40 years with:
Unexplained serum aminotransferase elevation, fulminant hepatic failure,
chronic hepatitis or cirrhosis.
- Neurological features of unexplained a etiology.
- Psychiatric disorders with sings of hepatic or neurological disease or patients
who are refractory to therapy.
- Kayser-Fleischer rings on routine eye examination.
- Unexplained acquired coombs-negative hemolytic anemia.
- A sibling or a parent carrying the diagnosis of Wilson disease.
(Wisam et al., 1998)
Investigations of WD:
- Low serum ceruloplasmin 20mg/dl.
- High 24hrs urine copper 100 microgram.
- High hepatic copper content 250 microgram/g of dry liver.
- Kayser-Fleischer rings were found in 96% on routin eye examination.
- A combination of any two of the above finding is strong support for
diagnosis WD (Seo, 2006).
5- Alpha-1-antitrypsin deficiency:
Alpha 1-antitrypsin deficiency is an inherited metabolic disorder that
predisposes the affected individual to chronic pulmonary disease, in addition to
chronic liver disease, cirrhosis and HCC. Just over one third of genetically
susceptible adult patients with the most severe phenotype, develop clinically
significant liver injury (Fairbanks and Tavill, 2008).
It is the most common metabolic deficiency. It should be considered in the
differential diagnosis in any adult who present with chronic hepatitis or cirrhosis of

50
unknown a etiology. The incidence of liver disease in adolescent with alpha-1-
antitrypsin deficiency is 2% by age 20-40 years, 5% by age of 40-50 years and 15%,
thereafter with slight male predominance (Hugo, 1998).
6) Haemochromatosis:
Hereditary haemochromatosis is a common disorder with a prevalence of up to
1/250-300 in persons of northern European descent. It was first described in
1886 as Bronze diabetes; it is an autosomal recessive metabolic disorder in
which there is an increased iron absorption over many years.
The disease is often recognized and diagnosed only in the setting of advanced
liver disease. With increased awareness of the disease, the most common
presenting symptoms are:
- Incidental diagnosis because of elevated serum iron markers.
- Chronic liver disease.
- Arthritis.
It is to be noted that liver biopsy with determination of hepatic iron
concentration is the best method for establishing a definitive diagnosis
(Freidmann and Keeffe, 1998).
7- Budd- chiari syndrome (BCS):
BCS is characterized by hepatic venous outflow obstruction at any level from
the small hepatic veins to the atriocaval junction (Horton et al., 2008).
Hepatic vein occlusion or BCS is an disorder characterized by abdominal pain,
hepatomegaly and ascites.
The majority of patients with BCS have an underlying thrombotic diathesis. In
less than 30% of cases the disorder is idiopathic. Disorders associated with BCS
include the following:

51
a) Hematological:
Polycythemia rubra vera.
Myeloproliferative disorders.
Paroxysmal nocturnal haemoglobulinuria.
Antiphospholipid syndrome.
b) Inherited thrombotic diathesis:
Protein C deficiency.
Protein S deficiency.
Antithrombin III deficiency.
Factor V Leiden mutation.
(Horton et al., 2008)
8- Immunologic:
a- Autoimmune hepatitis.
b- Graft-versus-host disease.
(Horton et al., 2008)
Autoimmune hepatitis:
It is unresolving inflammation of the liver of unknown aetiology that is
characterized by at least periportal hepatitis on histologic examination,
autoantibodies in serum and hypergammaglobuli-naemia. Because there are no
pathognomonic features, the diagnosis requires the exclusion of chronic viral
hepatitis, Wilson disease, alpha-1-anti-trypsin deficiency, haemochromatosis,
drug induced hepatitis, alcoholic and non alcoholic hepatitis and other
immunologic condition such as autoimmune cholangitis, primary biliary
cirrhosis and primary sclerosing cholangitis (Cazaja et al., 2000).
Now is recognized as a multisystem disorder that can occur in males and females of
all ages. This condition can coexist with other liver diseases (e.g., chronic viral
hepatitis) and chemicals (e.g minocycline) (Vento and Cainelli, 2004).

52
Pathophysiology:
Liver cells injury in autoimmune hepatitis patients results from cell mediated
immunologic attack. This attack is directed against genetically predisposed
hepatocytes. Aberrant display of human leucocyte antigen (HLA) class II on the
surface of hepatocytes facilitates the presentation of normal cell membrane
constituents to antigen processing cells. These activated cells stimulate clonal
expansion of autoantigen sensitized cytotoxic T-lymphocytes. Cytotoxic T-
lymphocytes infilterate liver tissue, release cytokines and help to destroy liver
cells (Seki et al., 1990).
Autoantibodies:
Three types of autoimmune hepatitis have been recognized:
Type I with antibodies:
I. Antinuclear.
II. Anti-smooth muscle (Anti-actin).
Type II with antibodies:
Anti-liver/kidney microsomal (Anti-LKM1). Most frequently in girls and young
women.
Type III with soluble liver antigen:
Same as type I (Burroughs and Westaby, 2002).
Diagnosis of liver cirrhosis:
Diagnosis of liver cirrhosis is based on, history, clinical examination looking
for:
1- Stigmata of chronic liver disease like, spider naevi, gynaecomastia and
testicular atrophy.
2- Features of protal hypertension like ascites and spleno megaly.

53
3- Features of hepatic encepahlopathy like flapping tremer.
Laboratory investigations:
1- Full blood count.
2- Liver function tests.
Special tests looking for the under lying causes.
Imaging studies like abdominal ultrasound, computed tomography and
magnetic resonance imaging.
The gold standard for diagnosis is liver biopsy.
(Lowrence S and Emmet., 2012)
R
ETINOLBINDINGPROTEIN
4
A
DIPOSETISSUEINHEALTHANDDISEASE
Adipose tissue is found in the skin as subcutaneous fat, and within the body
cavity surrounding the heart, in the mesentery and in the retroperitonium. This
portal fat drains directly into the portal circulation and has been linked to
morbidities, such as cardiovascular disease and type 2 DM. Adipose tissue has a
considerable effect on glucose homeostatis by secreting adipokines, some like
leptin, adiponectin has anti diabetic action while others like tumor necrosis
factor, interleukin 6 and retinol binding protein 4 has diabetogenic actions
(Masur et al., 2008).
The adipose tissue is an important endocrine organ that secretes a variety of
proteins termed adipocytokines which are biologically active polypeptides that
are produced either exclusively or substantially by the adipocytes and act by the
endocrine, paracrine, or autocrine mechanism.The adipokines appear to be
involved in a wide range of physiological processes; these include haemostasis,

54
lipid metabolism, blood pressure regulation, insulin sensitivity and angiogenesis
(Petersen et al., 2007).
Inflammatory cytokines are key players in the pathogenesis and severity of
atherosclerosis and its complications (Fonseca et al., 2009).
Retinol-binding protein (RBP)-4 was reported in 2005 by Yang
et al as a new
fat-derived adipokine that specifically binds to retinol, that has been proposed as
an adipokine involved in the regulation of systemic glucose metabolism and
pathogenesis of insulin resistance, and that it may provide a link between
obesity and insulin resistance. It has been demonstrated that RPB4 is secreted by
human adipose tissue and that it is expressed almost exclusively in mature
adipocytes. The expression of RBP4 has been demonstrated in subcutaneous
and, in visceral adipose tissue in humans
(Weiping et al., 2007).
More than 50 adipokines has been Identified leptin, adiponectin, resistin and
retinol binding protein 4 among others. Obesity has been associated with a
chronic inflammatory response, characterized by elevated circulating levels of
tumor necrosis factor, interleukin 6 and c reactive protein (Engelis et al., 2003).
RBP4 is predominantly secreted by visceral adipose tissue and the liver. It is the
only specific transport protein for retinol and by interacting with nuclear retinal
x receptor (RXR), it takes part in control of metabolic and proliferative cell
functions (Youssef., 2011).
A large number of studies in rodents and also in humans confirm an association
of increased level of RBp4 with obesity, insulin resistance, type 2 diabetes,
dyslipidemia, hypertension and metabolic syndrome (Rabe et al., 2008).
Retinol binding protein4 (RBP4) a 21-KDa protein synthesized in the liver and
adipose tissues, formerly recognized for its role as a specific transport for
vitamin A, now it is known that it plays a crucial role in insulin resistance and

55
diabetes mellitus. Adipose RBP4 expression and serum RBP4 level are elevated
in mouse model of insulin resistance, elevated circulating RBP4 increase blood
glucose by inhibiting insulin signaling in skeletal muscle and up regulating
hepatic gluconeogenesis (Koch et al., 2010).
Fig. (4): Retinol binding protein 4 (Rask et al., 1987).
Vitamin A circulates in human plasma as retinol (Vitamin A alcohol) bound to a
specific transport protein. This protein differs from the known low and high density
plasma lipoproteins. There appears to be one binding site for retinol per molecule
of RBP. Solutions of RBP are fluorescent (characteristic of retinol). There are no
fatty acids or fatty aryl chains in purified RBP. The usual concentration of RBP
in plasma is of the order of 4-15 mg/100 ml (Kanai et al., 1968).

56
R
ETINOID
R
ECEPTORS
:
Retinoid X receptor (RXR) is a member of the nuclear hormone receptor super
family of ligand-controlled transcription factors. These receptors modulate gene
expression by binding coperatively as dimers to sequences called hormone
responsive elements. RXR forms homodimers and is involved in 9-cis retinoic
acid (a naturally occurring retinoid isomer) (9c RA)-mediated gene activation. It
also forms heterodimers with other receptors, including all-trans retinoic acid
receptor (RAR) and peroxisome proliferators activated receptor (PPAR)
(Mangelsdorf and Evans., 1995).
There are three RXR isotypes, RXR , , and , among them, RXR is
abundantly expressed in the liver and plays important role in regulating cell
proliferation and differentiation. In addition, PPAR ­ RXR a heterodimer is
deeply involved in lipid metabolism (Youssef et al., 2011).
More over RBP4 gene expression in humans was associated with inflammatory
markers and RBP4 levels were associated with inflammatory response in obese
patients (Blagobal et al., 2007).
Increased serum RBP4 levels impair post receptor insulin signaling at the level
of phosphoinositide-3-Kinase in muscle and enhance the expression of
phosphoenolpyruvate carboxykinase in liver (Yang et al., 2005) and increases
basal glucose production, and reduce insulin action to suppress glucose
production in hepatocytes (Shin et al., 2002).
Therefore, increased serum RBP4 levels in humans might contribute to impaired
insulin stimulated glucose uptake in muscle and elevated hepatic glucose
production, both of which are characteristic of type 2 diabetes (Kahn et al.,
1998). Regions near the RBP4 locus on human chromosome 10q have been
linked to hyperinsulinemia or early onset of type 2 diabetes, a finding consisting
with a pathogenic role for RBP4 in insulin resistance and type 2 diabetes (Meigs
et al., 2002).

57
Berry and Noy., 2009 showed that binding of retinol-bound RBP(holo-RBP) to
it's receptors induces phosphorylation and regulates certain genes that control
adipocyte lipid homeostasis and insulin responses.
Fig. (5): RBP4 and insulin interactions at cellular level (Newcomer et al., 1984).
R
ETINOL
B
INDING
P
ROTEIN
4
AND
I
NSULIN
R
ESISTANCE
:
Mouse and human studies have highlighted a pathogenic link among 1R,
diabetes, and high serum and adipose levels of RBP4, identifying RBP4 as a
novel adipocytokine. There is clinical evidence that circulating RBP4 levels are
related to the severity of 1R and to the various features of the metabolic
syndrome (Von Eynatten and Humpert., 2007). Specifically, raised serum
levels of RBP4 have been linked to NAFLD (non alcoholic fatty liver disease),
assessed by ultrasonography in a cohort of subjects with and without diabetes
(Janke et al., 2006).

58
D
EFECTSINTHEABILITYOFFATCELLSTOTRANSPORTGLUCOSE
ARELINKEDTOINSULINRESISTANCEINMUSCLEANDLIVERS
:
Liver, skeletal muscle and adipose tissue are the three major targets for the
metabolic actions of insulin. Insulin regulates glucose output and by increasing
the rate of glucose uptake by skeletal muscle and adipose tissue. Stimulation of
glucose uptake into muscle cells and adipocytes by insulin depends largely on
translocation of the glucose transporter GLUT4 from an intracellular
compartment to the cell surface (Shepherd and Kahn., 1999).
The expression of GLUT4 is reduced in adipocytes, but not in skeletal muscle,
in obesity and type 2 diabetes (Shepherd and Kahn., 1999). Given that skeletal
muscle is the major sink for glucose disposal, the hyperglycemia associated with
obesity type 2 diabetes can not be explained by the decreased uptake of
glucose into adipose tissue that is attributable to the decreased expression of
GLUT4 in adipocytes. However, over expression of GLUT4 specifically in
adipose tissue enhances systemic glucose tolerance and insulin sensitivity in
mice (Shepherd et al., 1993).
Furthermore, adiposity-selective ablation of GLUT4 results in a degree of
systemic insulin resistance similar to that induced by muscle selective GLUT4
ablation. In addition, insulin resistance is apparent in both the liver and skeletal
muscle of mice lacking GLUT4 in adipose tissue (Specifically).These findings
suggested the possibility that expression of GLUT4 in adipocytes regulates
whole ­ body insulin sensitivity through an unknown mechanism (Abel et al.,
2001).
Barbara kahn and her colleagues predicted the existence of a factor secreted
from adipose tissue (an adipokine) that induces insulin resistance in the liver and
skeletal muscle (Abel et al., 2001) In nature, (Yang et al., 2005) have now
identified RBP4 as such a factor. These researchers found that expression of the
gene encoding RBP4- a protein whose only function was thought to be the
delivery of retinol to tissues was increased in adipose tissue of mice with

59
adipocyte specific ablation of GLUT4. Over expression of RBP4 or injection of
recombinant RBP4 in normal mice induced insulin resistance, whereas mice
heteroszygous or homozygous for knockout of the gene encoding RBP4 showed
increased insulin sensitivity compared with wild-type mice. Furthermore, the
synthetic retinoid fenretinide, which reduced the serum level of RBP4 through
urinary excretion, ameliorated insulin resistance in mice fed a high-fat diet.
S
UBJECTSAND
M
ETHODS
This cross- sectional study was conducted on 120 subjects recruited from
endocrinology outpatient clinic and hepatology clinics and wards, Ain Shams
University Hospital.
The subjects were divided into 30 diabetic patients, 30 patients with liver
cirrhosis, 30 patients with diabetes and liver cirrhosis, and 30 control subjects
matched for age and sex.
Study Design:
Subjects were divided into 4 groups:
Group 1: 30 diabetic patients.20 of them were females and 10 were males.
Group 2: 30 cirrhotic patients.18 of them were males and 12 were females.
Group 3: 30 diabetic and cirrhotic.16 of them were males and 14 were
females.
Group 4: 30 control subjects. 16 of them were males and 14 were females.
Patients with early liver cirrhosis were selected according to Childs
classification. (table 10)

60
Table (10): Modified child's classification (Pugh).
Clinical variable
1 Point
2 Point
3 Point
Encephalopathy
Absent
Stage 1-2
Stage 3-4
Ascitis
Absent
Slight
Moderate
Bilirubin(mg/dl)
2
2-3
3
Bilirubin in PBC or PSC (mg/dl)
4
4-10
10
Albumin (gm/dl)
3.5
2.8-3.5
2.8
Prothrombin time
(seconds above normal) or INR
4 Sec
or INR 1.7
4-6 Sec
or INR 1.7-2.3
6 Sec
or INR 2.3
(Mullen and Dasarthy., 1999)
Exclusion criteria:
1- Pregnant ladies.
2- Renal dysfunction.
3- Critically ill patients.
4- Late stage liver cirrhosis.
All cases enrolled into the study were submitted to:
1- Full medical history.
2- Thorough clinical examination.
3- Anthropometric examination:
- Weight, measurement in kg.
- Height in cm
- Body mass index (BMI); = Wt. (kg) /Ht.(m)
2
.
- Waist circumference in cm.
4- Blood Samples were taken to measure the following:
a) Fasting plasma glucose.mg/dl
b) HbA
1c
%.

61
c) Lipid profile including total cholesterol, LDL HDL, and TG.
Mg/dl.
d) Liver function tests including ALT, AST,in u/l serum albumin in
g/dl and prothrombin time in seconds.
e) Retinol binding protien 4(RBP4) in mg/dl by Elisa.
5- Radiological examination; Abdominal ultrasound was done for all
patients and control subjects to assess liver morphology,size,
echopattern, and to detect the presence of ascites.
S
PECIMENCOLLECTIONANDPREPARATION
:
A fasting morning serum sample should be obtained, 8 hours for glucose
and 12 hours for lipid profile. The blood should be in a plain red top
venipuncture tube without additions or gel barrier. Allow the blood to clot.
Centrifuge the specimen to separate the serum from the cells.
Samples refrigerated in deep freeze -20 °C.
Samples for prothrombin time was collected in a blue top venipuncture
tube, samples for HbA
1c
% was collected in pink top venipuncture tube.
HbA
1
C
%;
estimation of HbA
1c
% was done by glycohemoglobin reagent
set from pointe scientific Inc. normal range: 4.2 - 6.2 %. (Bates,. 1978).
Lipid profile : after 12 to 14 hours overnight fasting:
o
Cholesterol ; estimation of cholesterol an triglyceride by cholesterol
enzyme colorimetric assay.
Normal range: cholesterol : 150 - 240 mg/dl
Triglyceride: 150 - 200 mg/dl (Brain and Eric., 2009).
o
High density lipoprotein (HDL); estimation of HDL by
precipitation with dextran sulphate normal range: 40 mg/dl low
60 mg/dl high (Brain and Eric., 2009).

62
o
Low density lipoprotein (LDL); was calculated according to
Edward formula :
LDL= total cholesterol ­ TG /5 ­ HDL.
Normal range: LDL= 100-160 mg/d (Brain and Eric., 2009).
Fasting plasma Glucose: after 8 hours overnight fasting.
It was done by the timed endpoint method using hexokinase enzyme, the
change in absorbance is measured at 340 nm. It was performed on Syn chron
CX9 autoanalyzer.
Normal range = 70-100 mg/dl (Gaede et al., 2008).
o
Assay of serum RBP4:
Measurement of serum RBP4 was done by enzyme ­linked
immunosorbent assay (ELISA). The AssayMax Human RBP4 ELISA Kit,
Immundiagnostic AG, Stubenwald-Allee 8a, D 64625 Bensheim desgined
for detection of human RBP4 in serum. This assay employs a quantitive
sandwitch enzyme immunoassay technique that measures RBP4. Blood
samples were incubated in duplicate wells of micro titer plates.Which had
been recoated with antibodies specific for the analyte RBP4.During this
incubation,the analyte present. In the standards samples was bound by
immobilized antibodies in the respective assay plates. After repeated
washing and aspiration to remove all unbound substances, an enzyme ­
linked polyclonal antibody specific for the analyte was added to the wells
of the wells of the assay plates.Unbound enzyme conjugate streptavidin­
peroxidase conjugate was removed by repeated washing and substrate
solution was added to the wells of the assay plates,with color developing in
proportion to the amount of the analyte bound in the initial step. Color
devolpment was stopped with the addition of an acid solution,and the
intensity of color was read using a programmable spectrophotometer. The
concentration of RBP4 in samples were determined by interpolation from
individual standard curves.

63
Normal range 4-15mg/dl (Graham et al., 2006).
S
TATISTICALANALYSIS
Data were statistically described in terms of mean
standard deviation (SD),
range, or frequencies (number of cases) and percentages when appropriate.
Comparison of numerical variables between the study groups was done using
one way analysis of variance (ANOVA) test with posthoc multiple 2-group
comparisons. For comparing categorical data, Chi square (
2) test was
performed. Exact test was used instead when the expected frequency is less than
5. All statistical calculations were done using computer programs SPSS
(Statistical Package for the Social Science; SPSS Inc.,Chicago, IL,USA)
version15 for Microsoft Windows.
Significant level (P) was express as follows:
P value 0.05 =Non Significant (N.S)
P value0.05 = Significant (Sig)
a) P value 0.001 = Highly Significant (H.S)

64
R
ESULTS
The present study was conducted on 120 subjects divided into four groups:
group (1) included 30 diabetic patients, group (2) included 30 patients with liver
cirrhosis, group (3) included 30 patients with diabetes and liver cirrhosis and
group (4) included 30 control subjects. They were selected from patients
attending the Endocrinology Clinic and Hepatology clinics and wards, Ain
Shams University Hospital.
Group (I): (DM) included (30) thirty diabetic patients they were 10 (33.3%)
males, and 20(66.7%) females. Their age ranged from 30- 60 with a
mean of (51.97+7.52) years. The mean body mass index was (28.5 +
6.17) kg/m
2
. The mean waist circumference was (103.7± 17.76) cm.
The
mean HbA
1
c% was (10.35 + 2.83). The mean fasting plasma glucose was
(142.43 +23.38) mg/dl. The mean cholesterol was (209.97 + 28.10)
mg/dl. The mean LDL was (151.13 + 22.32) mg/dl. The mean HDL was
(34.83 + 4.13) mg/dl. The mean triglyceride was (115.53 + 21.27) mg/dl.
The mean ALT was (18.1 + 5.37) u/l. The mean AST was (18.73 + 5.55)
u/l. The mean serum albumin was (4.17 + 0.52) g/dl. The mean
prothrombin time was (10.30 +2.35) The mean Retinol binding protein
was (20.1± 8.31) mg/dl.
Group (2): Included 30 cirrhotic patients they were 18 (60%) males and 12
(40%) females. Their age ranged from 30- 60 with a mean of
(46.93+9.90) years. The mean body mass index was (25.6+ 4.15) kg/m.
The mean waist circumference was (83.43+ 7.40) cm. The mean
HbA
1C
% was (5.92 + 0.68). The mean fasting plasma glucose was (97.87
+ 8.68) mg/dl. The mean cholesterol was (237.53 + 23.87) mg/dl. The
mean LDL was (169.89 + 25.52) mg/dl. The mean triglyceride was
(122.3± 15.25) mg/dl. The mean HDL was (37.97 + 6.17) mg/dl. The
mean ALT was (33.00 + 18.35) u/l. The mean AST was (33.00 + 18.35)
u/l. The mean Albumin was (2.39 + 0.64) g/dl. The mean prothrombin

65
time was (18.33 + 3.99) seconds. The mean RBP4 was (9.31 + 3.99)
mg/dl.
Group (3): Included 30 patients with diabetes and liver cirrhosis they were 16
(53.3%) males and 14 (46.7%) females. Their age ranged from 30- 60
with a mean of (51.47 + 6.80) years. The mean body mass index was
(29.1+4.1) kg/m
2
. The mean waist circumference was (88.33+6.00) cm.
the mean HbA
1C
% was (7.40+2.60).
The mean fasting plasma glucose was (123.77 +24.45) mg/dl the mean
cholesterol was (228.67 +31.87)
mg/dl. The mean LDL was (159.57 +28.05) mg/dl. The mean HDL was
(36.83+5.37) mg/dl. The mean Triglycerides was (119.83 + 21.29) mg/dl.
The mean ALT was (28.33+8.63) u/l. The mean AST was (38.33 + 37.58)
u/l. The mean albumin was (2.33+0.49) g/dl. The mean prothrombin time
was (17.13±3.66) seconds. The mean RBP4 was (8.59 ±7.17) mg/dl.
Group (4): Include 30 control subjects they were 16 (53.3%) males and 14
(46.7%) females. Their age ranged from 30- 60 with a mean of (47.83 ±
8.74) years. The mean body mass index was (22.5±2.53) kg/m2. The
mean waist circumference was (79.73 ±8.98) cm. The mean HbA1c%
was (5.8 ± 0.46). The mean fasting plasma glucose was (95.93 ± 7.52)
mg/dl. The mean cholesterol level was (198.97 ±17.58) mg/dl. The mean
LDL was (138.83 ± 28.35) mg/dl. The mean HDL was (38.17 ± 5.03)
mg/dl. The mean triglycerides was (98.33 ±11.29) mg/dl. The mean ALT
was (19.33±4.90) u/l. The mean AST was (19.33±0.46) u/l. The mean
serum Albumin was (4.19 ± 0.46) g/dl. The mean prothrombin time was
(10.0±1.7) seconds. The mean RBP4 was (13.5± 3.97) mg/dl.
As regard the clinical and laboratory data of different groups, the data were
arranged in tables according to the groups and results.

66
1- BMI (body mass index) kg/m
2
)
On comparing the 4 groups as regards BMI the mean BMI of group 1 (28.5
±6.17), group 2 (25.6 ±4.15), group 3 (29.1± 4.1), group 4 (22.5±2.53).
There is a highly statistical significant difference between group 4 (Control)
(22.5±2.53) and group I (diabetic)(28.5 ±6.17) P= 000, group 4 (control) (22.5±
2.53) and group 2 (liver cirrhosis) (25.6 ±4.15) P=0.047, group 4 (control) and
group 3 (diabetes and liver cirrhosis) a significant difference was also found p=
000,between group 2 (cirrhosis) (25.6± 4.15) and group 3 (diabetes and liver
cirrhosis) (29.1± 4.1) p=0.02.
It was found that there is no significant difference between group I (diabetes)
(28.5± 6.17) and group 2(liver cirrhosis) (25.6± 4.15) p= 0.08, and group 3
(diabetes and liver cirrhosis) (29± 4.1) p= 1.
2- Waist circumference (cm):
It was found that there is a high significant statistical difference between group 4
(controls) (79.9 ± 8.9) and groupI (diabetic) (103.07± 17.76) p= 000, group
3(DM and liver cirrhosis) (88.33±6.00) p = 0.000. A significant difference was
also found between group 1 (DM) (103.07± 17.76) , group 2 (liver cirrhosis)
(83.43± 7.40) p= 0.000, and group 3 (DM and liver cirrhosis) (88.33±6.00)
p=0.001.
It was found that there is no significant difference between group 4 (controls)
(79.73± 8.98), and group 2 (liver cirrhosis) (83.43+ 7.40) p=0.413.
3- FPG (fasting plasma glucose) (mg/dl):
It was found that there is a high significant statistical difference between group 4
(control) (95.93± 7.52), group I (diabetes) (142.43± 23.38) p= 000, and group 3
(diabetes and liver cirrhosis) (123.77± 24.45).

67
It was found that there is no significant difference between group 4 (control)
(95.93± 7.52) and group 2 (liver cirrhosis) (97.87± 8.68).
4- HbA
1C
%
It was found that there is a high significant statistical difference between group 4
(controls) (5.80± 0.46), group I (diabetes) (10.35± 2.83) p= 000, and group 3
(diabetes and liver cirrhosis) (7.40.0.62) p = 0.000.
It was also found that there is a high significant statistical difference between
group 1 (DM) (10.35± 2.83), and group 2 (liver cirrhosis) (5.92± 0.68) p= 000.
It was found that there is no significant difference between group 4 (control)
(5.80± 0.46) and group 2 (liver cirrhosis) (5.92± 0.68).
It was found that there is no significant difference between group 1 (diabetes)
(10.35±2.83) and group 3 (DM and liver cirrhosis) (7.40±0.62), p = 0.523.
2 (liver cirrhosis) (169.89± 25.52) p= 0.00 and group 3 (diabetes and liver
cirrhosis) (159.57± 28.05) p= 0.016.
It was found that there is no statistically significant difference between group I
(diabetes) (151.13± 22.32), group 2 (cirrhosis) (169.89± 25.52) p 0.42, group 3
(diabetes and liver cirrhosis) (159.57± 28.05) p=1.00 and group 4 control
(138.83 ± 28.35) p= 0.42.
There was also no significant difference between group 2 (liver cirrhosis)
(169.89± 25.52) and group 3 (diabetes and liver cirrhosis) (159.57± 28.05) p=
0.941.
9- Alanine aminotransferase (ALT u/l):
It was found that there is a high significant statistical difference between group 4
(controls) (19.33±4.90) , group 2 liver cirrhosis) (33.00± 18.35) p = 0.00,and
group 3 (diabetes and liver cirrhosis) (28.33±8.63) p= 0.00

68
It was found also that there is a high siginificant statistical between group I
(diabetes) (18.10 ± 5.37), group 2 (liver cirrhosis) (33.00±18.35) p= 0.001, and
group 3 (diabetes and liver cirrhosis) (28.33±8.63) p= 0.00.
It was found that there is no significant difference between group I diabetes
(18.10 ± 5.37) and group 4 (control) (19.33±4.90) p=0.924.There was also no
significant
5- Cholesterol mg/dl:
It was found that there is a high significant statistical difference between group 1
(diabetes) (209.97± 28.1) group 2 (liver cirrhosis) (237.53± 23.87) p= 000 and
group 3 (diabetes and liver cirrhosis) (228.67± 31.87) p= 0.031.
There was also statistically significant difference between group 4 (control)
(198.97± 17.58), group 2 (liver cirrhosis) (237.53± 23.87) p= 000 and group 3
(diabetes and liver cirrhosis) (228.67± 31.87) p= 000.
It was found that no statistically significant difference between group 2
(cirrhosis) (237.53± 23.87) and group 3 (diabetes and liver cirrhosis) (228.67±
31.87) p=1. There was no difference between group 4 (control) (198.97± 17.58)
and group 1 (diabetes) (209.97± 28.1) p= 0.576.
6-High density lipoprotein mg/dl;
It was found that there is no statistically significant group 1 (diabetes)
(34.83±4.13), group 2 (liver cirrhosis) (37.97±6.17), group 3 (diabetes and liver
cirrhosis) (36.83±5.37), and group 4 (control) (38.17±5.03).p=0.058
7- Triglycerides mg/dl:
It was found that there is a high siginificant statistical difference between group
4 (control) (98.33± 11.29), group 2 (liver cirrhosis) (122.30± 15.25) p=0.00 and
group 3 (diabetes and liver cirrhosis) (119.83± 21.29) p= 0.00

69
It was found that there is no significant difference between group 1 (diabetes)
(115.53± 21.27), group 2 (cirrhosis) (122.3± 15.25) p 0.877 and group 3
(diabetes and liver cirrhosis) (119.83±21.29) p= 1.00 No statistically significant
difference was found between group 2 (cirrhosis) (122.33± 15.25) and group 3
(diabetes and liver cirrhosis) (119.83± 21.29) p= 1.00
8- Low density lipoproteins:
It was found that there is a high significant statistical difference between group 4
(control) (138.83± 28.35), group2 (liver cirrhosis) (169.89± 25.52) p= 0.00 and
group 3 (diabetes and liver cirrhosis) (159.57± 28.05) p= 0.016.
It was found that there is no statistically significant difference between group I
(diabetes) (151.13± 22.32), group 2 (cirrhosis) (169.89± 25.52) p 0.42, group 3
(diabetes and liver cirrhosis) (159.57± 28.05) p=1.00 and group 4 control
(138.83 ± 28.35) p= 0.42.
There was also no significant difference between group 2 (liver cirrhosis)
(169.89± 25.52) and group 3 (diabetes and liver cirrhosis) (159.57± 28.05) p=
0.941.
9- Alanine aminotransferase (ALT u/l):
It was found that there is a high significant statistical difference between group 4
(controls) (19.33±4.90) , group 2 liver cirrhosis) (33.00± 18.35) p = 0.00,and
group 3 (diabetes and liver cirrhosis) (28.33±8.63) p= 0.00
It was found also that there is a high siginificant statistical between group I
(diabetes) (18.10 ± 5.37), group 2 (liver cirrhosis) (33.00±18.35) p= 0.001, and
group 3 (diabetes and liver cirrhosis) (28.33±8.63) p= 0.00.
It was found that there is no significant difference between group I diabetes
(18.10 ± 5.37) and group 4 (control) (19.33±4.90) p=0.924.There was also no

70
significant difference between group 2 (liver cirrhosis) (33.00±18.35) and group
3 (diabetes and liver cirrhosis) (28.33±8.63) p=0.751.
10- Aspartate Aminotransferase (AST u/l).
It was found that there is statistically significant difference between group 3
(diabetes and liver cirrhosis) (38.33± 37.58), group I (diabetes) (18.73± 5.55),
group 2 (liver cirrhosis) (33.00± 18.35) and group 4 (control) (19.33± 4.90)
p=0.04.
It was found that there is no significant difference between group 1 (diabetes)
(18.73± 5.55), group 2 (liver cirrhosis) (33.00± 18.35), and group 4 (control)
(19.33± 4.90) p= 0.63.
11- Serum Albumin g/dl.
It was found that there is a high significant statistical difference between group I
(diabetes) (4.17± 0.52), group 2 (liver cirrhosis) (2.39± 0.64) and group 3
(diabetes and liver cirrhosis) (2.33 ±0.49) p= 0. 00
There was also a high significant statistical between group 4 (control) (4.19±
0.46), group 2 (liver cirrhosis) (2.39± 0.64) and group 3 (diabetes and liver
cirrhosis) (2.33± 0.49). P= 0.00
There was no significant difference between group 4 (control) (4.19± 0.46)
group 1(diabetes) (4.17 ± 0.52) p=0.1
There was also no significant difference between group 2 (liver cirrhosis) (2.39±
0.64) and group 3 (diabetes and liver cirrhosis) (2.33± 0.49) p= 0.1
12- Prothrombin time/ seconds:
It was found that there is a high significant statistical difference between group I
(diabetes) (10.30± 2.35), group 2 (liver cirrhosis) (18.33± 3.99) and group 3
(diabetes and liver cirrhosis) (17.13± 3.66) p=0.00

71
It was found that there is a high significant statistical between group 4 (control)
(10.00+ 1.70), group 2 (liver cirrhosis) (18.33± 3.99) and group 3 (diabetes and
liver cirrhosis) (17.13± 3.66) p= 0.00
It was found that there is no significant difference between group I (diabetes)
(10.30± 2.35) and group 4 (control) (10.10± 1.70) p= 0.81
13- Retinol Binding Protein4 mg/dl:
It was found that there is a significant statistical difference between group 4
(control) (13.5± 3.97), group I diabetes (20.10± 8.31) p= 0.002 and group 3
(diabetes and liver cirrhosis) (8.59± 7.17) p= 0.045.
It was found that there is a high significant statistical difference between group I
(diabetes) (20.10± 8.31), group 2 (liver cirrhosis) (9.31±7.63) and group 3
(diabetes and liver cirrhosis) (8.59± 7.17) p= 0.00
A statistically significant difference was found between group 4 (control) (13.5±
3.97) and group 2 (liver cirrhosis) 9.31± 3.99) P =0.02.
No difference was found comparing group 2 (cirrhosis) (9.31± 3.99) and group 3
(diabetes and liver cirrhosis (8.59± 7.17) p=1.
RBp4 was highest in group1 (20.10 ± 8.31) followed by group p 4 (13.5 ± 3.97)
and group 2 (9.31 ± 3.99) and lastly group 3 (8.59 ± 7.17).

72
Table (11): Post hoc test to detect LSD between group 1 (DM) and group 2
(liver cirrhosis) as regarding all clinical and laboratory
parameters in the studied groups.
Group 1
(DM)
Group 2
(liver cirrhosis)
P value Sig
Age (years)
51.97 ±7.52
46.93 ±9.90
0.05
S
BMI kg/m
2
28.5±6.17
25.6±4.15
0.05
N.S
Waist
circumference (cm)
103.07±17.76 83.43±7.40
0.001 H.S
HbA
1
C %
10.35
2.83 5.92
0.68
0.001 H.S
FPG (mg/dl)
142.43
23.38
97.87
8.68
0.001 H.S
LDL (mg/dl)
151.13
22.32
169.89
25.52
0.05
N.S
HDL (mg/dl)
34.83
4.13
37.97
6.17
0.05
N.S
TG (mg/dl)
115.53
21.27
122.3
15.25
0.05
N.S
CHOL (mg/dl)
209.97
28.1
237.53
23.87
0.05
N.S
ALT (u/l)
18.10
5.37
33.00
18.35
0.001 H.S
AST (u/l)
18.73
5.55
33.00
18.35
0.05
N.S
ALB (g/dl)
4.17
0.52
2.39
0.64
0.001 H.S
PT (sc)
10.3
2.35
18.33
3.99
0.001 H.S
RBP4 (mg/dl)
20.1
8.31
9.31
3.99
0.001 H.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

73
On comparing group 1(DM) and group 2(liver cirrhosis), a high statistical
significant difference was found (p0.001) regarding FPG, waist circumference,
HbA
1C
%, cholesterol, ALT, serum albumin, PT and RBP4. NO statistical
significant difference as regards BMI, LDL, HDL, TG and AST. (table 11)
Table (12): Post hoc test to detect LSD between group 1 (DM) and group 3
(DM liver cirrhosis) as regarding all clinical and laboratory
parameters in the studied groups.
Group 1 (DM)
Group 3
(DM liver
cirrhosis)
P value Sig
Age (years)
51.97 ±7.52
51.47 ± 6.80
0.05
S
BMI (kg/m
2
)
28.5±6.17
29.1±4.1
0.05
N.S
Waist
circumference (cm)
103.07±17.76
88.33±6.00
0.001
H.S
HbA
1C
%
10.35
2.83
7.40
0.62
0.05
N.S
FPG (mg/dl)
142.43
23.38
123.77
24.45
0.001 H.S
LDL (mg/dl)
151.13
22.32
159.57
28.05
0.05
N.S
HDL (mg/dl)
34.83
4.13
36.83
5.37
0.05
N.S
TG (mg/dl)
115.53
21.27
119.83
21.29
0.05
N.S
CHOL (mg/dl)
209.97
28.1
228.67
31.87
0.05
N.S
ALT (mg/dl)
18.10
5.37
28.33
8.63
0.001 H.S
AST (mg/dl)
18.73
5.55
38.33
37.58
0.05
N.S
Alb (g/dl)
4.17
0.52
2.33
0.49
0.001 H.S

74
PT( sc)
10.3
2.35
17.13
3.66
0.001 H.S
RBP4 (mg/dl)
20.1
8.31
8.59
7.17
0.001 H.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
On comparing group 1(DM) and 3 (DM and liver cirrhosis), a high statistical
significant difference was found (P0.001) regarding FPG, ALT, serum
albumin, PT and RBP4 level but no statistical significant difference was found
as regards BMI waist circumference, HbA
1C
%, LDL, HDL, TG, cholesterol
level, AST.(table 12)
Table (13): Post hoc test to detect LSD between group 1 (DM) and group 4
(Controls) as regarding all clinical and laboratory parameters
in the studied groups.
Group 1 (DM)
Group
4(Controls)
P value Sig
Age (years)
51.97 ±7.52
47.83 ± 8.74
0.05
S
BMI (kg/m
2
)
28.5±6.17
22.5±2.53
0.001 H.S
Waist circumference
(cm)
103.07±17.76
79.73±8.98
0.001 H.S
HbA
1
C %
10.35
2.83
5.80
0.46
0.05
Sig
FPG (mg/dl)
142.43
23.38 95.93
7.52
0.001 H.S
LDL (mg/dl)
151.13
22.32 138.83
28.35 0.05
N.S

75
P value Non 0.05 =Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
On comparing group 1(DM) and group 4 (controls) a high statistical significant
difference was found (P0.001) regarding BMI, waist circumference, HbA
1C
%,
FPG, TG, and RBP4 level but no statistical significant differences was found as
regards LDL, HDL, cholesterol level, AST, ALT, serum albumin, and PT.(table
13)
HDL (mg/dl)
34.83
4.13
38.17
5.03
0.05
N.S
TG (mg/dl)
115.53
21.27 98.33
11.29
0.001 H.S
CHOL (mg/dl)
209.97
28.1
198.97
17.58 0.05
N.S
ALT (mg/dl)
18.10
5.37
19.33
4.90
0.05
N.S
AST (mg/dl)
18.73
5.55
19.33
4.9
0.05
N.S
ALB (g/dl)
4.17
0.52
4.19
0.46
0.05
N.S
PT (sc)
10.3
2.35
10.00
1.7
0.05
N.S
RBP4 (mg/dl)
20.1
8.31
13.5
3.97
0.001 H.S

76
Table (14): Post hoc test to detect LSD between group 2 (liver cirrhosis) and
group 3 (DM liver cirrhosis) as regarding all clinical and
laboratory parameters in the studied groups.
Group 2
(liver
cirrhosis)
Group 3
(DM liver cirrhosis)
P value Sig
Age(years)
46.93 ±9.90
51.47 ± 6.80
0.05
S
BMI (kg/m
2
)
25.6±4.15
29.1±4.1
0.05
N.S
Waist
circumference
(cm)
83.43±7.40
88.33±6.00
0.05
N.S
HbA
1C
%
5.92
0.68
7.40
0.62
0.001
H.S
FPG (mg/dl)
97.87
8.68
123.77
24.45
0.001
H.S
LDL (mg/dl)
169.89
25.52 159.57
28.05
0.05
N.S
HDL (mg/dl)
37.97
6.17
36.83
5.37
0.05
N.S
TG (mg/dl)
122.3
15.25
119.83
21.29
0.05
NS
CHOL (mg/dl)
237.53
23.87 228.67
31.87
0.05
N.S
ALT (u/l)
18.10
5.37
28.33
8.63
0.05
N.S
AST (u/l)
33.00
18.35
38.33
37.58
0.05
N.S
ALB (g/dl)
2.39
0.64
2.33
0.49
0.05
N.S
PT (sc)
18.33
3.99
17.13
3.66
0.05
N.S
RBP4 (mg/dl)
9.31
3.99
8.59
7.17
0.05
N.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
On comparing group 2 (liver cirrhosis) and 3 (DM and liver cirrhosis), apart
from FPG, and HbA
1c
%, no statistical significant difference was found regarding
all variables. (table 14)

77
Table (15): Post hoc test to detect LSD between group 3 (DM liver
cirrhosis) and group 4 (controls) as regarding all clinical and
laboratory parameters in the studied groups.
Group3 (DM
liver cirrhosis)
Group
4(Controls)
P value Sig
Age (years)
51.47 ± 6.80
47.83 ± 8.74
0.05
S
BMI (kg/m
2
)
29.1±4.1
22.5±2.53
0.001
H.S
Waist
circumference
(cm)
88.33±6.00
79.73±8.98
0.001
H.S
HbA
1
C %
7.40
0.62
5.8
0.46
0.001
H.S
FPG (mg/dl)
123.77
24.45
95.93
7.52
0.001
H.S
LDL (mg/dl)
159.57
28.05
138.83
28.35
0.001
H.S
HDL (mg/dl)
36.83
5.37
38.17
5.03
0.05
N.S
TG (mg/dl)
119.83
21.29
98.33
11.29
0.001
H.S
CHOL (mg/dl) 228.67
31.87
198.97
17.58
0.001
H.S
ALT (u/l)
28.33
8.63
19.33
4.90
0.001
H.S
AST (u/l)
38.33
37.58
19.33
4.90
0.001
H.S
ALB (g/dl)
2.33
0.49
4.19
0.46
0.001
H.S
PT (sc)
17.13
3.66
10.0
1.7
0.001
H.S
RBP4 (mg/dl)
8.59
7.17
13.5
3.97
0.001
H.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
On comparing group 3 (DM and liver cirrhosis) and 4 (controls) a high
statistical significant difference was found (P0.001) regarding BMI, waist
circumference, FPG, LDL, TG, cholesterol level, ALT, AST, PT, serum albumin
and RBP4 level.(table 15)

78
Table (16): Post hoc test to detect LSD between group 2 (liver cirrhosis)
and group 4 (controls) as regarding all clinical and laboratory
parameters in the studied groups.
Group 2
(liver cirrhosis)
Group 4
(Controls)
P value
Sig
Age (years)
46.93 ±9.90
47.83 ± 8.74
0.05
S
BMI (kg/m
2
)
25.6±4.15
22.5±2.53
0.001
H.S
Waist circumference
(cm)
83.43±7.40
79.73±8.98
0.05
N.S
HbA
1C
%
5.92
0.68
5.8
0.46
0.05
N.S
FPG (mg/dl)
97.87
8.68
95.93
7.52
0.05
N.S
LDL (mg/dl)
169.89
25.52
138.83
28.35
0.05
N.S
HDL (mg/dl)
37.97
6.17
38.17
5.03
0.05
N.S
TG (mg/dl)
122.3
15.25
98.33
11.29 0.05
NS
CHOL (mg/dl)
237.53
23.87
198.97
17.58
0.05
N.S
ALT (u/l)
33.00
18.35
19.33
4.90
0.05
S
AST (u/l)
33.00
18.35
19.33
4.90
0.05
N.S
ALB (g/dl)
2.39
0.64
4.19
0.46
0.001
H.S
PT (sc)
18.33
3.99
10.0
1.70
0.001
H.S
RBP4 (mg/dl)
9.31
3.99
13.5
3.97
0.05
S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)

79
P value 0.001 = Highly Significant (H.S).
On comparing group 2 (liver cirrhosis) and 4 (controls) a high statistical
significant difference was found, (P001) regarding BMI, PT and serum
albumin. A statistical significant was found as regard ALT and RBP4. No
statistical significant difference was found as regards waist circumference,
HbA
1
c%, FPG, LDL, HDL, TG, cholesterol level, and AST.(table 16)
On comparing all groups with each other there was a high statistical significant
difference (p0.001) regarding BMI, waist circumference, HbA
1
C%
,
FPG,
cholesterol level, TG, ALT, AST, serum albumin PT and RBP4 level. No
statistical significant difference was found (P0.05) as regards HDL.
On comparing RBP4 between all groups a high stasistically significant
difference was found between group 4 (controls), group I (DM), and group 3
(DM and liver cirrhosis) P 0.001. A statistical significant difference was found
between group 4 (control) and group 2 (liver cirrhosis) p 0.05.
Table (17): Correlation coefficient between RBP4 and all clinical and
laboratory parameters in the studied groups.
Pearson correlation
R
Sig
Waist circumferance
(cm)
0.227
0.021 Sig
HBA
1
C%
0.189
0.031 Sig
FPG (mg/dl)
0.268
0.004 Sig
LDL (mg/dl)
- 0.119
0.196 N.S
HDL (mg/dl)
-0.370
0.689 N.S

80
TG (mg/dl)
-0.145
0.115 N.S
Chol (mg/dl)
-0.187
0.04
Sig
ALT (u/l)
-0.174
0.058 N.S
AST (u/l)
-0.172
0.063 N.S
Alb (g/dl)
0.410
000
H.S
**.Correlation is significant at the 0.01 level (2-tailed).
*. Correlation is significant at the 0.05 level (2-tailed).
The correlation study showed that there is a highly significant direct correlation
between RBP4, serum albumin, HbA
1
C %, waist circumference, FPG and
cholesterol but was indirect with , LDL, HDL, TG,AST, and ALT. (table 17)
Table (18): Descriptive data of clinical parameter among the 4 groups.
Group 1
(DM)
Group 2
(liver
cirrhosis)
Group 3
(DM Liver
cirrhosis)
Group 4
(Controls)
P
value Sig
Age (years)
51.97± 7.52
46.93 ± 9.90
51.47 ± 6.80
47.83 ± 8.74
0.044 Sig
Body mass
index (kg/m
2
)
28.5± 6.17
25.6 ± 4.15
29.1 ± 4.1
22.5 ± 2.53
0.00
H.S
Waist
circumference
cm
103.07 ± 17.76 83.43 ± 7.40
88.33 ± 6.00
79.73 ±8.98
0.00
H.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
Table (19): Comparison between pateints and controls as regards sex.

81
Cases
Controls
P value
Number
90
30
0.67
(N.S)
no
%
no
%
Males
44
48.88%
16
53.3%
Females
46
51.12%
14
46.7%
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

82
Table (20): Descriptive data of laboratoryfindings among the 4 groups.
Group 1
(DM)
Group 2
liver
cirrhosis
Group 3 DM
and liver
cirrhosis
Group 4
controls
Anova
Variables
Mean ± SD
Mean ± SD
Mean ± SD
Mean ± SD
F
P
Value
sig
HBA
1
C%
10.35 ± 2.83
5.92 ±0.68
7.40±0.62
5.80 ±0.46
2.189
0.093
N.S
FPG
(mg/dl)
142.43±23.38
97.87±8.68
123.77±24.45
95.93±7.52
46.569
0.000
H.S
LDL mg/dl
151.13±22.30
169.89±25.52
159.57±28.05
138.83±28.35
7.273
0.000
H.S
HDL mg/dl
34.83±4.13
37.97±6.17
36.83±5.37
38.17±5.03
2.560
0.058
N.S
TG mg/dl
115.53±21.27
122.3±15.25
119.83±21.29
98.33±11.29
10.930
0.000
H.S
CHOLmg/dl 209.97±28.1
237.53±23.87
228.67±31.87
198.97±17.58
14.276
0.000
H.S
ALT (u/l)
18.10±5.37
33.00±18.35
28.33±8.63
19.33±4.90
15.826
0.000
H.S
AST u/l
18.73±5.55
33.0±18.35
38.33±37.58
19.33±4.9
6.453
0.000
H.S
ALB g/dl
4.17±0.52
2.39±0.64
2.33±0.49
4.19±0.46
116.134
0.000
H.S
PT sc
10.3±2.35
18.33±3.99
17.13±3.66
10.0±1.7
60.785
0.000
H.S
BRP4 mg/dl
20.1±8.31
9.31±3.99
8.59±7.17
13.5±3.97
17.182
0.000
H.S
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
Table (21): Shows sex distribution in the 4 groups.
Group
1 DM
Group 2
Cirrhosis
Group 3
DM+Cirrhosis
Group
4
Control
Total
Sex F
Count
20
12
14
14
60
%within
Group
66.7%
40.0%
46.7%
46.7%
50.0%
M Count
10
18
16
16
60
%within
Group
33.3%
60.0%
53.3%
53.3%
50.0%
Total
Count
30
30
30
30
120

83
%within
Group
100.0% 100.0%
100.0%
100.0% 100.0%
Fig. (7): Sex distribution among the studied groups.
Table (22): Shows comparison between the 4 groups as regards waist
circumference (cm).
Mean ±SD
P
value
Waist
Circumference
(cm)
Group 1 (DM)
103.07 ± 17.76
0.000
(H.S)
Group 2 (Liver cirrhosis)
83.43±7.40
Group 3 (DMliver cirrhosis) 88.33 ±6.00
Group 4 ( controls)
79.73 ±8.98
P value 0.05 = Non Significant (N.S)
66.7
33.3
46.7
53.3
46.7
60
40
53.3
0
10
20
30
40
50
60
70
P
ercentage
DM
Control
Cirrhosis
DM+Cirrhosis
Female
Male

84
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
Fig. (8): Comparison between the 4 groups as regards waist circumference (cm).
Table (23): Shows comparison between the 4 groups as regards body mass
index kg/m
2
.
Mean ±SD
P
value
Body mass
index
kg/m
2
Group 1 (DM)
28.5 ± 6.17
0.000
(H.S)
Group 2 (Liver cirrhosis)
25.6 ± 4.15
Group 3 (DMliver cirrhosis)
29.1 ± 4.1
Group 4 ( controls)
22.5 ± 2.53
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
0
20
40
60
80
100
120
Datenreihen1

85
Fig. (9): Comparison between the 4 groups as regards body mass index kg/m2.
Table (24): Shows comparison between the 4 groups as regards HbA
1
C %
Mean ±SD
P value
HbA
1
C
%
Group 1 (DM)
10.35 ± 2.83
0.05
Sig
Group 2 (Liver cirrhosis)
5.92 ± 0.68
Group 3 (DMliver cirrhosis)
7.40 ± 0.62
Group 4 ( controls)
5.8 ± 0.46
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

86
Fig. (10): Comparison between the 4 groups as regards HbA
1
C %.
Table (25): Shows comparison between the 4 groups as regards fasting
plasma glucose mg/dl.
Mean ±SD
P
value
Fasting
plasma
glucose
(mg/dl)
Group 1 (DM)
142.43±23.38
0.000
(H.S)
Group 2 (Liver cirrhosis)
97.87 ± 8.68
Group 3 (DM liver cirrhosis) 123.77 ± 24.45
Group 4 (controls)
95.93 ± 7.52
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
.
0
2
4
6
8
10
12
Group 1
(DM)
Group 2
(Liver
cirrhosis)
Group 3
(DMliver
cirrhosis)
Group 4 (
controls)
Datenreihen1

87
Fig. (11): Comparison between the 4 groups as regards fasting plasma glucose mg/dl.
Table (26): Shows comparison between the 4 groups as regards low density
lipoprotein mg/dl.
Mean ±SD
P
value
Low density
lipoprotein
LDL
mg/dl
Group 1 (DM)
151.13 ± 22.32
0.000
(H.S)
Group 2 (Liver cirrhosis)
169.89 ±25.52
Group 3 (DM liver cirrhosis) 159.57±28.05
Group 4 (controls)
138.83±28.35
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

88
Fig. (12): Comparison between the 4 groups as regards low density lipoprotein mg/dl.
Table (27): Shows comparison between the 4 groups as regards high density
lipoprotein mg/dl.
Mean ±SD
P value
High
density
lipoprotein
mg/dl
Group 1 (DM)
34.83±4.13
0.058
N.S
Group 2 (Liver cirrhosis)
37.97±6.17
Group 3 (DM liver cirrhosis) 36.83±5.37
Group 4 (controls)
38.17±5.03
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

89
Fig.(13): Comparison between the 4 groups as regards high density lipoprotein mg/dl.
Table (28): Shows comparison between the 4 groups as regards total
cholesterol mg/dl.
Mean ±SD
P
value
Total
cholesterol
mg/dl
Group 1 (DM)
209.97±28.10
0.000
(H.S)
Group 2 (Liver cirrhosis)
237.53±23.87
Group 3 (DM liver cirrhosis) 228.67±31.87
Group 4 (controls)
198.97±17.58
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

90
Fig. (14): Comparison between the 4 groups as regards total cholesterol mg/dl.
Table (29): Shows comparison between the 4 groups as regards triglyceride
mg/dl .
Mean ±SD
P value
Triglyceride
mg/dl
Group 1 (DM)
115.53±21.27
0.000
(H.S)
Group 2 (Liver cirrhosis)
122.3±15.25
Group 3 (DM liver cirrhosis) 119.83±21.29
Group 4 (controls)
98.33±11.29
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

91
Fig. (15): Shows comparison between the 4 groups as regards triglyceride mg/dl.
Table (30): Shows comparison between the 4 groups as regards alanine
aminotransferase (ALT) U/L.
Mean ±SD
P value
Alanine
aminotransferase
(u/l)
Group 1 (DM)
18.10±5.37
0.000
(H.S)
Group 2 (Liver cirrhosis)
33.00±18.35
Group 3 (DM liver
cirrhosis)
28.33±8.63
Group 4 (controls)
19.33±4.90
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

92
Fig. (16): Comparison between the 4 groups as regards alanine aminotransferase (ALT) U/L.
Table (31): Shows comparison between the 4 groups as regards aspartate
aminotransferase (AST) U/L.
Mean ±SD
P
value
Aspartate
aminotransferase
(AST).u/l
Group 1 (DM)
18.73±5.55
0.000
(H.S)
Group 2 (Liver cirrhosis)
33.00±18.35
Group 3 (DM liver cirrhosis) 38.33±37.58
Group 4 (controls)
19.33±4.9
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)
0
5
10
15
20
25
30
35
Group 1
(DM)
Group 2
(Liver
cirrhosis)
Group 3
(DM
liver
cirrhosis)
Group 4
(controls)
Datenreihen1

93
Fig. (17): Comparison between the 4 groups as regards.aspartate aminotransferase (AST) U/L.
Table (32): Shows comparison between the 4 groups as regards serum
albumin g/dl.
Mean ±SD
P value
Serum
albumin
g/dl
Group 1 (DM)
4.17±0.52
0.000
(H.S)
Group 2 (Liver cirrhosis)
2.39±0.64
Group 3 (DM liver cirrhosis) 2.33±0.49
Group 4 (controls)
4.19±0.46
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

94
Fig. (18): Comparison between the 4 groups as regards serum albumin g/dl.
Table (33): Shows comparison between the 4 groups as regards
prothrombin time / seconds.
Mean ±SD
P value
Prothrombin
time
(seconds)
Group 1 (DM)
10.30±2.35
0.000
(H.S)
Group 2 (Liver cirrhosis)
18.33±3.99
Group 3 (DM liver cirrhosis)
17.13±3.66
Group 4 (controls)
10.0±1.7
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

95
Fig. (19): Comparison between the 4 groups as regards prothrombin time / seconds.
Table (34): Shows comparison between the 4 groups as regards serum
retinol binding protein mg/dl.
Mean ±SD
P value
Serum retinol
binding
protein 4
Group 1 (DM)
20.1±8.31
0.000
(H.S)
Group 2 (Liver cirrhosis)
9.31±3.99
Group 3 (DM liver
cirrhosis)
8.59±7.17
Group 4 (controls)
13.5±3.97
P value 0.05 = Non Significant (N.S)
P value 0.05 = Significant (Sig)
P value 0.001 = Highly Significant (H.S)

96
Fig. (20): Comparison between the 4 groups as regards serum retinol binding protein mg/dl.
Fig. (21): Correlation between RBP4 and total cholesterol.

97
Fig. (22):
Correlation between RBP4 and serum albumin.
Correlation between RBP4 and waist circumference

98
Fig. 24 correlation between RBP4 and HbA1c
D
ISCUSSION
Type 2 DM is the predominant form of diabetes worldwide accounting for 90-
95% of cases globally. The prevalence of type 2 DM is expected to rise more
rapidly in the future because of increasing obesity and reduced activity levels
(Kasper and Fauci., 2005).
The chronic hyperglycemia of diabetes is associated with long term damage,
dysfunction and failure of various organs especially the eyes, kidneys, nerves,
heart and blood vessels. The basis of the abnormalities in carbohydrate, fat and
protein metabolism in diabetes is deficient action of insulin on target tissues
(American Diabetes Association., 2009).
Liver disease is an important cause of death in type 2 diabetes.In the population-
based Verona Diabetes Study, cirrhosis was the fourth leading cause of death
and accounted for 4.4% of diabetes-related deaths (Marceau et al., 1999).

99
RBP4 is predominantly secreted by visceral adipose tissue and the liver. A large
number of studies in rodents and also in humans confirm an association of
increased level of RBP4 with obesity, insulin resistance, type 2 diabetes,
dyslipidemia, hypertension and metabolic syndrome (Rabe et al., 2008).
Hyperinsulinemia and insulin resistance are found in nearly all patient with liver
cirrhosis, and insulin resistance is a risk factor for both survival and disease
progression in patient with liver cirrhosis. Recent finding also showed that
RBP4 is an independent risk factor in type 2 diabetes, impaired glucose
tolerance, and healthy individuals with strong family history of diabetes
(Bugianesi et al., 2005).
Exercise training reduced RBP4 levels in patients whose insulin resistance
improved with exercise. In a mouse model, mice lacking adipocyte glucose
transporter 4 (GLUT4) had increased levels of RBP4 and RBP4 was shown to
cause insulin resistance in mouse muscle and liver. An inverse relationship
between GLUT4 in adipocytes and serum RBP4 was demonstrated in the human
study, as well. Whether RBP4 in humans causes, or is correlated with, insulin
resistance has not been determined. (Graham et al,. 2006).
The aim of this study was to estimate RBP4 level in patients with type 2
diabetes mellitus, with and without liver cirrhosis.
The study was conducted on 120 adult persons age range from 30-60 years
they were divided into 4 groups,
Group 1: 30 diabetic patients.
Group 2: 30 cirrhotic patients.
Group 3: 30 diabetic and cirrhotic.
Group 4: 30 control subjects.

100
Both patients and controls were subjected to full medical history, clinical
examination, anthropometric measurements, and laboratory tests, (FPG,
HBA1c%, Lipid profile, AST, ALT, serum Albumin, prothrombin time, RBP4
and abdominal ultrasound).
With regard to sex; males predominate in group 2 (liver cirrhosis), 18 (60%) of
them were males and 12 (40%) were females, group 3 (DM and liver cirrhosis)
16 (53.3%) of them were males and 14 (46.7%) were females, and group 4
(controls), 16 (53.3%) were males and 14 (46.7%) were females. This is
consistent with those of (Camma et a. 2006), who conducted a study on 311
patients with chronic liver disease and found that males are more than females.
Also in a population based, matched retrospective study done by Liane to study
the relationship between diabetes and chronic liver disease, males were more
than females and is inconsistent with the present study regarding group 1(DM)
we found that 10 (33.3%) were males, and 20(66.7%) were females.(Liane.,
2010), because the sample was small in our study.
In our study we found that in group 1 (DM), body mass index (28.5±6.17)
kg/m
2
, and waist circumference (103.07±17.76) cm, were high, because DM is
associated with central obesity. These findings are in accordance with (Young et
al., 2009) who studied diabetic patients and found the same results concerning
body mass index and waist circumference .
In group 2 (liver cirrhosis) and group 3 (DM and liver cirrhosis), our study
showed a highly significant difference regarding ALT (33.00±18.35) u/l and
(28.33±8.63) respectively compared to controls (21.90±3.22) u/l, this results
were matched with (EL-Tabey et al., 2011) who found a highly statistical
difference (p0.001) between cases and controls regarding liver enzymes.
The cirrhotic patients in the present study group 2 (liver cirrhosis) and 3(DM
and liver cirrhosis) had a significant lower albumin (2.39±0.64) g/dl and

101
(2.33±0.49) g/dl respectively, and prolonged prothrombin time (18.33±3.99)
seconds and (17.13±3.66) seconds respectively compared to controls
(10.00±1.7) seconds , these results are in agreement with (Erlanger and
Benhamou., 1999).who found low serum albumin and prolonged prothrombin
time in patients with liver cirrhosis .
In the present study there was a highly significant difference in RBP4 level
mean value was (20.10±8.31) mg/dl, waist circumference (103.07 ±17.76) cm,
and body mass index (28.5±6.17) kg/m
2
between group 1 (DM) and group 4
(controls) mean value was (13.53.97) mg/dl, (79.73±8.98) cm, (22.5±2.53)
kg/m
2
respectively, due to insulin resistance, similarly this finding is consist
with Graham who conducted a study on 60 patients 20 obese, 20 diabetic and
20 lean. He measured serum RBP4, insulin resistance, and components of the
metabolic syndrome in these groups. Measurements were repeated after exercise
training in one group. GLUT4 protein was measured in isolated adipocytes, and
he found that serum RBP4 levels correlated with the magnitude of insulin
resistance in subjects with obesity, impaired glucose tolerance, or type 2
diabetes and in nonobese, nondiabetic subjects with a strong family history of
type 2 diabetes. Elevated serum RBP4 was associated with components of the
metabolic syndrome, including increased body-mass index, waist-to-hip ratio,
serum triglyceride levels, and systolic blood pressure and decreased high-density
lipoprotein cholesterol levels. Exercise training was associated with a reduction
in serum RBP4 levels only in subjects in whom insulin resistance improved.
Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated.
Graham concluded that RBP4 is an adipocyte-secreted molecule that is elevated
in the serum before the development of frank diabetes and appears to identify
insulin resistance and associated cardiovascular risk factors in subjects with
varied clinical presentations. These findings provide a rationale for antidiabetic
therapies aimed at lowering serum RBP4 levels. (Graham et al,. 2006).

102
Our study also going with (Yang et al,.2005) who conducted a cohort study in
obesity and type 2 diabetes and showed that serum RBP4 levels are elevated in
insulin-resistant mice and humans with obesity and type 2 diabetes, RBP4 levels
are normalized by rosiglitazone, an insulin-sensitizing drug, and transgenic
overexpression of human RBP4 or injection of recombinant RBP4 in normal
mice causes insulin resistance. Conversely, genetic deletion of RBP4 enhances
insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary
excretion of RBP4, normalizes serum RBP4 levels and improves insulin
resistance and glucose intolerance in mice with obesity induced by a high- fat
diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic
enzyme phosphoenolpyruvate carboxykinase and impairs insulin signalling in
muscle. They concluded that, RBP4 is an adipocyte-derived 'signal' that may
contribute to the pathogenesis of type 2 diabetes, and lowering RBP4 could be a
new strategy for treating type 2 diabetes.
Sussane, studied women with polycystic ovary syndrome and impaired glucose
metabolism and showed similar result to our study (Sussane, 2007) since
polycystic ovary syndrome is associated with insulin resistance.
In another study on patients with normal glucose tolerance, impaired glucose
tolerance and type 2 diabetes mellitus, Plasma Plasma RBP4 concentrations
were found to be high in impaired fasting glucose median (18.9), microgram/ ml
and diabetic patients median (20.9) microgram/ ml compared to normal glucose
tolerance (18.1) microgram/ ml and is in accordance with our study (Young et
al., 2009).
Contrary to the result of the present study, (Jurgen., 2006) showed in a cross
sectional study done on 30 obese menopausal Caucasian women during weight
loss protocol and found that no relationship between RBP4 level and gene
expression in adipose tissue but Jurgen study was on subcutaneous fat and not
visceral fat. Because visceral fat drains directly in the portal circulation and has

103
a high number of macrophages which liberates adipokines like RBP4 and
cytokines like tumor necrosis factors (TNF ) and interleukin 6 which are
important in the pathogenesis of insulin resistance.
In the present study there was significant difference between patients with group
2 (liver cirrhosis) and group 3(DM and liver cirrhosis) mean value (9.31± 3.99)
mg/dl and (8.5±1.3) mg/dl respectively, and controls, mean value (13.5±0.7)
mg/dl p 0.05 as regards RBP4, This result came also in agreement with Koch
et al who stated that on his prospective single centered study on 123 critically ill
patients followed for 3 years, RBP4 is reduced in liver cirrhotic patients and is a
marker of bad prognosis.( Koch et al,.2010)
This results is also consistent with Yagmour who found in their study RBP4
levels were significantly lower in 111 patients with liver cirrhosis as compared
to 99 age and sex matched healthy controls. In addition, in animal model study a
high gene expression of RBP4 in hepatic tissue was reduced after induction of
experimental cirrhosis (Yagmour et al., 2007).
Our study is consistant with (Frank,. 2008) who conducted a study on patients
with chronic liver disease and concluded that serum retinol binding protien 4 is
reduced in liver cirrhosis.
It was reported that in 19 HCV infected patients in advanced stages, RBP4 is
decreased compared to 19 healthy controls because of reduced hepatic
production as the liver the major source of RBP4.(Bahr et al., 2009).
Huang found that RBP4 is inversely correlated with disease severity, they
found in their HCV infected patients a significant decreasing linear trend of
RBP4 dependent on histological grading (Huang et al., 2008).
Similar to the current study, (Iwaza et al., 2009) found in their HCV
infected patients that plasma levels of RBP4 were lower in patients than

104
controls p 0.001. They found higher RBP4 levels were linked to normal
liver function.
Similar to the present study, is Kwon et al., study done on 573 chronic liver
disease patients including hepatitis C patients, RBP4 was assayed and
hyaluronic acid (marker for liver fibrosis); serum RBP4 levels were significantly
reduced and hyaluronic acid increased in patients in comparison to controls.
They concluded that RBP4 is a serologic marker for disease severity in patients
with chronic liver diseases (Kwon et al., 2009).
Contrary to the present study, (Petta et al., 2008) showed that serum RBP4 is
high in patients with liver cirrhosis, but Petta study was on hepatitis C virus and
patients with steatohepatitis, and he explained that HCV is directly incorporated
into the hepatocytes and increase RBP4 level.
A high significant correlation was found between RBP4, fasting plasma glucose
R = 0.004 and serum albumin R= 0.00, while a significant correlation was found
between RBP4, waist circumference R=0.013, HbA
1
c% R= 0.039, and total
cholesterol R= 0.04.
In agreement with our study Iwaza et al conducted a study on 311 patients with
chronic liver disease and reported that RBP4 is reduced and positively correlated
with FPG and total cholesterol. Iwaza also concluded that RBP4 levels return to
normal after interferon therapy. (Iwaza et al,. 2009)
These results are also consistent with (Sussane., 2007) who conducted a study
on obese diabetic females with polycystic ovary sundrome and found that there
is a significant direct correlation between RBP4 and FPG.
Our statistical analysis showed that there was a highly significant direct
correlation between RBP4 and serum albumin, R = (0.00), and also there was a
significant direct correlation between RBP4, HbA
1
C %, R = (0.031), and total

105
cholesterol R=(0.04), and is in accordance with an epidemiologic cohort study,
conducted on 273 subjects with FPG 110 mg/dl and 234 patients with type 2
diabetes, by Naoyuki and found that RBP4 significantly correlates with
HbA
1
C%, total cholesterol, and serum albumin (Naoyuki., 2006).
On the other hand our study is not goining with (John., 2008) who conducted a
study on 285 subjects with and without diabetes mellitus attending a hospital
lipid disorders clinic he found that there is no correlation between RBP4 and
FPG. These results can be explained by different patients, different medications
(lipid lowering drugs), or samples collection.

106
S
UMMARY
Diabetes mellitus is a common disease despite the fact that only half or two
thirds are diagnosed, the figure is around 189 million people in 2003, and this
may reach 324 million by 2025.
Egypt is expected to be among ten countries with the highest number of
estimated cases of diabetes for 2030.
The prevalence of type 2 DM continues to rise at alarming rate. Significant
defect in glucose homeostasis and fuel metabolism are detectable long before
overt diabetes occurs. One of the earliest derangements in metabolism is insulin
resistance.
The liver plays important roles in the homeostasis of glucose metabolism since it
acts as a major target organ for insulin and a site for gluconeogenesis and
glycogen storage. Diabetes mellitus, commonly develops in patients with liver
cirrhosis as the result of hepatocyte dysfunction, is known as hepatogenous
diabetes mellitus.
Retinol binding protein4 (RBP4) a 21-KDa protein synthesized in the liver and
adipose tissues, formerly recognized for its role as a specific transport for
vitamin A, now it is known that it plays a crucial role in insulin resistance and
diabetes mellitus.
Recently attention has been paid to the role of retinol ­binding protein 4 (RBP4)
in the pathogenesis of insulin resistance.
The aim of this study is to estimate RBP4 level in type 2 diabetic patients
with and without liver cirrhosis. Fasting plasma glucose was high in
group 1 (DM) (142.43±23.38) mg/dl and group 3 (DM and liver cirrhosis)
(123.77±24.45) mg/dl and normal in group 2 (liver cirrhosis)
(97.87±8.68) compared with group 4 (controls) (95.93±7.52).

107
As regards HbA
1
C% it was high in group 1 (DM) (10.35±2.83) and group
3 (DM and liver cirrhosis) (7.40±0.62) and normal in group 2 (liver
cirrhosis) (5.92±0.68) compared with group 4 (controls) (5.80±0.46).
Concerning BMI, it was high in group 3 (DM and liver cirrhosis)
(29.1±4.10) kg/m
2
followed by group 1 (DM) (28.5±6.17) kg/m
2
and
group 2 (liver cirrhosis) (25.60±4.15) kg/m
2
compared with group 4
(controls) (22.50±2.35) kg/m
2
.
Waist cicumference found to be high in group 1 (DM) (103.07±17.76) cm
followed by group 3 (DM and liver cirrhosis) (88.33±6.00) cm and group
2 (liver cirrhosis) (83.43±7.40) cm compared with group 4 (controls)
(79.73±8.98) cm.
The study was conducted on 120 of adult persons age range from 30-60
years, they where divided into 4 groups:
Group 1: 30 diabetic patients.
Group 2: 30 cirrhotic patients.
Group 3: 30 diabetic and cirrhotic.
Group 4: 30 control subjects.
The data were statistically analysed and it is found that:
RBP4 was highest among group 1 (DM) (20.10±8.31) mg/dl compared to
group 4 (controls) (13.50±3.97) mg/dl and was low in group 2 (liver
cirhosis) (9.31±3.99) mg/dl and group 3 (DM and liver cirrhosis)
(8.59±7.17) mg/dl.
Toatl cholsterol was found (209.97±28.10) mg/dl in group 1 (DM),
(237.53±23.87) mg/dl in group 2 (liver cirrhosis), (228.67±31.87) mg/dl

108
in group 3 (DM and liver cirrhosis) and (198.97±17.58) mg/dl in control
group.
Low density lipoprotien LDL, was found to be (151.13±22.32) mg/dl in
group1(DM), (169.89±25.52) mg/dl in group 2 (liver cirrhosis), and
(159.57±28.05) mg/dl in group 3 (DM and liver cirrhosis), compared with
group 4 (controls) (138.83±28.35) mg/dl.
High density lipoprotein HDL was found to be low in group 1 (DM)
(34.83±4.13) mg/dl, group 2 (liver cirrhosis) (37.97±6.17) mg/dl, and
group 3 (DM and liver cirrhosis) (36.83±5.37) mg/dl compared with
group 4 (controls) (38.17±5.03) mg/dl.
Triglyceride was found to be (115.53±21.27) mg/dl in group 1 (DM),
(122.3±15.25) mg/dl in group 2 (liver cirrhosis), and (119.83±21.29)
mg/dl in group 3 (DM and liver cirrhosis) compared with group 4
(controls) (98.33±11.29) mg/dl.
ALT and AST, were found be (18.10±5.37) u/l and (18.73±5.55) u/l
respectively in group 1 (DM), (33.00 ±18.35) u/l and (33.00±18.35) u/l
respectively in group 2 (liver cirrhosis) u/l, and (28.33±8.63) u/l and
(38.33±37.58) u/l respectively in group 3 (DM and liver cirrhosis)
compared with group 4 (controls) (21.90±3.22) u/l and (19.33±4.90) u/l
respectively.
While serum albumin was low in group 2 (liver cirrhosis) (2.39±0.64) g/dl
and group 3 (DM and liver cirrhosis) (2.33±0.49) g/dl and normal in
group 1 (DM) (4.17±0.52) g/dl compared with group 4 (controls)
(4.19±0.46) g/dl.
The prothrombin time was found to be high in group 2 (liver cirrhosis)
(18.33±3.99) seconds, and group 3 (DM and liver cirrhosis) (17.13±3.66)

109
seconds, and normal in group 1(DM), (10.30 ±2.35) seconds, compared to
group 4 (controls) (10.00±1.70) seconds.
In this study on comparing the four groups, a high significant difference
was found as regards BMI, waist circumference, FPG, HBA
1
c%, total
cholesterol, LDL, TG, ALT, AST, serum albumin and no significant difference
was found regarding HDL.
A high significant correlation was found between RBP4, fasting plasma
glucose R = 0.004 and serum albumin R= 0.00, while a significant correlation
was found between RBP4, waist circumference R=0.013, HbA
1
c% R= 0.039,
and total cholesterol R= 0.04.
Conclusions:
From the previous results our study suggests that:
1. Serum RBP4 concentrations are significantly increased in type 2 diabetic
patients.
2. The liver is the major source of circulating RBP4 in humans, and
therefore the hepatic biosynthetic capacity may greatly influence serum
RBP4.
R
ECOMMENDATIONS
1. RBP4 can be used as a new marker of insulin resistance.
2. Serum concentrations of RBP4 may be used for follow up of patients with
type 2 diabetes mellitus aiming to reduce its level.
3. Future studies are to be done to assess the relation between RBP4 as a
marker of insulin resistance and it's association with different liver
diseases such as NASH and HCV positive patients.

110
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Details

Title
Retinol Binding Protein-4 in Type 2 Diabetic Patients with and without Liver Cirrhosis
Grade
C
Author
Year
2017
Pages
128
Catalog Number
V385499
ISBN (Book)
9783668617919
File size
2366 KB
Language
English
Tags
retinol, binding, protein-4, type, diabetic, patients, liver, cirrhosis
Quote paper
Hyder Mirghani (Author), 2017, Retinol Binding Protein-4 in Type 2 Diabetic Patients with and without Liver Cirrhosis, Munich, GRIN Verlag, https://www.grin.com/document/385499

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