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Chapter One
Introduction
-1-
INTRODUCTION
1.1. Definition and Classification of Diabetes Mellitus:
The
term
diabetes
mellitus
(DM)
illustrate
a
chronic
progressive metabolic disease distinguished by hyperglycemia as
a result of too little insulin secretion, resistance to the action of
insulin or both(1). Insulin is a hormone that controls blood glucose
levels in the circulation and is released by the beta cells of the
islets of langerhans in pancreas (2,3).
Symptoms
of
marked
hyperglycemia
involve
extreme
excretion of urine (polyuria), increase thirst (polydipsia), weight
loss, sometimes with increased hunger (polyphagia). High blood
glucose levels for prolong time can result in absorption
of glucose
in the eye lens, which causes modifying in its shape, leading to
blurred vision. Chronic hyperglycemia may also be associated
with impairment of growth and susceptibility to certain infections
(4)
.
Diabetes can be categorized to:
 Type 1 diabetes (immune-mediated diabetes) is result from
an absolute reduction in insulin production because of
damaging of the pancreatic β-cells. The majority of type 1
diabetes
cases
are
develop
from
a
cellular-mediated
autoimmune deterioration of the β-cells of the pancreas.
This type of diabetes has several genetic predispositions,
and it is also accounted for environmental factors that are
still inadequately defined(5).
Chapter One
Introduction
-2-
Although this type of diabetes is more frequent in childhood, it can happen at any time in life. There are a number of
markers of autoimmunity existing to help identify patients with
type 1 diabetes; these involve anti-glutamic acid decarboxylase-65
antibodies, anti-islet, anti-insulin autoantibodies and anti tyrosine
phosphatase. Some type 1 diabetic patients, especially children
and adolescents, may be found with ketoacidosis as the primary
manifestation of the disease. It is necessary to note that history of
diabetic ketoacidosis (DKA) of type 1 diabetes is indicative not
diagnostic
because
many
type
2
diabetic
patients
may
also
develop this problem(6).
 Type 2 diabetes ( ranging from mainly insulin resistance
with relative insulin deficiency to
insulin
secretion
associated
with
predominantly defect in
insulin
resistance)
(7)
.
Insulin resistance is thought to precede insulin deficiency in
most tye 2 diabetic patients, and autoimmune damaging of
pancreatic β-cells does not happen, while the mass of β-cell
may be decreased. Since the deficiency of insulin is relative
rather than absolute, DKA take places less frequently in
type 2 diabetes than in type 1 diabetes, when seen, it
generally arises in correlation with the stress of another
disease like infection(6).
 Gestational diabetes mellitus (GDM)
has been defined as
glucose intolerance with beginning of or first recognition
through pregnancy.
 Other specific types of diabetes involve a wide variety of
conditions that are relatively infrequent, largely specific
genetically classified forms of diabetes (genetic disorders in
insulin function or β-cell) or diseases of the exocrine
Chapter One
Introduction
-3-
pancreas or related to the drug use. American Diabetes
Association (ADA) distinguishes more than 56 other special
forms of diabetes (8).
2.1 Criteria for the Diagnosis of Diabetes

HbA1c ≥6.5%. The test should be carried out in a laboratory
utilizing a manner that is NGSP certified and standardized to
the DCCT assay. Or

Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L).
Fasting is defined as no caloric ingestion for at least 8 h. Or

Two-hour
plasma
glucose
≥200
mg/dL
(11.1
mmol/L)
through an oral glucose tolerance test (OGTT). The test
should be carried out as illustrated by the World Health
Organization,
utilizing
a
glucose
load
containing
the
equivalent of 75 g anhydrous glucose melted in water. or

In a persons with classic symptoms of hyperglycemia or
hyperglycemic crisis, a random plasma glucose ≥200 mg/dL
(11.1 mmol/L).

In the lack of unequivocal hyperglycemia, end result must be
proved by repeat testing(9,10).
Chapter One
Introduction
-4-
1.3 .Type 2 Diabetes:
Type 2 diabetes is the more frequent form of diabetes, that
accounts for 90–95% of cases(11). The
essential
reasons
multifactorial,
physical
activity and
genetic
but
overweight,
predisposition
are
decreased
considered
to
be
most
are
important
underlying factors(12). It is generally start as insulin resistance, a
disorder in which the response of target cells to the concentration
of
insulin
significantly
decreased
but
never
absolutely
lost.
Twofold increases in basal insulin levels are frequent in patients
with insulin resistance correlated with type 2 diabetes. Because
the need for insulin increase, the pancreas increasingly loses its
capacity to generate it(13).
1.4. Complications of Diabetes:
Many different organ systems in the body may influenced
by the uncontrolled diabetes; and over a prolonged period of time,
DM can result in severe health problems. the deleterious effects of
hyperglycemia are
macrovascular.
the
nervous
categorized
Microvascular
system
(nephropathy)
and
eye
disease,
(14)
.
damaging
of
damage (retinopathy).
peripheral
and
microvascular
complications involve
(neuropathy),
complications involve
stroke
as
The
vascular disease,
glycaemic
and
destroying
renal
system
Macrovascular
cardiovascular
control,
duration
of
diabetes and hypertension are the most strongest risk factors for
microvascular
disease;
while,
smoking,
blood
pressure,
hyperlipidemia, and albuminuria are the strongest risk factors for
macrovascular diabetic complications (15).
Chapter One
Introduction
-5-
1.5. Development of Type 2 Diabetes:
The
metabolic
functions
of
insulin
preserve
glucose
homeostasis by facilitating glucose entry in skeletal muscle and
inhibiting glucose manufacture in the liver
develops
when
β-cells
of
pancreas
fail
(16)
. Type 2 diabetes
to
release
adequate
amounts of insulin to meet the metabolic requirement. At first
β-cells respond
pancreatic
for
the
insulin
resistance
by
hypertrophy and proliferation of presented β-cells and enhanced
production and secretion of insulin to preserve normoglycemia, a
process named β cell compensation. The elevated insulin secretion
and
β-cell
mass
associating
with
insulin
elucidated by glucose signaling and the
resistance
can
be
inducing effect of high
levels of free fatty acid on the secretion of insulin as well as other
circulating
factors
capable
of
inducing
the
replication
of
pancreatic β-cell involve growth hormone, IGF-1, and glucagonlike peptide 1(Glp1). This occurs by number of mechanisms,
involving increases in intracellular calcium, the production of
reactive
oxygen
species
and
the
activation
of
endoplasmic
reticulum stress as illustrated in figure (1-1).
The failure of pancreatic β-cell that follow this period of βcell compensation may occur due to β-cell decreasing number as a
result of apoptosis) programmed cell death( or alterations in β cell
function. Each of these 2 possible scenarios might occur due to
defect in insulin and IGF-1 signaling in β-cells of pancreas(17,18)
Chapter One
Figure( 1-1)
-6-
Introduction
(18)
The pathway from glucose metabolism to enhanced the
mass of β-cell by increased β-cell replication and survival.
glucose transporter 2 (Glut2) , glucose-6-phosphate (G6P) , glucokinase
(Gck),insulin receptor substrate 2(Irs2), , cyclic adenosine monophosphate
(cAMP),
dependent
responsive
calcium
calmodulin-dependent
element–binding
channels
protein
protein
(VDCCs),
kinases
(CREB)
endoplasmic
(CaMKs),
Ser133
,
reticulam
phospatidyl
voltage(ER),
inositol
3
kinase (PI3K) ,glucagon- like peptide 1 (Glp1), glucagon- like peptide 1
receptors (Glp1r), 3-phosphoinositide– dependent protein kinase-1 (Pdpk1),
forkhead transcription factor (FoxO1).
Chapter One
Introduction
-7-
1.6 Insulin-Like Growth Factor One (IGF-1):
Insulin-like growth factor (IGF-1) is a polypeptide trophic
factor consist of 70-amino acid, it plays an essential role in the
regulation
of
metabolism,
growth,
cellular
function
and
differentiation. The biological functions of IGF-I are mediated
through the IGF-I receptor, which is a tyrosine kinase receptor
(19,20,21)
.
Insulin-like growth factor is included in growth regulation
and cellular proliferation in the human body. Comparisons of the
chemical structures of IGF-I and proinsulin demonstrate great
amino acid sequence similarity (about 40%). The receptor of IGFI mediate the biological effects of IGF-I,and has a 60% amino
acid sequence similarity with the insulin receptor (22).
Age and sex influence the serum concentrations of IGF-1;
at the age of 65 years, daily spontaneous GH secretion is declined
by 50–70% and therefore the levels of IGF-1in serum decrease
progressively(23).
More
recent
investigation
show
that
growth
hormone-
stimulated IGF-1 secretion is decreased in elderly persons and
suggest that resistance to growth hormone action may be occur as
a secondary contributing factor in the low concentrations of IGF-1
in serum
(24)
.
Most of IGF-1 in the circulation is produced in the liver
(approximately 80%), and liberated into the systemic circulation
where its making is initially regulated by GH. It is also made
locally in many other tissues, where it act locally in a paracrine
manner and does not circulate into the blood stream. Most of the
circulating IGF-1 (approximately80%) is bound to IGFBP-3,the
Chapter One
Introduction
-8-
unbound fraction is <1%, and the rest is bound to other binding
proteins (25).
1.6.1.Insulin-Like Growth Factor-Binding Proteins
There are a family of six IGF-binding proteins (IGFBPs1–
6) which is play an essential role in modulating IGF activities via
high affinity binding that separates IGFs from their receptors, thus
reducing their actions. The liberation of bioactive IGF result from
proteolytic cleavage of the IGFBPs in the central domain
(26)
.
IGFBP-6 is distinctive among the IGFBPs as it consider a
relatively specific IGF-II inhibitor because it has an 50-fold higher
binding affinity for IGF-II than IGF-I (27).
IGFBP-5 is the principal binding protein in muscle, and previous
study have suggested that IGFBP-5 is effective inhibitor of muscle
differentiation through its capability to neutralize IGF actions via
high binding affinity to growth factor separated it away from the
IGF-I receptor (28).
IGF-binding protein 4(IGFBP-4) is the one component of
IGFBP family that attaches IGF-I with high affinity. IGFBP-4
differ from other members of the IGFBP family, that it does not
attach to extracellular matrix or to cell surfaces, and it has been
seen to prevent the binding of IGF-I to cell surface receptors(29).
Insulin-like growth factor (IGF)-I initially synthesized in the liver
beside IGF-binding protein-3 (IGFBP-3) (30).
It is establish that this protein connects about 75% to 90%
of circulating IGF-I, accompanied by an acid-labile subunit, and is
therefore consider to be an essential determinant of the amount of
IGF-I present in the target tissues and arrive at IGF-I cellular
receptors(31,32).
Chapter One
-9-
Introduction
Furthermore, insulin resistance has been thought to play a
role in the proteolysis of IGFBP-3. Therefore, enhanced the
proteolysis of IGFBP could increase bioavailability of IGFI to its
target tissues(33). IGFBP-2 appeared a positive association with
insulin sensitivity, signifying that resistance to the actions of
(34)
insulin may be responsible for the IGFBP-2 diminishing
.
IGFBP-1 is unique among the IGFBPs in human plasma in its
quick regulation by metabolic alterations(35).
Insulin is the initial regulator of IGFBP-1 in the circulation. It
inhibits
the
hepatocyte.
expression
Negative
and
production
regulation
of
of
IGFBP-1
hepatocyte
gene
in
production
of
IGFBP-1 by insulin related to the postprandial decline in serum
concentration of IGFBP-1, diet composition
influence on the
serum levels of IGFBP-1, and the inverse association between
circulating insulin and IGFBP-1 levels(36).
1.6.2.Role of Insulin in the Regulation of the Insulin Like
Growth Factor-One:
It has been thought that portal insulin enhances the hepatic
sensitivity to GH by up-regulation of GH receptors, thus it
stimulate
additionally,
the
hepatic
synthesis
hyperinsulinemia
may
of
IGF-I
elevate
the
(34)
indirectly
magnitude
.
of
bioavailable IGF-I by reducing levels of IGF binding protein
(IGFBP)-1 and IGFBP-3 directly or indirectly. Lower levels of
these binding proteins leading to more unbound IGF-I that is free
to interact with the IGF-I receptor (IGF-IR) (37,38).
However, with increasing duration of DM, the pancreas
loses its ability to produce insulin due to the pancreatic β-cell
damaging and reducing the circulating levels of insulin
(39)
. So
that, low concentration of portal insulin reduce the expression of
Chapter One
Introduction
- 10 -
growth hormone receptor on the surface of hepatocyte and reduce
the sensitivity of the hepatocyte for growth hormone, eventually
reduce IGF-1 releasing from the liver(40).
1.6.3.Insulin Receptors and IGF-Receptors:
The biologic effects of the IGFs are mediated by the IGF-1
receptor (IGF-1R), a receptor tyrosine kinase with similarity to the
insulin receptor (IR) (41,42).
There are two isoforms of insulin receptor) IR-A and IR-B(,
the main functional difference between them is represented by the
different binding affinity related to IGF2 and IGF1. This idea was
confirmed by the observation that IR-A is a high-affinity receptor
for IGF-II
(43)
. Whereas the affinity of insulin for the A-type is
twofold higher than B-type IR (44).
Insulin
receptor
and
IGF-IR
connect
the
same
ligands
(insulin, IGF-I, and IGF-II) with very different affinities, where
IR-A is a high-affinity receptor not only for insulin, but also for
IGF-II and IGF-I; while, IR-B may be believed to be as insulin
specific receptor (45).
The binding of insulin to the insulin receptor-B stimulate
superior activation of metabolic signals. This cascade begins with
the insulin
receptor
activation,
which
PDK1.
targeted
The
sequentially,
metabolic
substrates
homeostasis
substrate1/2
like
signals
generally
Glut4,
phosphorylation
phosphorylates
propagates
included
GSK3,
in
Foxa2,
and
AKT
from
AKT
lipid
and
PDE3B
and
PI3K
through
which
glucose
AMPK
figure(1-2A). The activation of insulin receptor-A and IGF1R by
insulin and IGFs leads to the predominance of proliferative signals
and growth through the phosphorylation of the insulin receptor
substrate1/2 and Shc proteins. Activation of Shc result in the
Chapter One
Introduction
- 11 -
recruitment of Grb2/Sos complex with subsequent activation of
Ras/Raf/MEK1 and Erk1/2.
This latter kinase translocates to the nucleus and stimulates
several
genes
transcription
included
in
cell
proliferation
and
survival figure(1-2B) (46).
I
Figure (1-2A)
(46)
Binding of insulin to IR-B resulting in phosphorylation
of the insulin receptor substrate
with phosphorylation of the p85 regulatory
Chapter One
- 12 -
Introduction
subunit of phosphatidylinositol 3-kinase and activation phosphatidylinositol
3,4,5 phosphate. PIP3 then activates Akt.
Solid
lines
indicate
signaling
pathways
preferentially activated
whereas
dashed lines indicate pathways less markedly activated.
IR-B(insulin
receptor
B)
;
IRS
(insulin
receptor
substrate
)
;
phosphatidylinositol 3-kinase (PI3K) ; phosphatidylinositol 3,4,5 phosphate
(PIP3) ; phosphoinositide-dependent kinase 1 (PDK1) ; mammalian target of
rapamycin (mTOR) ; glucose transporter 4(GLUT 4) ; SHC (Src homology 2
domain containing) transforming protein 1 ; Growth factor receptor-bound
protein 2(Grb2) ; AMP-activated protein kinase(AMPK) ; Glycogen synthase
kinase 3(GSK3) ; Forkhead-Box-Protein A2 (Foxa2 ) ; phosphodiesterase 3B
(PDE3B) ; Protein kinase B (AKT) ; extracellular regulated kinase (Erk) ;
MEK(mitogen-activated protein kinase ) ; Raf ( rapidly fibrosarcoma); Ras(
rat sarcoma) ; NFκB(Nuclear factor kappa B).
Chapter One
figure(1-2B)
Introduction
(46)
- 13 -
Binding of insulin and IGFs to insulin receptor-A
and IGF1R activates the intrinsic tyrosine kinase receptor domain,
resulting
in
the
activation
of
the
PI3K/Akt/mTOR
signaling
stimulates the adaptor proteins Shc and Grb2, ultimately causing
cell proliferation.
Chapter One
Introduction
- 14 -
1.6.4.Increase of IGFs Synthesis and/or Bioavailability
Mediated by Hyperinsulinemia
Hyperinsulinemia
is
a
compensatory
response
that
preserves glucose homeostasis in persons who develop resistant to
the action of insulin. So that, pancreatic β-cells produce and
release higher concentrations of insulin. Enhanced serum levels of
insulin
in
the
circulation
may
result
in
enhanced
the
bioavailability of IGF-I due to insulin-mediated alterations in
IGFBP concentrations. However, most of IGF-I in the circulation
is bound to the IGFBPs, particularly
IGFBP-3, which connects
more than 90% of the IGF-I in the circulating system(47).
The main site for the production of IGFBP-3 is in the
hepatocyte, where its expression is stimulated by the growth
hormone (GH) and suppressed by insulin. Similar to IGFBP-3, the
IGF-I biosynthesis take places initially in the hepatocyte, where
its manufacture is depend on the GH, and is enhanced by insulin.
Consistently, elevated expression of GH receptors with enhanced
the production of IGF-I protein can be distinguished in patients
with persistent hyperinsulinemia and type 2 DM(48).
1.6.5. IGF-1 Synthesis and Tissue Growth
Insulin-like growth factor one is produced in several tissues
involving
liver,
bone,
cartilage
and
skeletal
muscle.
Approximately 80% of the total IGF-1 in serum is produced and
released from the liver and its concentration is controlled by sex
steroids, nutritional status and liver function (49).
The remainder of IGF-1 is created in peripheral tissues by
connective tissue cell types like stromal cells. These cells have
growth hormone receptors and can respond to growth hormone
(GH)
which
is
enter
the
tissues
from
circulation.
recently
Chapter One
Introduction
- 15 -
produced IGF-1 is released and moved to the neighboring cells
(paracrine action), where it induces cellular growth in organized
manner. In addition, it can be released and after that rebind to the
cell of origin, where it induces the growth of cell (autocrine
action) (figure 1-3) (50 ).
Growth factors utilize autocrine or paracrine pathways to
signal epithelial and stromal cells in the microenvironment, also it
regulates the development of normal, hyperplastic and malignant
epithelium(51).
So
that,
IGF-1
play
an
essential
role
in
understanding the etiology of prostate disorder, involving BPH.
IGF-1 exhibit autocrine, paracrine pathway to accelerate normal
growth and cellular proliferation(52,53).
Chapter One
Introduction
Figure (1-3) (50 )Autocrine and paracrine actions of IGF-1
- 16 -
Chapter One
Introduction
- 17 -
1.7.Benign Prostate Hypertrophy(BPH):
Benign prostatic hyperplasia (BPH) is more common in
older men. Histologically, BPH is differentiated by the existence
of nonmalignant, unregulated enlargement of the prostate gland.
Clinically, BPH
may be
correlated
with
lower urinary tract
symptoms (LUTS) secondary to the ensuing prostate overgrowth.
The histologic evidence of BPH is about 60% in men aged＞50
years. The incidence of BPH enhances to 80% in individuals aged
≥70 years( 54).
Benign
enhancing
in
prostatic
the
hyperplasia
epithelial
and
is
distinguished
stromal
cells
of
by
an
prostate,
particularly the latter(55). Stromal androgen/AR signaling may be
capable to increase the expression and/or secretion of growth
factors that act on prostatic epithelial cells. Therefore, epithelial
and stromal cells of prostate may each maintain proliferation of
the other cell type via growth factors in a paracrine way. Hence,
resulting in the development of BPH with urinary obstruction(56).
Chapter One
Figure(1-4)
Introduction
(56)
- 18 -
Schematic of prostate structure. BPH is attributable
to enlargement of the transitional zone (TZ), particularly in the
periurethral
area.
The
urethra
enters
the
periurethral
sandwiched between left and right adenoma and flattened in BPH.
area,
Chapter One
Introduction
Although
there
is
evidence
that
ageing
and
- 19 -
hormonal
modifications are included in growth of stromal and epithelial
components
in
the
overgrowth,
BPH
prostate
and
pathogenesis
stimulation
remains
of
still
fibromuscular
indistinguishable.
The pathogenesis of BPH appears to be multifactorial(57).
1.7.1.The Physiology of the Prostate Gland:
The
organized
stroma
prostate
in
gland
glandular
consisted
compartment also
is
consist
acini
principally
of
secretory
surrounded
of
smooth
by
a
epithelium
fibromuscular
muscle.
The
stromal
includes vasculature, fibroblasts, nerves and
immune constituents. Functionally, the prostate of adult is an
exocrine accessory reproductive
gland
that
drives
a
complex
proteolytic solution consistsed of citric acid, fibrinolysin, acid
phosphatase, prostate specific antigen(PSA) and other enzymes
and nutrients innside the urethra (58).
There are three main proteins released from the adult prostate
gland.
They are :
1. Prostate Specific Antigen (PSA). It is also named seminin, or γseminoprotein or seminogelase.
2. Prostatic Acid Phophatase (PAP).
3. Prostate Specific Protein -94 (PSP-94). It is also known as βinhibin or β-micro seminoprotein( 59).
1.7.2.Symptoms of BPH
The major reason of lower urinary tract symptoms in ageing
men
is
benign
prostatic
hyperplasia.
Lower
urinary
tract
symptoms secondary to BPH can commonly be categorized as
voiding symptoms and storage symptoms.
Chapter One
Introduction
- 20 -
Voiding symptoms like slow stream, splitting of the urine
stream,
discontinuous
stream,
hesitancy
and
straining
are
considered to be caused by the obstruction at the level of the
prostate. This obstruction can be result from an enhance in
prostate size and/or by an enhanced the contraction of smooth
muscle in the prostate, bladder neck, and urethra. In contrast,
storage symptoms like nocturia, urgency, enhanced the frequency
at daytime, and urinary incontinence are suggesed to be due to
obstruction- and/or age stimulated detrusor instability (60).
Men were questioned about the frequency of symptoms and
the
resultant
alterations
in
quality
of
life.
Men
with
mild
symptoms experienced only a minimum decline in quality of life
and therefore did not required medical care. In such cases,
obstruction of bladder outlet in the absence of LUTS may remain
undistinguished ('silent obstruction') (61).
1.7.3.Initial Assessment of BPH:
The initial assessments of BPH should include the following
domains:
1.7.3.1.Patient History:
A family history of prostatic disorder and cancer, a history
of lower urinary tract disease like bladder stones, transurethral
surgery, some systemic illness (like DM, hypertension) and a
history of
inhibitors,
management
with
antimuscarinics,
or
alpha-blockers,
neurological
5-alpha
drugs
reductase
should
be
documented(62).
1.7.3.2.Transabdominal Ultrasound :
It can be utilized to evaluate prostate size, which is the most
widely studied of the risk factors for BPH development. Men with
a prostate size of ≤ 30 ml are more expected to undergo moderate-
Chapter One
Introduction
- 21 -
to-severe lower urinary tract symptoms in comparison to men with
prostate size < 30 ml(63).
The prostate gland of patient was scanned in the transverse
and sagittal directions with the individual in supine position.
Prostate size was established utilizing the following formula:
width * length * height *0.52(64).
1.7.3.3.
Physical
Examination
Including
a
Digital
Rectal Examination (DRE) :
Digital rectal examination is the principal manner for the
prostate examination. This procedure permits the examiner to
appreciate
the
morphology
of
prostate
gland,
involving
any
irregular, firm nodule, or indurate regions, that may be indicated
for the presence of malignancy(65).
The existence of locally advanced prostate cancer, which
also can generate LUTS, must be eliminated by DRE. Digital
rectal exam be liables to underestimate true prostate size: if the
prostate believes to be large by DRE, it generally also appear to be
enlarged by ultrasound or other measurement methods(66).
1.7.3.4. Serum Prostate Specific Antigen( PSA)
Measurement:
Prostate specific antigen is a serine protease manufactured
by benign and malignant prostate tissue. Functionally, PSA is the
enzyme responsible for liquefaction of the seminal fluid after
ejaculation. Although small amounts are produced in other tissues,
it must be considered to be prostate specific (67).
Determination the concentration of PSA in serum (together
with DRE) is a moderately sensitive method to eliminate prostate
cancer as a diagnosis (66).
Chapter One
PSA
- 22 -
Introduction
(a
glycoprotein
valuable
tumor
composed
carbohydrates.
In
of
healthy
marker)
93%
men,
is
amino
the
a
single
acids
epithelium
chain
and
of
7%
prostate
produces and releases PSA and effectively prevents the protease
escape inside the systemic circulation. However, minor amount of
PSA does input into the circulation. Therefore, it is valuable to
measure the concentrations of serum PSA in patients of benign
and malignant
conditions of prostate, which could
differential identification
(68)
assist
in
. The normal range is (0-4) ng/ml;
30% of men with a PSA in the range of (4-10) ng/ml and 50% of
those with a PSA >10 mg/ml will have cancer (69).
1.7.3.5. Prostatic Acid Phosphatase (PAP) :
Prostatic acid phosphatase is still utilized in association
with prostate-specific antigen (the main marker of the prostate
carcinoma) in diagnosis of pathological alterations in prostate
tissue (70).
The
acid
phosphatase
involve
all
phosphatases
that
hydrolyze phosphate esters with the most favorable pH of less
than 7. Although acid phosphatase is synthesized initially by the
prostate gland, it is also present in red blood cells, pletelets,
leukocytes, bone morrow, liver, splaen, kidney, and intestine.
Increasing of the enzymatic activity of PAP are distinguished in
the serum of about 60% of patients with prostatic cancer. In
addition, it may be increased in some benign conditions like
osteoporosis, BPH, and hyperparathyroidism (59).
Chapter One
Introduction
- 23 -
2.7.4.Risk Factors Associated Benign Prostatic Hyperplasia:
2.7.4.1.Age:
Benign
prostatic
hyperplasia
is
a
common
urological
disorder in men. Its incidence enhances with age and may
influence 3 of 4 males in their sixties(71).
About age 50, the steady prostate growth is gradually
promotes. An enhance expression of α1A-adrenoceptor mRNA
has been detected in aged prostate. Accordingly there is an
enhance in the prostatic smooth muscle tone, which contracts the
urethra, result in appearance the LUTS related to BPH
(72)
.
However, the direct correlation between the aging process and the
occurrence
and
predominance
of
benign
prostatic
hyperplasia
implies that definite risk factors correlated with the progression of
disease enhance with the aging process. So that, prostatic stromal
fibroblasts from older males are less capable to stop proliferation
of epithelial cell than those from younger males(73).
1.7.4.2.Circulating Androgens:
Testosterone and its active metabolite 5-dihydrotestosterone
(5-DHT)
are
important
for
normal
growth
and
physiological
control of the prostate. Epithelial and stromal cells of prostate are
induced by 5-DHT to generate hormones or growth factors. These
hormones are either act in autocrine manner(mean affect locally
on
the
same
cells
that
produced
them)
or
in
paracrine
manner(mean affect on other neighboring cells (74).
Dihydrotestosterone (DHT) is principally the most effective
androgen
and
it
derives
through
irreversible
declining
of
testosterone by catalytic activity of 5α-reductase enzyme. The
effect of androgens on adipose tissue in men either directly by
Chapter One
induction
Introduction
on
the
androgen
receptor
or
indirectly,
- 24 -
after
aromatization through its action on the estrogen receptor(75).
By
P450
aromatase,
testosterone
is
metabolised
to
oestradiol(E2) in the cytoplasm of adipocytes and prostate cells, to
enhance oestradiol concentration inside the cells at the expense of
testosterone. Therefore, any molecule that up regulates aromatase
enzyme, or any compound that resembles oestrogen, will not just
enhance the activation of the primarily proliferative oestrogen
receptors
to
stimulate
oestrogen-sensitive
growth
tissues,
disorders
but
also
and
adipogenesis
stimulate
the
in
newly
recognized transmembrane G protein-coupled oestrogen receptors
(GPER),
and
deleteriously
change
the
necessary
intracellular
signaling sequences, that accelerate mitogenic growth (76).
Testosterone itself may combine in the pathogenesis of
insulin resistance and DM by enhancing the mass of skeletal
muscle at the expense of fat accumulation and reducing abdominal
obesity via inhibition the activity of lipoprotein lipase enzyme.
Low concentrations of free or total testosterone have been always
connected
with
overall
or
abdominal
fatness,
hyperglycemia,
insulin resistance or hyperinsulinemia (77).
1.7.4.3. Obesity:
Obesity may effect prostatic overgrowth by increasing the
concentration of estrogen and may deteriorate urinary obstructive
symptoms by enhancing
sympathetic nervous systems activity
(
78)
.
Distribution of abdominal fat is correlated with a number of
metabolic
and
hormonal
derangements
involving
reduced
concentrations of sex hormone binding globulin (SHBG), reduced
concentrations
of
testosterone,
enhanced
concentrations
of
Chapter One
estrogen,
Introduction
hyperglycemia
and
insulin
resistance.
- 25 -
Abdominal
obesity is correlated with an enhanced the risk of DM and recent
study have also investigate into its association with the health of
prostate ( 79).
Testosterone
is
changed
to
estradiol
in
adipose
tissue.
Therefore, obese men have a low levels of testosterone, high
(80)
levels of estrogen compared with normal-weight men
. One
consequence of obesity is an enhanced the activity of aromatase
enzyme that causes an elevated the level of oestradiol and reduced
the balance of testosterone/oestradiol ( 81).
The levels of RhoA/ROCK signaling have been shown to
be up regulate by estrogens, RhoA/ROCK is the most important
factor responsible for preserving smooth muscle tone in the
bladder, hyperactivity of the RhoA/ROCK way may be result in
overactivity of bladder. Therefore, high levels of estrogen may
lead to up regulation of RhoA/ROCK signaling, resulting in
changed the tone and overactivity of bladder smooth muscle. As
well to alters in the levels of steroid hormone, obese men are also
more
probable
to
detect
hyperinsulinemia,
which
has
been
correlated with enhanced the growth of prostate and potential
progression of symptomatic BPH (82).
1.7.4.4. Glucose Homeostasis:
Disturbances in glucose homeostasis at multiple different
levels(from changings in
the serum concentrations
of
insulin
growth factor to identification of clinical DM) are correlated with
higher probability of prostate overgrowth, BPH and LUTS
However,
accumulating
involving unusual
facts
refers
that
glucose homeostasis,
metabolic
(83)
.
disorders
insulin resistance, and
hyperinsulinemia may enhance the possibility of BPH. There are a
Chapter One
Introduction
- 26 -
number of mechanisms by which DM may potentially effect BPH.
initially,
the
trophic
influence
of
elevated
the
serum
concentrations of insulin detected through the development of
type 2 DM might stimulate the growth of prostate. As a
consequence
of
its
structural
homolgy
to
insulin-like
growth
factor (IGF), insulin can bound to the IGF receptor in the cells of
prostate, activating the receptor to stimulate prostatic enlargement
and proliferation. High serum levels of insulin may also enhance
sympathetic nerve activity, which may result in an enhance the
tone of prostate smooth muscle. Secondly, hyperglycemia itself
may play a role by enhancing cystolic-free calcium in smooth
muscle cells also in neural tissue resulting in the activation of
sympathetic nervous system (84).
1.7.4.5. Inflammation:
Inflammatory processes may take part in the development
of histologic benign prostatic hypertrophy among aging males.
Inflammation of prostatic may play an essential role in the growth
of prostate and ultimate progression of acute urinary retention(85).
The high existing of immune cells and their periglandular
organisation in the prostate gland propose that the prostate may
play an immune role in ensuring the sterility of the genitourinary
tract.
The
prostate
could
therefore
be
believed
an
immunocompetent organ, a deregulation of the immune response
may take place in the prostate, stimulating prostatic disorder.
Inflammatory
cells
secret
inflammatory
mediators,
involving
cytokines and growth factors, to interact with further immune
cells.
These
inflammatory
mediators
are
included
in
the
orgnization of the immune response and may also interact with the
Chapter One
Introduction
- 27 -
neighboring prostatic cells. They may therefore participate to the
development of BPH(86).
1.8.The Impact of Type 2 Diabetes in the Pathogenesis of
Benign Prostatic Hyperplasia:
The high prevelance of urologic complications correlated
with
diabetes
mellitus(DM)
is
an
enhancing
health
problem
throughout the entire world. DM is frequently correlated with
benign prostatic hypertrophy, due to the age of incidence
(87)
.
Additionally, enhanced the peripheral sympathetic nerve tone and
the
autonomic
nervous
system
activity
as
a
result
of
hyperinsulinemia (88).
Insulin
assists
glucose
uptake
into
the
ventromedial
hypothalamic neurons, which regulate the sympathetic system .
Prostatic obstruction is not only a result of static obstruction
attributable to the prostatic mass, but also a consequence of the
dynamic
obstruction
result
from
the
contraction
of
alpha-
adrenergic smooth muscle placed in bladder neck and the prostate.
The enhanced sympathetic tone produced by hyperinsulinemia is
also
correlated
with
pathophysiology
of
BPH
(89)
.
However,
insulin inhibits the manufacture of IGF-binding proteins which
orgnized the free portion of IGF-1(90).
The increase insulin like growth factors-I and decrease
insulin-like growth factors binding protein-3 were suggested to be
correlated with the enlargement of the prostate. elevated body
mass index directly associated with the development of type 2
DM and also enhances intra-abdominal pressure, resulting in
urinary incontinence.
Additionally,
Hyperlipidemia
to be an independent factor for bladder overactivity ( 91).
is
suggested
Chapter One
Introduction
- 28 -
1.9.Aims of the Study:
1-The study was designed to investigate the association between
BPH and diabetes and the contribution of metabolic changes
associated with DM on development of BPH in type 2 diabetic
males.
2- The study was designed to study the correlation of prostate size
with serum IGF-1 ,age and
type 2 diabetic patient groups.
prostatic specific antigen levels in