Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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