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THE ROLE OF INSULIN LIKE GROWTH FACTOR-1(IGF-1) IN DEVELOPING PROSTATE DISORDER IN TYPE 2 DIABETIC PATIENTS
Abstract
This study was to investigate on the coexistence of diabetes mellitus type 2 and BPH and to correlate among these conditions could exist. Furthermore, the relationship between benign prostatic hyperplasia and serum insulin-like growth factor-1 levels in those patients, by examination the correlation of prostate size with serum IGF1, age, prostatic specific antigen levels in patient groups are to be compared to non diabetic age-matched controls. Fasting blood specimens from sixty type 2 diabetic males, 33 of them had normal prostatic specific antigen levels (<4 ng/ml) and enlarged prostate according to digital rectal examination and trans abdominal ultrasound with lower urinary tract symptoms as a result of benign prostatic hyperplasia (BPH), as group a-(with a mean age of 62.4±5.1 years) and the rest (27) of them without BPH, as group b-(had a mean age of 56 ±5.2 years), who were attending the Al-Sader Teaching Hospital in Al-Najaf/Iraq, besides nineteen apparently healthy control males. Serum insulin-like growth factor-1, insulin, prostate specific antigen (PSA) concentrations were measured by a ELISA kits. The mean serum IGF-1 levels were significantly elevated in type 2 diabetic patients with BPH compared to diabetics without BPH (145 ± 41.1 and 88 ± 41.1 ng/ml respectively), while control group had a mean serum IGF-1 levels of 75±19.1ng/ml, Whereas, PSA values (2.37±0.98) were significantly elevated in diabetics with BPH compared to the other groups (0.7 ± 0.3 and 0.9± 0.2). A significant correlation was detected between prostatic size & IGF-1 levels in diabetics with BPH (r= 0.554, p˂ 0.001), which was undetectable in diabetics without BPH (r=0.256 , P=0.197). Our findings suggest that insulin-like growth factor-1 may have an etiologic role in BPH development in type 2 diabetic patient whose duration of diabetes less than 7 years.
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Diabetes mellitus is considered one of the main threats to human health in the 21st century. Diabetes is a metabolic disorder or a chronic condition where the sugar levels in blood are high. Diabetes is associated with long-term complications that affect almost every part of the body and often leads to blindness, heart and blood vessel disease, stroke, kidney failure, amputations, and nerve damage. Also it is associated with significantly accelerated rates of several debilitating microvascular complications such as nephropathy, retinopathy, and neuropathy, and macrovascular complications such as atherosclerosis and stroke. In the present article it has been discussed about the resistance of insulin and its consequences in diabetic patients. Insulin resistance results in various disorders. Metabolic syndrome is predicted to become a major public health problem in many developed, as well as developing countries.
Benign prostatic hyperplasia (BPH) is highly prevalent in older men and causes substantial adverse effects on health. The pathogenesis of this disease is not totally clear. Recent reports have suggested a possible relationship between metabolic syndrome (MetS) and BPH. Single components of MetS (obesity, dyslipidemia, hypertension, and insulin resistance) as well as the syndrome itself may predispose patients to a higher risk of BPH and lower urinary tract symptoms (LUTS). This may stem from changes in insulin resistance, increased autonomic activity, impaired nitrergic innervation, increased Rho kinase activity, pro-inflammatory status, and changes in sex hormones that occur in association with MetS. However, the exact underlying mechanisms that regulate the potential relationship between MetS and BPH/LUTS still need to be clarified. Increased physical activity and dietary strategies may help in decreasing the incidence of MetS and its impact on BPH/LUTS. However, differences in the definitions used to address the examined predictors and endpoints preclude the possibility of arriving at definitive conclusions.
The emergent epidemic of metabolic syndrome and its complex list of sequelae mandate a more thorough understanding of benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) in the context of systemic metabolic disease. Here we discuss the nature and origins of BPH, examine its role as a component of LUTS and review retrospective clinical studies that have drawn associations between BPH/LUTS and type II diabetes, inflammation and dyslipidemia. PPARγ signaling, which sits at the nexus of systemic metabolic disease and BPH/LUTS through its regulation of inflammation and insulin resistance, is proposed as a candidate for molecular manipulation in regard to BPH/LUTS. Finally, we introduce new cell and animal models that are being used to study the consequences of obesity, diabetes and inflammation on benign prostatic growth.
The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.
Since its first description by Reavan in 1988, accepted criteria for clinical identification of the components of metabolic syndrome have been promulgated by the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) and the World Health Organization (WHO) as well as the International Diabetes Federation (IDF), and the American Association of Clinical Endocrinologists (AACE). Insulin resistance is a common metabolic abnormality underlying type 2 diabetes mellitus and is also an independent risk factor for cardiovascular disease. Although ATP III identified cardiovascular disease (CVD) as the primary clinical outcome of the metabolic syndrome, we now have evidence that metabolic syndrome is associated with type 2 diabetes mellitus, polycystic ovarian disease, nonalcoholic fatty liver disease, and possibly some cancers. This review summarizes evidence in support of the relationship between metabolic syndrome and various cancers and possible underlying mechanisms and therapeutic interventions.
CONTEXt: Benign prostatic hyperplasia poses a significant public health problem, but its etiology remains unclear. Obesity and associated abnormalities in glucose homeostasis may play a role in benign prostatic hyperplasia development by influencing prostate growth.
The objective of this study was to determine whether obesity, fasting plasma glucose concentration, and diabetes are associated with radiologically determined prostate enlargement, an objective measure of benign prostatic hyperplasia.
This study was a cross-sectional analysis with robust variance estimates to account for multiple measures over time in the same individuals.
This prospective cohort study was composed of community volunteers.
Patients studied were 422 adult men enrolled in The Baltimore Longitudinal Study of Aging.
Total prostate volume as determined by pelvic magnetic resonance imaging was measured.
Among 422 participants, 91 (21.6%) had prostate enlargement (defined as total prostate volume >/= 40 cc) at first visit. Compared with men of normal weight [body mass index (BMI) < 25 kg/m(2)], the age-adjusted odds ratio (OR) for prostate enlargement for overweight men (BMI, 25-29.9 kg/m(2)) was 1.41 (95% CI, 0.84-2.37), for obese men (BMI, 30-34 kg/m(2)) was 1.27 (95% CI, 0.68-2.39), and for severely obese men (BMI >/= 35 kg/m(2)) was 3.52 (95% CI, 1.45-8.56) (P = 0.01). Men with elevated fasting glucose (>110 mg/dl) were more likely to have an enlarged prostate than men with normal fasting glucose (</=110 mg/dl) (OR, 2.98; 95% CI, 1.70-5.23), as were men with a diagnosis of diabetes (OR, 2.25; 95% CI, 1.23-4.11).
Obesity, elevated fasting plasma glucose, and diabetes are risk factors for benign prostatic hyperplasia.
Introduction: Benign prostatic hyperplasia (BPH) is the commonest benign tumour in the ageing man. The exact cause of BPH remains unknown. Methods: Systematic literature review from 1986 to 2006. Results: The benign prostatic syndrome is a disease that can develop as a result of hyperplasia and adenoma of the transition zone of the prostate. This syndrome is characterized by the presence of prostate enlargement, lower urinary tract symptoms and bladder outlet obstruction, to varying degrees. No clear correlation between these three components has so far been found. The aim of assessment in BPH is to clarify the interrelationships between prostate size, lower urinary tract symptoms and bladder outlet obstruction. In addition, the urinary tract should be investigated for functional or anatomical changes. Evaluation of BPH should be performed according to the guidelines of the German Urologists's society, who recommended a patient history, symptom and quality-of-life questionnaires, physical examination, laboratory tests, uroflowmetry, measurement of postvoiding residual urine, and ultrasound of the urinary tract. Optional tests, for use where the diagnosis is still unclear or a special treatment is being considered, include transrectal ultrasound of the prostate, voiding diary, urodynamic measurement, excretory urography, urethro-cystoscopy and urethro-cystography.
Aim Investigation of the relationship between Prostate Specific Antigen (PSA) and digital rectal examination(DRE) and transrectal ultrasonography(TRUS) findings in different prostate pathologies. Material and Methods 12-quadrant prostatic biopsy was performed for 229 patients who were admitted to our outpatient clinic between August 2008-January 2009, with lower urinary tract symptoms (LUTS) and PSA levels over 4 ng/ml. Histopathological evaluation were as benign adenomatous hyperplasia (BPH) in 91, BPH with chronic prostatitis in 60 and adenocarcinoma in 63 patients. PSA levels between 4.0 and 9.9 ng/ml and PSA level higher than10 ng/ml were determinated as Group1 and Group 2. The relationship between pathologic diagnosis and DRE /TRUS findings were evaluated. Results While the determination of toughness in DRE didn't show any difference in terms of pathological diagnosis in group-1, the rate of toughness in group-2 was higher in favor of PCa. In 3 patients, there was nodule in DRE and PSA was below 10ng/ml, 2 of them were diagnosed as BPH and the other one was diagnosed as PCa. PSA was above 9.9ng/ml in other 3 patients and all of them were diagnosed as PCa. While there was no statistically significant relationship between pathologic results and positive or negative TRUS findings in group-1, group-2 had statistically significant relationship. Conclusions TRUS and DRE are more valuable tests for PCa diagnosis but these tests effectiveness is related to PSA.
With digital rectal examination (DRE), prostate-specific antigen (PSA) is a major screening tool for prostate cancer. PSA is specific for the prostate, but not for prostate cancer. Multiple factors influence PSA value. Determination of PSA levels is not 100% sensitive for prostate cancer, as PSA levels may be normal despite presence of prostate cancer. The cutoff value for PSA of 4.0 ng/mL gives the highest sensitivity and highest specificity. Several modifications of PSA testing have been developed and may be beneficial for select populations. Uncertainty about the natural progression of prostate cancer and inherent limitations of PSA testing make it unclear whether universal screening is beneficial, and the recommendations of various organizations conflict. Randomized studies are in progress to address the role of PSA testing and of modifications of this test in the early detection of prostate cancer.
β cell dysfunction with subsequent apoptosis is considered a significant contributor to the development of type 2 diabetes. Emerging data from Talchai et al. suggest β cell dedifferentiation as an alternative mechanism of insulin insufficiency that might be more amenable to intervention in at least a subset of patients.
In our radioimmunoassay laboratory, we handled around 110,000 blood samples for prostate specific antigen (PSA) tests for screening or disease diagnosis every year. It proved that PSA is still a clinically favorite and preferential item as a serum marker for prostate diseases, especially for urologist. Patients aged over 50 years who visit our urological out-patient-department are routinely requested for PSA test. From literature reviews, we found that PSA used to be a powerful prostate tumor marker. Up to now, the specificity of PSA for detecting prostate disorders is good, but not for prostate cancer because increased PSA levels are often seen in prostate related diseases such as benign prostate hypertrophy and prostatitis or even prostate-unrelated diseases such as breast cancer. These draw-backs inevitably decrease the clinical value of PSA in prostate cancer detection. Methods provided in this pre-sentation may enable us to use PSA test properly and efficiently in the detection of prostate cancer, avoiding mis-interpretation from other diseases. While popularity and controversy of PSA remain, related works are needed to recognize the dimensions of PSA and re-evaluate its use in clinical applications.
The condition known as benign prostatic hyperplasia may be defined as a benign enlargement of the prostate gland resulting from a proliferation of both benign epithelial and stromal elements. It might also be defined clinically as a constellation of lower urinary tract symptoms (LUTSs) in aging men. The purpose of this review is to consider the ways in which inflammatory cytokines belonging to the interleukin family, members of the IFG family, and stem cells may contribute to the development and progression of BPH-LUTS. This might occur in three mechanisms: One, interleukin signaling, IFG signaling and stem cells may contribute to reactivation of developmental growth mechanisms in the adult prostate leading to tissue growth. Two, given that epidemiologic studies indicate an increased incidence of BPH-LUTS in association with obesity and diabetes, IFG signaling may provide the mechanistic basis for the effect of diabetes and obesity on prostate growth. Three, expression of interleukins in association with inflammation in the prostate may induce sensitization of afferent fibers innervating the prostate and result in increased sensitivity to pain and noxious sensations in the prostate and bladder and heightened sensitivity to bladder filling.
Insulin resistance is a hallmark of obesity, diabetes, and cardiovascular diseases, and leads to many of the abnormalities associated with metabolic syndrome. Our understanding of insulin resistance has improved tremendously over the years, but certain aspects of its estimation still remain elusive to researchers and clinicians. The quantitative assessment of insulin sensitivity is not routinely used during biochemical investigations for diagnostic purposes, but the emerging importance of insulin resistance has led to its wider application research studies. Evaluation of a number of clinical states where insulin sensitivity is compromised calls for assessment of insulin resistance. Insulin resistance is increasingly being assessed in various disease conditions where it aids in examining their pathogenesis, etiology and consequences. The hyperinsulinemic euglycemic glucose clamp is the gold standard method for the determination of insulin sensitivity, but is impractical as it is labor- and time-intensive. A number of surrogate indices have therefore been employed to simplify and improve the determination of insulin resistance. The object of this review is to highlight various aspects and methodologies for current and upcoming measures of insulin sensitivity/resistance. In-depth knowledge of these markers will help in better understanding and exploitation of the condition.
Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH.
Some men have rapid increases in benign prostatic enlargement and lower urinary tract symptoms (LUTS), and it is not clear how sex steroid hormones contribute to the rates of change in these urologic outcomes. Therefore, the authors conducted a population-based cohort study of 648 men residing in Olmsted County, Minnesota, from 1990 to 2007, to examine associations between baseline sex steroid hormones, the rate of change in these hormones, and the rates of change in LUTS, maximum urinary flow rate, and prostate volume. Annual changes in hormone levels and urologic outcomes were calculated using mixed-effects regression models. Associations between hormone variables and rates of change in urologic outcomes were assessed with linear regression models. Higher baseline estradiol levels and rapid declines in estradiol over time were associated with rapid increases in LUTS and rapid decreases in maximum flow rate. Lower baseline bioavailable testosterone levels and more rapid declines in bioavailable testosterone were associated with more rapid increases in prostate volume. These results suggest that both absolute sex steroid hormone levels and the rates at which the levels change may be important in the development of urologic conditions in aging men.
The insulin receptor (IR) isoforms and the IGF type 1 receptor (IGF-1R) share a high degree of structural homology but differ in ligand binding kinetics and functions. We developed a highly specific quantitative PCR assay to quantify and compare IR-A, IR-B, and IGF-1R expression within an RNA population. We determined receptor expression in primary murine mammary epithelial cells (MECs) during postnatal development. Both IR isoform mRNAs were 3- to 16-fold higher than IGF-1R expression at all developmental times. IR protein was also 3- to 10-fold higher than IGF-1R protein; however, significantly less IGF-1R was found in hybrid receptors at early (49%) vs. late (79%) pregnancy, indicating that the amount of hybrid receptor is developmentally regulated. Despite high IR expression, IGF ligands were more effective than insulin in stimulating the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt pathway in acutely isolated MECs from virgin glands. Although approximately 40% of IR transcripts were the IGF-II-sensitive IR-A isoform, IGF-II failed to stimulate IR phosphorylation, and an IGF-1R-specific blocking antibody completely abrogated IGF-II-mediated Akt phosphorylation in the virgin MECs. Taken together, these data suggest that the IGF-1R is more active in signaling than the IR and is the predominant mediator of IGF actions in virgin MECs.
Type 2 diabetes results from pancreatic ss-cell failure in the setting of insulin resistance. This model of disease progression has received recent support from the results of genome-wide association studies that identify genes potentially regulating ss-cell growth and function as type 2 diabetes susceptibility loci. Normal ss-cell compensation for an increased insulin demand includes both enhanced insulin-secretory capacity and an expansion of morphological ss-cell mass, due largely to changes in the balance between ss-cell proliferation and apoptosis. Recent years have brought significant progress in the understanding of both extrinsic signals stimulating ss-cell growth as well as mediators intrinsic to the ss-cell that regulate the compensatory response. Here, we review the current knowledge of mechanisms underlying adaptive expansion of ss-cell mass, focusing on lessons learned from experimental models of physiologically occurring insulin-resistant states including diet-induced obesity and pregnancy, and highlighting the potential importance of interorgan cross talk. The identification of critical mediators of islet compensation may direct the development of future therapeutic strategies to enhance the response of ss-cells to insulin resistance.
Insulin resistance is not often a clinical problem, but it is a silent concomitant to many clinical disorders. The mechanisms responsible for hormone resistance are diverse, but recent studies have shown that abnormalities of the insulin receptor in patients with insulin resistance have led to the identification of previously unknown syndromes with novel pathogenic mechanisms, such as the syndrome of insulin resistance caused by antibodies to the insulin receptor. Although anti-insulin antibodies account for only a small amount of the diabetes in the general population, studies of these antibodies have provided important insights into insulin action and the possible mechanisms for a variety of other pathologic states.
There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.
To evaluate and quantify the association between consumption of specific food groups/macronutrients and concentrations of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3).
Data from a comprehensive food-frequency questionnaire administered to 115 healthy subjects were used to study cross-sectionally the relationship between nutritional factors and circulating IGF-1 and IGFBP-3 concentrations. Adjustment for the effect of total energy intake and a series of epidemiologic parameters (age, sex, height, body mass index, smoking, alcohol consumption, and coffee drinking) was implemented through multivariate linear regression.
We observed that serum levels of IGF-1 are positively associated with consumption of red meats, fats, and oils. In addition, serum levels of IGF-1 are independently and positively associated with energy intake from lipids and negatively associated with energy intake from carbohydrates. Finally, serum levels of IGFBP-3 are independently and negatively associated with energy intake from saturated fat.
Serum IGF-1 and/or IGFBP-3 concentrations are associated with red meat, carbohydrate intake, and fat intake and, thus, may mediate the effect of these dietary factors on the pathogenesis of several disease states. Additional studies are needed to further quantify these associations and elucidate the underlying mechanisms.
One previous study has suggested that diabetes may decrease risk of prostate cancer but only several years after diagnosis of diabetes. The authors examined the role of timing of diabetes diagnosis in relation to risk of prostate cancer among men in the Cancer Prevention Study II Nutrition Cohort. Participants in the study completed a mailed questionnaire including information on diabetes at enrollment in 1992 and at follow-up questionnaires in 1997 and 1999. Historical information on diabetes was also available from a previous study in 1982. The authors documented 5,318 cases of incident prostate cancer through August 31, 2001, among 72,670 men. Results from Cox proportional hazards models showed that diabetes was associated with a lower incidence of prostate cancer (rate ratio (RR) = 0.67, 95% confidence interval (CI): 0.60, 0.75). This association differed significantly by time since diagnosis of diabetes (p < 0.0002); risk of prostate cancer was slightly increased during the first 3 years after diagnosis of diabetes (RR = 1.23, 95% CI: 0.92, 1.65) but was reduced among men diagnosed 4 or more years before (RR = 0.63, 95% CI: 0.56, 0.71). Study results are consistent with the hypothesis that diabetes is associated with reduced risk of prostate cancer but only several years after diagnosis of diabetes.
Over the last decade, management of benign prostatic hyperplasia (BPH) has changed with a substantial decrease in the use of transurethral prostatectomy (TURP) and a simultaneous increase in the use of medical therapy and minimally invasive surgical therapy (MIST). The goal of management of this chronic progressive condition is not only to provide relief of lower urinary tract symptoms (LUTS) but also to reduce the lifetime risk of adverse outcomes. Recent clinical evidence has demonstrated a clear role for medical therapy, particularly with 5-alpha-reductase inhibitors (5ARIs) either alone or in combination with alpha-blockers, to reduce the risk of acute urinary retention and need for surgery and provide symptom relief. Clinical data on MISTs also indicate a more pronounced short-term effect; however, the long-term durability of these therapies remains uncertain. Minimally invasive surgical therapies confer treatment benefits in a single 1-h treatment session under local anesthesia. Recovery times and adverse events are improved compared with TURP, but issues such as hematuria, prolonged catheterization, urinary tract infection and retreatment remain commonly reported issues. Today, urologists are faced with the challenge of identifying the most appropriate treatment option for the long-term management of BPH. The initial choice for any given patient will depend on his presenting circumstances and the influence of treatment risks on these circumstances. Providing patients with informed treatment decisions is a key element of management.
To evaluate the relationship between clinical benign prostatic hyperplasia (BPH) and atherosclerosis, using colour Doppler ultrasonography (CDUS) and symptom scores.
CDUS was used to evaluate prostatic vascularity in four groups of men, comprising young healthy subjects, patients presenting with coronary artery disease (CAD), diabetes mellitus, or peripheral arterial occlusive disease (PAOD). Resistive index (RI) measurements and computer-assisted quantification of colour pixel density (CPD) were used to objectively evaluate perfusion. The International Prostate Symptom Score (IPSS) and the International Index of Erectile Function were used to quantify symptoms.
In diabetic patients and men with PAOD, perfusion of the transition zone (TZ) of the prostate was significantly lower (P < 0.001) and the RI of the TZ was significantly higher (P < 0.001) than in healthy controls and men with CAD. In diabetics and men with PAOD, the mean prostate volume was greater than in healthy controls and men with CAD. The IPSS in patients with vascular damage (diabetes, PAOD) was significantly worse than in the control group.
The significantly lower CPD and higher RI values of the TZ in patients with vascular disease than in healthy subjects support the hypothesis that an age-related impairment of blood supply to the prostate has a key role in the development of BPH.
There is a progressive deterioration in β-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in β-cell mass of about 60% was shown at necropsy. The reduction of β-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of β-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired β-cell function and possibly β-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased β-cell mass has probably not been passed.
Among the interventions to preserve or “rejuvenate” β-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve β-cell function, usually leading to a temporary remission time. Another intervention is the induction of β-cell “rest” by selective activation of ATP-sensitive K+ (KATP) channels, using drugs such as diazoxide.
A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human β-cell function.
The TZDs improve insulin secretory capacity, decrease β-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on β-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor γ activation in pancreatic islets, with TZDs consistently improving basal β-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs.
Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic β-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on β-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating β-cell proliferation, induction of islet neogenesis, and inhibition of β-cell apoptosis, thus promoting expansion of β-cell mass, as observed in rodent diabetes and in cultured β-cells. Exenatide and liraglutide enhanced postprandial β-cell function.
The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted β-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial β-cell function.
Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on β-cells in humans, and there is no clinical evidence that these drugs really have protective effects on β-cells.
Benign prostatic hyperplasia (BPH) is a complex disease that is progressive in many men. BPH is commonly associated with bothersome lower urinary tract symptoms; progressive disease can also result in complications such as acute urinary retention (AUR) and BPH-related surgery. It is therefore important to identify men at increased risk of BPH progression to optimise therapy. Several factors are associated with progression, including age and prostate volume (PV). Serum prostate-specific antigen level is closely correlated with PV, making it useful for determining the risk of BPH progression. Medical therapy is the most frequently used treatment for BPH. 5-alpha-reductase inhibitors impact the underlying disease and decrease PV; this results in improved symptoms, urinary flow and quality of life, and a reduced risk of AUR and BPH-related surgery. Alpha-blockers achieve rapid symptom relief but do not reduce the overall risk of AUR or BPH-related surgery, presumably because they have no effect on PV. Combination therapy provides greater and more durable benefits than either monotherapy and is a recommended option in treatment guidelines. The Combination of Avodart and Tamsulosin (CombAT) study is currently evaluating the combination of dutasteride with tamsulosin over 4 years in a population of men at increased risk of BPH progression. A preplanned 2-year analysis has shown sustained symptom improvement with combination therapy, significantly greater than with either monotherapy. CombAT is also the first study to show benefit in improving BPH symptoms for combination therapy over the alpha-blocker, tamsulosin, from 9 months of treatment.
We investigated whether peptides involved in cellular proliferation and apoptosis, [insulin-like growth factor I (IGFI) and its major binding protein (insulin-like growth factor binding protein 3)], predicted risk of benign prostate hyperplasia (BPH).
We conducted a nested-case-control study in the placebo arm of the prostate cancer prevention trial (PCPT). Cases (n = 727) were men with surgical or medical treatment for BPH; two or more IPSS scores >14; or two scores of at least five points over baseline one of which was >or=12. Controls (n = 727) were frequency matched by age to cases, reported no BPH treatment, and no IPSS score >8. Cases and controls remained on the PCPT placebo and were followed closely until their 7-year PCPT anniversary. Baseline serum was analyzed for IGFI and IGFBP3. Unconditional logistic regression and polytomous regression estimated the multivariate-adjusted odds ratio (OR) for BPH risk.
IGFBP3 was inversely and the IGFI:IGFBP3 ratio was positively associated with BPH risk, but findings were statistically significant only for men with severe symptoms (OR = 0.60, 95% CI = 0.40-0.90 for the fifth vs. first quintile of IGFBP3, P-trend = 0.01). Associations did not differ by age (<65 or >or=65 years), and there was a suggestion that the IGFI:IGFBP3 - BPH risk association may be stronger among overweight men.
A high IGFI:IGFBP3 ratio was associated with increased BPH risk, and high serum IGFBP3 was associated with decreased BPH risk among men with severe symptoms. These results confirm findings from other recent studies.
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