|Year : 2019 | Volume
| Issue : 2 | Page : 50-56
Current understanding of diabetes mellitus-induced lower urinary tract dysfunction
Sasanka Kumar Barua1, Somor Jyoti Borah2, TP Rajeev1
1 Department of Urology, Guwahati Medical College Hospital, Guwahati, Assam, India
2 Department of Urology, GNRC Hospital, Guwahati, Assam, India
|Date of Submission||26-Jan-2019|
|Date of Acceptance||30-Mar-2019|
|Date of Web Publication||23-Jul-2019|
Dr. Sasanka Kumar Barua
Department of Urology, Guwahati Medical College Hospital, Guwahati - 781 032, Assam
Source of Support: None, Conflict of Interest: None
Diabetes mellitus (DM) is slowly emerging as an epidemic in India, afflicting majority of the population, thus having serious public health consequences. DM usually inflicts major insult to almost all organ systems of the body, including the urinary tract. However, there is a dearth of literature on potential hazardous effects of DM on the urinary tract in a particular population. Considering its negative impact on the quality of life, particularly among the growing elderly population in India, we performed literature search through PubMed and unbound Medline database using the terms “diabetic cystopathy,” “diabetic complication urinary tract,” “diabetic urethropathy,” and “diabetic bladder dysfunction” to study the current understanding on the pathophysiology of diabetes induced on the lower urinary tract dysfunction. All the literature based on DM relevant to lower urinary tract dysfunction were studied, and a comprehensive overview of the current understanding of the pathophysiology of diabetes induced on the lower urinary tract dysfunction is provided. These results will facilitate the future directions for research and clinical care of patients with DM-induced lower urinary tract dysfunction. In conclusion, the long-term hyperglycemic state may result in structural and functional changes in urinary bladder and urethra, contributing to deterioration of lower urinary tract coordinated function.
Keywords: Diabetes-induced lower urinary tract dysfunction, Diabetes mellitus, Diabetic cystopathy, Hyperglycemia
|How to cite this article:|
Barua SK, Borah SJ, Rajeev T P. Current understanding of diabetes mellitus-induced lower urinary tract dysfunction. J Health Res Rev 2019;6:50-6
|How to cite this URL:|
Barua SK, Borah SJ, Rajeev T P. Current understanding of diabetes mellitus-induced lower urinary tract dysfunction. J Health Res Rev [serial online] 2019 [cited 2020 Jan 20];6:50-6. Available from: http://www.jhrr.org/text.asp?2019/6/2/50/263250
| Introduction|| |
Diabetes mellitus (DM) is being recognized as an important public health problem worldwide as the global prevalence of diabetes has doubled since 1980. In India, particularly the number of diabetes cases is expected to increase from 40.6 million in 2006 to 79.4 million by 2030, with a prevalence of about 12.1%, and the onset of which is found to be a decade earlier than their Western counterparts.
DM can lead to complications in many parts of the body, including the urinary tract. Urological disorders are increasingly being recognized as a complication, thus having a negative impact on the quality of life. Studies have also revealed that overactive bladder, stress, and urge incontinence are also associated with diabetes. The prevalence of unrecognized diabetic bladder dysfunction (DBD) among women around 22%. The prevalence of DBD increases with the duration of diabetes, and DBD can occur in the early stage of disease. However, compared to DBD, little is known about the effects of persistent hyperglycemia on urethral function. It is speculated that due to peripheral polyneuropathy arising out of diabetes, diabetic urethropathy possibly contributes to deterioration of voiding function by altering the integrity of urethra vesicle coordination. As diabetes tends to affect the older population, concurrent factors such as benign prostatic hyperplasia (BPH), neurological disorders, and aging may contribute to voiding dysfunction in these patients. There are lot of scattered literature available on diabetes-induced lower urinary tract dysfunction, but there is no comprehensive paper summarizing this information. Hence, this review was planned to provide a comprehensive overview of the current understanding on the pathophysiology of diabetes induced on the lower urinary tract dysfunction is provided.
| Methods|| |
In this review, we performed literature search through PubMed using the terms “diabetic cystopathy,” “diabetic complication urinary tract,” “diabetic urethropathy,” and “diabetic bladder dysfunction” to study the current understanding on the pathophysiology of diabetes induced on the lower urinary tract dysfunction. All the literature on DM pertinent to lower urinary tract dysfunction were reviewed by the authors.
An alteration in the coordinated activity of urinary bladder induced by prolonged hyperglycemic state is called diabetic cystopathy. The term “Diabetic Cystopathy” was coined by Frimodt-Møller. Bladder cystopathy most likely reflects end-stage bladder failure and is characterized by reduced bladder sensation and poor contractility, leading to increased postvoid residual urine volume. The prevalence of urodynamically diagnosed bladder cystopathy ranges from 25% to 90%. A number of clinical studies in men and women with diabetes have reported bladder instability as the most frequent finding associated with diabetic cystopathy.
Role of detrusor muscle
Detrusor muscle-altered activity is considered to be due to changes in intercellular connections and excitability, receptor density and distribution, alteration in intracellular signaling, and genetic changes. The detrusor muscle shows an accelerated response to muscarinic agonists in patients with diabetes, which is attributed to an increased muscarinic receptor density or response increase in smooth muscle sensitivity to calcium, carbachol, potassium, and electrical field stimulation occurring in the diabetic bladder. Tong et al. reported a 70% increase in the density of M2-receptors within 2 weeks of induction of diabetes in rats.
Hyperglycemia-induced polyuria is considered as the only factor for bladder hypertrophy in DM. There is remodeling of bladder in response to alterations in urine volume, bladder filling rate, and urine osmolality. Glucosuria together with osmotic diuresis results in enlarged bladder stretch and elevated intravesical pressure, which leads to bladder hypertrophy and increased residual urine volume. The changes induced by polyuria can stimulate DNA synthesis, which in turn results in increased cell mass and hyperplasia. Review of the published literature on clinical manifestations of type 2 diabetes-induced bladder dysfunction (T2D-DBD) revealed that patients with type 2 diabetes have a predominant bladder storage problem, including increased frequency of urination and nocturia and the establishment of T2D DBD occurs at least 8–9 years after the onset of type 2 diabetes.
Alteration in morphology and changes in tissue component can also influence bladder dysfunction in DM. There is downregulation of transforming growth factor-β1 and collagen mRNA levels and simultaneous increase of elastin synthesis. Therefore, diuresis-driven reduction of collagen synthesis increased in compliance as well as elastin synthesis of the bladder.
Several studies have proposed that oxidative stress is a major contributing factor in the pathogenesis of diabetes-induced complications. Beshay and Carrier evaluated the oxidative status of the bladder in streptozocin-induced diabetes in rats and concluded that the oxidative stress was not mediated by diuresis. Changolkar et al. observed increased lipid peroxidation and overexpression of aldose reductase in alloxan-induced diabetic rabbits. Aldose reductase induction in cultured human microvascular endothelial cells by glycation end-cofactor products in the serum of patients with diabetes may be responsible for the endothelial cell damage by oxidative stress, leading to diabetes-associated microvascular dysfunction. Daneshgari et al. provided unpublished evidence suggesting increased aldose reductase expression in the human bladder smooth muscle cells under hyperglycemic conditions. Protein kinase C, which is a signal transduction protein, initiated by the activation of aldose reductase pathway. Protein kinase C-induced signal transduction or damage to myofilaments by free radicals might also contribute to contractile dysfunctions.
It has been shown that poly (ADP-ribose) polymerase is usually activated by oxidative stress in diabetes, which further causes activation of c-Jun N-terminal kinase mitochondrial apoptotic pathway that plays a significant role in bladder dysfunction by attenuating bladder apoptosis.
It is postulated that increased oxidative damage of proteins would be expected to bring about changes in the expression of genes involved in pathways, resulting in protein degradation and removal. Studies have shown upregulation of two key proteins involved in protein degradation (Nedd4 and LC3B) and also apoptosis-inducing protein BAX in the diabetic bladder.
Cells having similar morphological characteristics to the interstitial cells (of Cajal of the gastrointestinal tract) have also been demonstrated in the human urinary tract. Interstitial cells in the urinary tract have been suggested to play important functional roles such as detrusor contractions. Studies have demonstrated that the amount of both interstitial cells and neural tissue was significantly decreased in the bladder of rabbits with diabetes. However, no significant differences were found in the same cells at the level of urethra and prostate. Thus, the effect of DM on the interstitial cells may emerge as a new mechanism for the development of diabetes-induced lower urinary tract dysfunction. A study carried out by Yohannes et al. observed that during diabetes, there is downregulation of structural and extracellular matrix proteins in the smooth muscle, which is essential for normal muscle contraction and relaxation.
Temporal hypothesis of diabetic bladder dysfunction
It has been observed that bladder hypertrophy and remodeling and associated neurogenic changes develop soon after the onset of DM,, whereas bladder voiding problems associated with a marked decrease in the cystometric measure of peak voiding pressure develop only at a later stage., These time-dependent manifestations of DBD served as the basis for the temporal hypothesis of DBD, which conveys that DM causes the bladder to undergo two phases of alterations through two main mechanisms. In the early phase, hyperglycemia-induced osmotic polyuria is the predominant factor that results in compensatory bladder hypertrophy and associated myogenic and neurogenic alterations manifesting as storage symptoms; while in the later phase, accumulation of oxidative stress products during prolonged hyperglycemia causes decompensation of bladder tissue and function, which leads to bladder emptying problems.
Role of neuronal damage
Diabetes-related urinary bladder dysfunction in humans has been commonly attributed to altered neuronal control and/or neuronal injury. The possible mechanism is by the activation of the polyol pathway (which results in accumulation of sorbitol and fructose), increased production of free radicals, activation of protein kinase C, and enhanced formation of advanced glycated end products. The metabolic imbalance can cause axonal degeneration together with impairment of nerve conduction that later on manifest itself as bladder hyposensation.
Many previous investigations have suggested that DBD may be related to autonomic neuropathy, where there is a significant loss of neurons or nerve terminals.
It is further postulated that development of DBD occurred due to Aδ-fiber in bladder afferents C-fiber neuropathy is commonly seen in diabetic peripheral neuropathy; hence, it can also influence the function of C-fiber afferent pathways of the bladder. A study carried out by Lee et al. showed a strong association between the uroflowmetry parameters and the vesicle Aδ- and C-fiber neuropathy in diabetic women with detrusor underactivity. In addition, an increased threshold of C-fiber afferent pathway in diabetic patients with detrusor underactivity is a probable explanation for insensitivity to inflammations occurring in the bladder of diabetic patients.
The impairments of efferent pathways of the bladder in diabetic patients are regarded as a contributing factor causing detrusor overactivity with impaired contractility. Demyelination and axonal degeneration of the bladder efferents resulting decrease in acetylcholinesterase activity because of diabetes. M2 muscarinic receptors too play a pivotal role in the genesis of diabetic cystopathy. Partial autonomic denervation of the urinary bladder causes an upregulation of M2-receptors and decreased cholinergic transmission. Increased M2-receptors inhibit bladder relaxation and produce detrusor overactivity. A group of 53 diabetic patients showed an association between bladder dysfunction and autonomic neuropathy using “sympathetic skin response test.” Central nervous system dysfunction may interfere with DBD in conjunction with peripheral neuropathy. Detrusor overactivity is usually associated with DBD in a subset of patients with cerebrovascular accident having DM. In addition, there are possible lesions identified within the spinal cord that precipitates DBD. Nerve growth factor (NGF), a member of the neurotrophin factor family, is essential for maintaining the normal function of mature sensory and sympathetic neurons. It also promotes survival of the neurons during development. Studies have shown that NGF levels significantly decreased not only in the bladder, but also in the L6 to S1 dorsal root ganglia in a time-dependent manner after DM induction.
Release of NGF is found to be regulated by plasma and matrix metalloproteinase. Hence, DM may affect matrix metalloproteinase and influence the release of proform and mature NGF. Thus, it is apparent that changes in NGF levels in the bladder and bladder afferent pathways could be involved in the bladder dysfunction induced by peripheral neuropathy in DM.
Role of urothelium
Although alterations in smooth muscle and nerve innervations are predominant events in diabetes, there is little information on its influence on the urothelium.
The urothelium acts as a sensor for controlling bladder function. Few studies on the effects of DM on bladder urothelium in the streptozocin-induced diabetic rat model showed increased urothelial proliferation without a simultaneous increase in the thickness of the urothelial lining., This increase in proliferation is responsible for alteration in normal urothelial cell physiology, expression of urothelial cell receptors, and release of signaling molecules such as neurotransmitters. This potentiates changes in smooth muscle and nerve endings. The bladder epithelium produces prostanoids such as prostaglandins F2α and E2, which are important mediators of bladder function. There is an impaired endogenous prostaglandin release from epithelial preparations in type 1 diabetic rats, which may be related to bladder abnormalities occurring during diabetes. The prevalence of bacteriuria and urinary tract infections is found to be higher in diabetic women compared to healthy individuals. Epithelial cells of diabetic patients showed higher affinity in type 1 fimbriated Escherichia More Details coli. They bind to uroplakin proteins on the luminal surface of the bladder and then invade the bladder wall. It was proposed that common occurrence of chronic urinary tract infection among patients with diabetes was in part attributable to bladder stasis and may also be the result of altered expression of adherence receptors for bacteria by the urothelial cells.
Barrier function of the urothelium is often hindered either by infection or spinal cord trauma. This facilitates toxic substances to diffuse to the underlying tissues to induce symptoms of urgency, frequency, and pain during bladder filling and voiding. These cascades of events bring about change in the levels of chemical mediators such as nitric oxide (NO) and adenosine triphosphate (ATP), which are important in maintaining epithelial integrity and adequate functioning. It is observed that a significant amount of ATP is released from damaged or sensitized urothelial cells in response to injury or inflammation that triggers the sensation of pain.
Bladder dysfunction in men
In aging men, lower urinary tract symptoms (LUTS) secondary to BPH are common, and age-related complaints are often attributed to BPH. However, among men with diabetes, similar symptoms may also result from bladder dysfunction due to denervation and poor detrusor contractility in the absence of significant prostatomegaly. Diabetic men showed complex associations of LUTS and BPH, which results in urgency, frequency, and nocturia. It may occur due to detrusor overactivity, resulting from BPH and/or from microvascular complications associated with diabetes together with increasing hyperactivity of the detrusor.
The effect of diabetes on the development or presence of LUTS and BPH remains controversial. Recent evidence suggests that LUTS may occur more frequently among men with diabetes. In addition, among men with BPH, diabetes is associated with exaggerated LUTS compared with nondiabetic men. In a prospective study of BPH progression, diabetes was found to be associated with an increased risk of LUTS but was not associated with an increase in prostate volume. While there is a clinical overlap between the presence of BPH and LUTS, there can be manifestations of different pathophysiological pathways mediated through hormonal, environmental, genetic, neuropathic, and (micro) vascular influences, particularly in diabetic patients. Although there are only limited data on incontinence in men with or without diabetes, the number of diabetic men with incontinence is low at about 4%. The data derived from California Men's Health Study and Research Program in Genes, Environment and Health revealed significant association between LUTS and diabetes, particularly in those who were on oral hypoglycemic drugs for longer duration. Apart from urothelial dysfunction, polyuria associated with DM contributes to detrusor hypertrophy and together with oxidative stress due to persistent hyperglycemia results in the development of DBD. LUTS were found to be constantly associated with diabetics, with an estimated prevalence rate between 37% and 70%, with dysautonomia along with muscular hypotonia playing a major role in its pathogenesis.
Bladder dysfunction in women
Several epidemiological studies have shown that urinary incontinence is 50%–200% more common among women with type 2 diabetes. In the Nurses' Health Study, the 2-year incidence of weekly incontinence was 5% in those without diabetes and 9% in those with type 2 diabetes. However, despite mounting evidence of a link between diabetes and incontinence, little is known about the mechanisms, by which diabetes leads to incontinence. Investigations in women with type 2 diabetes suggest that microvascular complications further increase the prevalence and incidence of urinary incontinence. Physiological, microvascular, and neurological complications of diabetes result in changes that may impair the function of continence mechanisms, including damage to bladder innervation, altered detrusor muscle function, or urothelial dysfunction. However, at the same time, the increase in urinary incontinence in women with prediabetes, who generally lack these severe diabetic complications, suggests that other unknown factors may also contribute to the development of incontinence in women with prolonged hyperglycemic state.
Diabetes mellitus and benign prostatic hyperplasia/lower urinary tract symptoms
Several studies have been conducted to examine the influence of diabetes on prostate gland size. Diabetes-induced vascular damage and atherosclerosis causing hypoxia in the transitional zone of prostate were proposed as the initiating factor in the pathogenesis of BPH in diabetic men. It has been shown that physician-diagnosed diabetes was significantly associated with an increased prostate size consistent with BPH., These investigators observed that among patients with LUTS men with diabetes had a larger prostate gland than men without diabetes. Furthermore, they observed that men with rapidly growing prostate glands had a higher prevalence of type 2 DM. In the Baltimore Longitudinal Study of Aging men, increased fasting glucose and diabetic men were 3-fold more and 2-fold more likely to be associated with an enlarged prostate (40 cc or greater), as measured by magnetic resonance imaging, respectively. These findings suggest that BPH might be an insulin-resistant state with secondary hyperinsulinemia as a possible etiological factor for prostate enlargement. However, the positive associations described between measures of BPH/LUTS, and diabetes has not been consistently observed across studies. Boon et al. examined individuals with LUTS and diabetes and found little difference in prostate volume, peak urinary flow rate, and postvoid residual volume compared to individuals with LUTS only. Finally, in a recent prospective cohort study of the influence of diabetes on the progression of BPH markers, Burke et al. observed that men with diabetes reported a larger increase in the American Urological Association Symptom Index Score than men without diabetes. However, they found no difference in prostate volume change or prostate-specific antigen levels, perhaps suggesting that diabetes may be less directly associated with prostate growth and more closely associated with the dynamic components of lower urinary tract function.
| Hypothesized Mechanisms|| |
There are several mechanisms, by which diabetes may influence BPH. Apart from inducing prostate growth due to high insulin level, it also causes accentuation of sympathetic nerve activity, leading to enhanced prostate smooth muscle tone. The smooth muscle and neuronal tissues are flooded with cytosolic-free calcium secondary to hyperglycemia, which further activates sympathetic nervous system., Insulin binds with insulin-like growth factor receptors in prostate stimulating its growth and proliferation. Higher levels of insulin are associated with lower sex hormone-binding globulin, which may increase the amount of androgen/estrogen entering prostatic cells, thereby increasing the risk of BPH. Available data suggest that inflammation may have an important role in BPH development and its progression. While the mechanisms by which inflammation may lead to prostatic growth have not been properly understood, it was suggested that inflammatory mediators may contribute to prostatic epithelial and stromal cell growth directly through growth induction through cytokines that stimulate the production of prostatic growth factors and indirectly through decrease in prostate cell death through the downregulation of prostate cell apoptosis. Moreover, glucose insensitivity is a component of metabolic syndrome, which is associated with systemic inflammation and oxidative stress, whereas histological BPH is usually associated with inflammation and the extent and severity of inflammation correspond to BPH severity., A recent observational study has revealed significant association between the glycemic level of diabetic elderly men and the development of significant LUTS such as nocturia.
There is a paucity of literature on the deleterious effect of uncontrolled hyperglycemia on the urethral function as compared to its effect on the urinary bladder.
DM negatively affects the somatic, autonomic parasympathetic and sympathetic nerve of the urethra, thereby impairing the coordinated micturition reflexes. A clinical study has demonstrated that neurovesicourethral dysfunction among people with diabetes strongly correlates with DM-induced somatic neuropathy. An in vivo experiment carried out by Torimoto et al. showed that the intravesical pressure threshold for inducing urethral relaxation was higher in diabetic rats than in normal rats. Thus, it is not possible to conclude that the raised intravesical pressure threshold among patients with diabetes may be due to decreased excitability of bladder afferent pathways, which trigger urethral relaxation during voiding.
NO is a noradrenergic, noncholinergic neurotransmitter. It is mainly released from postganglionic parasympathetic neurons responsible for urethral smooth muscle relaxation during reflex micturition by activating cyclic guanosine monophosphate (cGMP). Animal models have demonstrated decreased responses of urethral muscle strips to NO. Cyclic adenosine monophosphate (AMP) and cGMP levels were found to be significantly decreased in rat diabetic tissues from the lower urinary tract. On the contrary, the activity of nicotinamide adenine dinucleotide phosphate diaphorase, a marker of NO synthase activity, has been found to be high among diabetic animals compared with controls, suggesting an increased production of NO in the lower urinary tract in DM. It is likely that decreased urethral smooth muscle relaxation in DM could be caused by low cyclic GMP production in the diabetic bladder neck and urethra rather than decreased NO production. Studies have also demonstrated increased production of superoxide in vascular smooth muscle in patients with diabetes. An interaction between NO and superoxide is very rapid and leads to the inactivation of NO. Hence, there is the absence of NO resulting in decreased urethral smooth muscle relaxation.
Any or all of these factors would be expected to increase outlet resistance, which in addition to diabetic cystopathy would exacerbate voiding dysfunction, creating a vicious cycle of progressive lower urinary tract damage and dysfunction.
| Conclusion|| |
DM is slowly emerging as a major public health challenge worldwide. Although other organ system complications inflicted by poor glycemic control are well understood, DM-induced lower urinary tract dysfunction is poorly defined and understudied. However, clinical and experimental studies have proven beyond any shadow of doubt that long-term hyperglycemic state brings about structural and functional changes both in urinary bladder and urethra, contributing to deterioration of lower urinary tract coordinated function. The clinician and health-care provider should be well aware of these lower tract dysfunctions induced by DM to avoid potential morbidity that could have serious implications on the overall quality of life.
Human and animal rights and informed consent
This article does not contain any studies with human participants or animals performed by any of the authors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311-21.
Mehta SR, Kashyap AS, Das S. Diabetes mellitus in India: The modern scourge. Med J Armed Forces India 2009;65:50-4.
Yu HJ, Lee WC, Liu SP, Tai TY, Wu HP, Chen J. Unrecognized voiding difficulty in female type 2 diabetic patients in the diabetes clinic: A prospective case-control study. Diabetes Care 2004;27:988-9.
Mitsui T, Kakizaki H, Kobayashi S, Morita H, Matsumura K, Koyanagi T. Vesicourethral function in diabetic patients: Association of abnormal nerve conduction velocity with vesicourethral dysfunction. Neurourol Urodyn 1999;18:639-45.
Frimodt-Møller C. Diabetic cystopathy. A review of the urodynamic and clinical features of neurogenic bladder dysfunction in diabetes mellitus. Dan Med Bull 1978;25:49-60.
Lee WC, Wu HP, Tai TY, Liu SP, Chen J, Yu HJ. Effects of diabetes on female voiding behavior. J Urol 2004;172:989-92.
Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol 1995;153:342-4.
Yuan Z, Tang Z, He C, Tang W. Diabetic cystopathy: A review. J Diabetes 2015;7:442-7.
Saito M, Nakamura I, Miyagawa I. Autoradiographic localization of muscarinic receptors in diabetic rat bladder. Nihon Hinyokika Gakkai Zasshi 1997;88:858-67.
Tong YC, Chin WT, Cheng JT. Alterations in urinary bladder M2-muscarinic receptor protein and mRNA in 2-week streptozotocin-induced diabetic rats. Neurosci Lett 1999;277:173-6.
Daneshgari F, Liu G, Imrey PB. Time dependent changes in diabetic cystopathy in rats include compensated and decompensated bladder function. J Urol 2006;176:380-6.
Wu L, Zhang X, Xiao N, Huang Y, Kavran M, Elrashidy RA, et al.
Functional and morphological alterations of the urinary bladder in type 2 diabetic FVB(db/db) mice. J Diabetes Complications 2016;30:778-85.
Kebapci N, Yenilmez A, Efe B, Entok E, Demirustu C. Bladder dysfunction in type 2 diabetic patients. Neurourol Urodyn 2007;26:814-9.
Gray MA, Wang CC, Sacks MS, Yoshimura N, Chancellor MB, Nagatomi J. Time-dependent alterations of select genes in streptozotocin-induced diabetic rat bladder. Urology 2008;71:1214-9.
Beshay E, Carrier S. Oxidative stress plays a role in diabetes-induced bladder dysfunction in a rat model. Urology 2004;64:1062-7.
Changolkar AK, Hypolite JA, Disanto M, Oates PJ, Wein AJ, Chacko S. Diabetes induced decrease in detrusor smooth muscle force is associated with oxidative stress and overactivity of aldose reductase. J Urol 2005;173:309-13.
Nakamura N, Obayashi H, Fujii M, Fukui M, Yoshimori K, Ogata M, et al.
Induction of aldose reductase in cultured human microvascular endothelial cells by advanced glycation end products. Free Radic Biol Med 2000;29:17-25.
Daneshgari F, Liu G, Birder L, Hanna-Mitchell AT, Chacko S. Diabetic bladder dysfunction: Current translational knowledge. J Urol 2009;182:S18-26.
Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 2013;112:393-405.
Li WJ, Oh SJ. Diabetic cystopathy is associated with PARP/JNK/mitochondrial apoptotic pathway-mediated bladder apoptosis. Neurourol Urodyn 2010;29:1332-7.
Kanika ND, Chang J, Tong Y, Tiplitsky S, Lin J, Yohannes E, et al.
Oxidative stress status accompanying diabetic bladder cystopathy results in the activation of protein degradation pathways. BJU Int 2011;107:1676-84.
Juszczak K. Not only diabetic polyneuropathy but also interstitial cells of Cajal dysfunction is a potential mechanism for diabetic cystopathy. Cent European J Urol 2014;67:375-6.
Yohannes E, Chang J, Christ GJ, Davies KP, Chance MR. Proteomics analysis identifies molecular targets related to diabetes mellitus-associated bladder dysfunction. Mol Cell Proteomics 2008;7:1270-85.
Liu G, Daneshgari F. Temporal diabetes- and diuresis-induced remodeling of the urinary bladder in the rat. Am J Physiol Regul Integr Comp Physiol 2006;291:R837-43.
Liu G, Daneshgari F. Alterations in neurogenically mediated contractile responses of urinary bladder in rats with diabetes. Am J Physiol Renal Physiol 2005;288:F1220-6.
Daneshgari F, Huang X, Liu G, Bena J, Saffore L, Powell CT. Temporal differences in bladder dysfunction caused by diabetes, diuresis, and treated diabetes in mice. Am J Physiol Regul Integr Comp Physiol 2006;290:R1728-35.
Fedele D. Therapy insight: Sexual and bladder dysfunction associated with diabetes mellitus. Nat Clin Pract Urol 2005;2:282-90.
Lee WC, Wu HP, Tai TY, Yu HJ, Chiang PH. Investigation of urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in women with type 2 diabetes. J Urol 2009;181:198-203.
Gandhi J, Dagur G, Warren K, Smith NL, Khan SA. Genitourinary complications of diabetes mellitus: An overview of pathogenesis, evaluation, and management. Curr Diabetes Rev 2017;13:498-518.
Tong YC, Cheng JT, Hsu CT. Alterations of M(2)-muscarinic receptor protein and mRNA expression in the urothelium and muscle layer of the streptozotocin-induced diabetic rat urinary bladder. Neurosci Lett 2006;406:216-21.
Golbidi S, Laher I. Bladder dysfunction in diabetes mellitus. Front Pharmacol 2010;1:136.
Yamaguchi C, Sakakibara R, Uchiyama T, Yamamoto T, Ito T, Liu Z, et al.
Overactive bladder in diabetes: A peripheral or central mechanism? Neurourol Urodyn 2007;26:807-13.
Sasaki K, Chancellor MB, Phelan MW, Yokoyama T, Fraser MO, Seki S, et al.
Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia. J Urol 2002;168:1259-64.
Pinna C, Zanardo R, Puglisi L. Prostaglandin-release impairment in the bladder epithelium of streptozotocin-induced diabetic rats. Eur J Pharmacol 2000;388:267-73.
Pitre DA, Ma T, Wallace LJ, Bauer JA. Time-dependent urinary bladder remodeling in the streptozotocin-induced diabetic rat model. Acta Diabetol 2002;39:23-7.
Stapleton A. Urinary tract infections in patients with diabetes. Am J Med 2002;113 Suppl 1A:80S-4S.
Geerlings SE, Meiland R, van Lith EC, Brouwer EC, Gaastra W, Hoepelman AI. Adherence of type 1-fimbriated Escherichia coli
to uroepithelial cells: More in diabetic women than in control subjects. Diabetes Care 2002;25:1405-9.
Tominaga M, Wada M, Masu M. Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci U S A 2001;98:6951-6.
Manning J, Korda A, Benness C, Solomon M. The association of obstructive defecation, lower urinary tract dysfunction and the benign joint hypermobility syndrome: A case-control study. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:128-32.
Apodaca G, Kiss S, Ruiz W, Meyers S, Zeidel M, Birder L. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol 2003;284:F966-76.
Michel MC, Mehlburger L, Schumacher H, Bressel HU, Goepel M. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol 2000;163:1725-9.
Burke JP, Jacobson DJ, Roberts RO, Girman CJ, Lieber MM, Jacobsen SJ. BPH progression and diabetes mellitus in Olmsted county, Minnesota (Poster Abstract). In: Urologic Complications of Diabetes. Bethesda, Maryland: National Institutes of Health; 2003. p. 61.
Engström G, Walker-Engström ML, Lööf L, Leppert J. Prevalence of three lower urinary tract symptoms in men-a population-based study. Fam Pract 2003;20:7-10.
Van Den Eeden SK, Ferrara A, Shan J, Jacobsen SJ, Quinn VP, Haque R, et al.
Impact of type 2 diabetes on lower urinary tract symptoms in men: A cohort study. BMC Urol 2013;13:12.
Liu G, Daneshgari F. Diabetic bladder dysfunction. Chin Med J (Engl) 2014;127:1357-64.
Capon G, Caremel R, de Sèze M, Even A, Fontaine S, Loche CM, et al.
The impact of mellitus diabetes on the lower urinary tract: A review of Neuro-urology Committee of the French Association of Urology. Prog Urol 2016;26:245-53.
Ebbesen MH, Hannestad YS, Midthjell K, Hunskaar S. Diabetes and urinary incontinence − Prevalence data from Norway. Acta Obstet Gynecol Scand 2007;86:1256-62.
Danforth KN, Townsend MK, Curhan GC, Resnick NM, Grodstein F. Type 2 diabetes mellitus and risk of stress, urge and mixed urinary incontinence. J Urol 2009;181:193-7.
Lifford KL, Curhan GC, Hu FB, Barbieri RL, Grodstein F. Type 2 diabetes mellitus and risk of developing urinary incontinence. J Am Geriatr Soc 2005;53:1851-7.
Berger AP, Deibl M, Halpern EJ, Lechleitner M, Bektic J, Horninger W, et al.
Vascular damage induced by type 2 diabetes mellitus as a risk factor for benign prostatic hyperplasia. Diabetologia 2005;48:784-9.
Hammarsten J, Högstedt B, Holthuis N, Mellström D. Components of the metabolic syndrome-risk factors for the development of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 1998;1:157-62.
Hammarsten J, Högstedt B. Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. Eur Urol 2001;39:151-8.
Hammarsten J, Högstedt B. Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia. Blood Press 1999;8:29-36.
Parsons JK, Carter HB, Partin AW, Windham BG, Metter EJ, Ferrucci L, et al.
Metabolic factors associated with benign prostatic hyperplasia. J Clin Endocrinol Metab 2006;91:2562-8.
Boon TA, Van Venrooij GE, Eckhardt MD. Effect of diabetes mellitus on lower urinary tract symptoms and dysfunction in patients with benign prostatic hyperplasia. Curr Urol Rep 2001;2:297-301.
Burke JP, Jacobson DJ, McGree ME, Roberts RO, Girman CJ, Lieber MM, et al.
Diabetes and benign prostatic hyperplasia progression in Olmsted county, Minnesota. Urology 2006;67:22-5.
Rohrmann S, Platz EA, Giovannucci E. Lifestyle and benign prostatic hyperplasia in older men: What do we know? J Mens Health Gender 2005;2:230-5.
McVary KT, Rademaker A, Lloyd GL, Gann P. Autonomic nervous system overactivity in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 2005;174:1327-433.
Sciarra A, Di Silverio F, Salciccia S, Autran Gomez AM, Gentilucci A, Gentile V. Inflammation and chronic prostatic diseases: Evidence for a link? Eur Urol 2007;52:964-72.
Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, et al
. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004;114:1752-61.
Ferreira FT, Daltoe L, Succi G, Cunha F, Ferreira JM, Lorenzetti F, et al
. Relation between glycemic level and lower tract urinary symptoms in elderly. Aging Male 2015;18:34-7.
Torimoto K, Fraser MO, Hirao Y, De Groat WC, Chancellor MB, Yoshimura N. Urethral dysfunction in diabetic rats. J Urol 2004;171:1959-64.
Mumtaz FH, Khan MA, Thompson CS, Morgan RJ, Mikhailidis DP. Nitric oxide in the lower urinary tract: Physiological and pathological implications. BJU Int 2000;85:567-78.
Mumtaz FH, Sullivan ME, Thompson CS, Dashwood MR, Naseem KM, Bruckdorfer KR, et al.
Alterations in the nitric oxide synthase binding sites and non-adrenergic, non-cholinergic mediated smooth muscle relaxation in the diabetic rabbit bladder outlet: Possible relevance to the pathogenesis of diabetic cystopathy. J Urol 1999;162:558-66.
Ischiropoulos H. Biological tyrosine nitration: A pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 1998;356:1-11.