Urologic Complications of Diabetes

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Urologic Complications of Diabetes

Jeanette S. Brown, MD1, Hunter Wessells, MD2, Michael B. Chancellor, MD3, Stuart S. Howards, MD4, Walter E. Stamm, MD2, Ann E. Stapleton, MD2, William D. Steers, MD4, Stephen K. Van Den Eeden, PHD5 and Kevin T. McVary, MD, FACS6

INTRODUCTION

Diabetes and urologic diseases are very common health problems that markedly increase in prevalence and incidence with advancing age (1–3). Diabetes is associated with an earlier onset and increased severity of urologic diseases, resulting in costly and debilitating urologic complications. Urologic complications, including bladder dysfunction, sexual and erectile dysfunction, as well as urinary tract infections (UTIs), have a profound effect on the quality of life of men and women with diabetes. This review presents a comprehensive overview of the current understanding of clinical and basic research on urologic complications of diabetes and recommendations for future directions for research and clinical care.

BLADDER DYSFUNCTION

Over 50% of men and women with diabetes have bladder dysfunction (4,5). Current understanding of bladder dysfunction reflects a progressive condition encompassing a broad spectrum of lower urinary tract symptoms including urinary urgency, frequency, nocturia, and incontinence. Previously, the dysfunction has been classically described as diminished bladder sensation, poor contractility, and increased postvoid residual urine, termed bladder cystopathy (6). However, bladder cystopathy most likely represents end-stage bladder failure with symptoms of infrequent voiding, difficulty initiating voiding, and postvoid fullness and is relatively uncommon.

A number of clinical studies in men and women with diabetes have reported bladder instability or hypersensitivity as the most frequent finding, ranging from 39–61% of subjects (5,7). Diminished bladder contractility or sensation has been found less often (5), and an acontractile bladder appears to be quite uncommon.

Bladder dysfunction in women
In women, urinary incontinence is estimated to affect nearly 50% of middle aged and older women, leading to significant distress, limitations in daily functioning, and poorer quality of life (8,9). Diabetes has been identified as an important independent risk factor for incontinence in several large observational studies, including the Nurses’ Health Study, and is associated with 30–100% increased risk (9–12). This suggests that interventions that prevent or delay onset of diabetes may also prevent urinary incontinence.

The Diabetes Prevention Program (DPP) randomized trial demonstrated that an intensive lifestyle intervention involving weight loss and exercise reduced the incidence of diabetes among women with impaired glucose tolerance (IGT) (13). Prevalence of weekly stress incontinence was also substantially decreased by the DPP intensive lifestyle intervention. Metformin had no effect on incontinence (14). Weight loss, as has been shown in other studies among women without IGT (15), was the most likely mechanism for the effect of the lifestyle intervention on stress incontinence. Differential diabetes incidence among the treatment groups appeared to play almost no mediating role. Importantly, reducing incontinence may be a powerful motivator for women with IGT to choose lifestyle modification to prevent diabetes. The DPP-Outcomes Study, a follow-up study of the DPP cohort, will examine longer-term effects of the intervention on incontinence.

Obesity is a significant and important risk factor for incontinence and type 2 diabetes. The Action for Health in Diabetes (Look AHEAD) is an ongoing randomized trial examining the effects of interventions designed to produce sustained weight loss on cardiovascular events in 5,145 obese and overweight participants ages 45–75 with type 2 diabetes. An ancillary study will evaluate incontinence annually throughout the trial and postintervention follow-up. The Look AHEAD study offers a unique opportunity to determine whether intentional weight loss also decreases incidence or severity of incontinence and the degree to which this may be mediated by effects on diabetes severity. Additionally, oversampling of racial/ethnic groups at elevated risk of diabetes will help to elucidate differential incontinence patterns observed in earlier studies (11).

Recent large observational studies have identified urge incontinence, an involuntary loss of urine with a feeling of urgency, as increased among women with diabetes, while there was no increased risk for stress incontinence, involuntary loss of urine with physical activity (16). Diabetic women treated with insulin are at considerably higher risk of urge incontinence than those treated with oral medications or diet (16). Other aspects of diabetes severity, including glycemic control and microvascular complications resulting in damage to innervation of the bladder, have been suggested as possible mechanisms for increasing incontinence (6). However, most previous studies of incontinence in women with diabetes were conducted in patients attending specialty clinics, did not differentiate between type 1 and type 2 diabetes, and did not adjust for other established incontinence risk factors, including age, parity, and obesity. As a result, little is known about how diabetes may contribute to the incidence or severity of urinary incontinence.

Common treatments for urinary incontinence in women include conservative management (e.g., pelvic muscle training or bladder training), medications, and surgery (17). Because the safety and efficacy of these treatments have not been determined in women with diabetes, conservative management should be the first line of treatment in this population.

Bladder dysfunction in men
In men, lower urinary tract symptoms (LUTS) are common, age-related complaints that are often attributed to benign prostatic hyperplasia (BPH). LUTS and BPH increase rapidly with age starting at about age 50 years (18). Straining, intermittency, postvoid dribbling, and weak stream may signify urethral obstruction from BPH. However, among men with diabetes, similar symptoms may also result from bladder dysfunction due to denervation and poor detrusor contractility. Other complex associations of LUTS and BPH among diabetic men include symptoms of urgency, frequency, and nocturia that may occur from detrusor overactivity, resulting from BPH, and/or microvascular complications associated with diabetes, increasing hyperactivity of the detrusor. The failure to differentiate LUTS from BPH in studies of diabetic men has contributed to the confusing evidence now seen in the literature (19). Other important factors that contribute to this confusion are concerns such as selected or different study populations, low response rates, inadequate control of potential confounders, and small sample sizes in many studies.

The effect of diabetes on the development or presence of LUTS and BPH remains controversial. As noted, this is due in part to a lack of uniformity in the definition of the outcome. Recent evidence suggests that LUTS may occur more frequently among men with diabetes, with an estimated 25% to nearly twofold increased risk of LUTS in men with diabetes (20–23). Additionally, among men with BPH, diabetes is associated with more LUTS symptoms compared with nondiabetic men (23). BPH may or may not be associated with diabetes. Early studies suggested that diabetes increases prostate size consistent with BPH (24). However, studies using surgery for BPH as the outcome have reported conflicting results, with some reporting that diabetic men were at higher risk (25) and others reporting high blood glucose levels to be associated with a lower risk (26). Two more recent cohort studies found conflicting results. In a study of BPH with LUTS or surgery, a nonsignificant increase was reported (27), whereas a large cohort study using cross-sectional data reported a decreased risk of BPH and increased risk of LUTS (22). In a prospective study of BPH progression, diabetes was found to increase the risk of LUTS but was not associated with an increase in prostate volume (28).

While there is clinical overlap between the presence of BPH and LUTS, they can be manifestations of different pathophysiological pathways mediated though hormonal, environmental, genetic, neuropathic, and (micro)vascular influences, particularly in the diabetic patient. A growing body of experimental evidence indicates that diabetes and obstruction affect different populations of visceral afferents supplying the bladder. In both conditions early alterations in sodium and potassium channels occur similar to neuropathic models. These changes trigger altered excitability, leading to detrusor overactivity and urinary frequency. With time, impaired contractility due to a myopathy can lead to incomplete emptying. Thus, a combination of several factors with differing time courses lead to LUTS and known urodynamic findings, making discerning an etiology and distinguishing classic diabetic cystopathy from neural plasticity accompanying obstruction due to BPH problematic.

Many of the difficulties in reconciling the literature are the broad variation in definitions used to define BPH and/or LUTS; often they are used interchangeably. Future studies need to take as much care as possible to delineate each condition and to examine each of the underlying pathways before we are able to better understand how diabetes affects BPH and LUTS. Whether outcomes for treatment of LUTS and/or BPH differ between diabetic and nondiabetic men has not been adequately examined in randomized trials.

Pathophysiology
The biology of diabetes-associated bladder complications can be due to an alternation in the detrusor smooth muscle, neuronal dysfunction, and urothelial dysfunction. The experimental model most often used to assess bladder complications is the streptozotocin (STZ) rat model. Pharmacological studies of smooth muscle dysfunction on isolated diabetic rat bladder strips have generated a considerable amount of controversy. Bladder smooth muscle contraction is mediated by acetylcholine released by the pelvic nerve acting on muscarinic receptors. Responsiveness of diabetic bladder strips to externally applied muscarinic agonists has been reported as increased, decreased, or described as little or no change in responsiveness (29,30). Even when an increased responsiveness is found, the mechanism is unclear. An increase in muscarinic receptor density has been found at both 2 and 8 weeks of STZ-induced diabetes (31). A recent study found an increase in ß1-receptor–mediated relaxation response in isolated detrusor smooth muscle strips from 8- to 10-week STZ-induced diabetic rats (32).

One diabetes-related change that most experts agree on is an increased responsiveness of isolated rat bladder strips to electrical field stimulation (33). Explanations for this change include an increased diabetes-related alteration in membrane lipid composition or increased neurotransmitter release. It has been suggested that changes are related to increased calcium channel activity or enhanced calcium sensitivity (33). Most recently, it has been reported that decreased function was more notable in strips from diabetic rats with enlarged bladders (34). An increased depolarization of myocytes in STZ-induced diabetic rat bladder strips to the application of acetylcholine has been found, indicating enhanced muscarinic sensitivity in the diabetic bladder (35).

Neuronal dysfunction may reflect the deficiency of axonal transport of nerve growth factor (NGF) and play an important role in inducing diabetic neuropathy. It has been recently reported in STZ-induced diabetic rats that decreased NGF levels in the bladder and lumbosacral dorsal root ganglia are associated with bladder dysfunction, suggesting the feasibility of NGF gene therapy for the treatment of diabetic cystopathy (36).

The bladder urothelium is important for the regulation of permeability, transport, and endocytosis across the bladder wall. It has become increasingly clear that the urothelium is not only a passive barrier against urea and ion diffusion, but that it can also function as a sensor, controlling bladder function and dysfunction. The effects of diabetes on urothelial receptors and urothelial signaling mechanisms have not been extensively studied. It has been well established that in the STZ-induced diabetic rat model, there are progressive increases in total bladder tissue with hypertrophy of the bladder wall and dilation of the bladder. Both smooth muscle and urothelium (percentage of total tissue) have been shown to increase significantly in a time-dependent manner. Thus, it has been found that the epithelium from STZ-induced diabetic rat bladders was at least twice as thick and heavy than that from controls (37).

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