Path of translational discovery of urological complications of obesity and diabetes

Abstract

Diabetes mellitus (DM) is a prevalent chronic disease. Type 1 DM (T1DM) is a metabolic disorder that is characterized by hyperglycemia in the context of absolute lack of insulin, whereas type 2 DM (T2DM) is due to insulin resistance-related relative insulin deficiency. In comparison with T1DM, T2DM is more complex. The natural history of T2DM in most patients typically involves a course of obesity to impaired glucose tolerance, to insulin resistance, to hyperinsulinemia, to hyperglycemia, and finally to insulin deficiency. Obesity is a risk factor of T2DM. Diabetes causes some serious microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, angiopathy and stroke. Urological complications of obesity and diabetes (UCOD) affect quality of life, but are not well investigated. The urological complications in T1DM and T2DM are different. In addition, obesity itself affects the lower urinary tract. The aim of this perspective is to review the available data, combined with the experience of our research teams, who have spent a good part of last decade on studies of association between DM and lower urinary tract symptoms (LUTS) with the aim of bringing more focus to the future scientific exploration of UCOD. We focus on the most commonly seen urological complications, urinary incontinence, bladder dysfunction, and LUTS, in obesity and diabetes. Knowledge of these associations will lead to a better understanding of the pathophysiology underlying UCOD and hopefully assist urologists in the clinical management of obese or diabetic patients with LUTS.

diabetes mellitus (DM) and its associated conditions, such as obesity, continue to be significant public health concerns in the US and around the globe and are marked sources of morbidity and mortality in men and women. DM has many well-defined classic complications, including vasculopathy, neuropathy, myopathy, nephropathy, and retinopathy (8, 120). DM is thought to be associated with a number of urological complications, including renal cell carcinoma, upper tract urothelial carcinoma, prostate cancer, bladder cancer, nephrolithiasis, pyelonephritis, chronic renal failure, urinary tract infections, infertility, and erectile dysfunction (7a, 28, 102). In addition, an increasing number of studies indicate that the increased prevalence of lower urinary tract (LUT) dysfunction in both sexes, such as bladder dysfunction, urinary incontinence (UI), and lower urinary tract symptoms (LUTS), is associated with the increased prevalence of obesity and DM (74, 88, 103, 108). In this review, we focus on the most prevalent urological complications in type 1 diabetes, type 2 diabetes, and its associated obesity, UI, bladder dysfunction, and LUTS. These conditions affect life quality and are associated with a substantial economic burden (56).

Obesity and Diabetes

Obesity [body mass index (BMI) >30 kg/m²] is considered to be a major risk factor for chronic diseases, such as hypertension, cardiovascular disease, and type 2 diabetes. Its prevalence is increasing, from 1999–2000 through 2013–2014, an increase in obesity was reported in both adults (from 30.5 to 37.7%) and young population (from 13.9 to 17.2%) in the US, according to the Centers for Disease Control and Prevention (CDC) 2015 National Center for Health Statistics.

The term “diabetes” was first used in 230 BC by the Greek Apollonius of Memphis (90). In 400–500 AD, the Indian physicians Sushruta and Charaka first defined that type 1 diabetes occurs in youths, whereas type 2 diabetes is related to being overweight (90). The term “mellitus” was added after “diabetes” by the Briton John Rollo to distinguish the pathological situation of diabetes insipidus in the late 1700s. In 1921 and 1922, insulin was isolated and purified by Canadians Frederick Banting and Charles Herbert Best (90).

Currently, we know that type 1 DM (T1DM) is a metabolic disorder that is characterized by hyperglycemia in the context of absolute lack of insulin caused by cellular-mediated autoimmune destruction of the pancreatic β-cells, whereas type 2 DM (T2DM) is due to insulin resistance and relative insulin deficiency (7). More than 29 million people in the United States have diabetes, and 86 million of US adults have prediabetic conditions, including metabolic syndrome, according to the CDC National Diabetes Fact Sheet (7). T2DM accounts for ~90-95% of all diagnosed cases of diabetes. Both lifestyle and genetic factors contribute the development of T2DM (94, 95), with the former being under personal control, whereas other factors, such as sex, genetics, and aging, are not. Reviews of the US data from the CDC indicate a significant role for race and sex in diabetes. From 1980 to 2014, the age-adjusted rates of diagnosed diabetes per 100 US civilians increased, with the highest raise, 152% (from 2.5 to 6.3), for white males, 116% (from 2.5 to 5.4) for white females, 136% (from 3.9 to 9.2) for black males, 30% (from 7.6 to 9.9) for black females, and 93% (from 3.0 to 5.8) for Asian males, whereas little changed for Asian females.

In contrast to T1DM, where the links between etiology, pathophysiology, and clinical signs and symptoms are straightforward, these links in T2DM are more complicated. The natural history and phenotypes of T2DM in most patients typically involve a course of obesity to impaired glucose tolerance, to prediabetes, to insulin resistance, to hyperinsulinemia, to hyperglycemia, metabolic syndrome, and finally insulin deficiency and insulin dependence. Depending on the stage in which the patient is, signs and symptoms and associated complications vary. Modeling after such an evolving phenotype is, therefore, increasingly challenging. The research approach to studies of T2DM and LUTS has to be carefully crafted, with identification of “upstream” or senior issues that would allow a more clear understanding of the “downstream” or junior findings and biological events.

Urological Complications of Obesity and Diabetes

Factors impacting on the LUT in DM include some or all the following: 1) hyperglycemia, 2) polyuria, 3) obesity/metabolic syndrome, 4) role of sex and sex hormones, and 5) cross talk between various elements of the neurogenic and myogenic system. Obesity-induced inflammatory response, alterations of sex hormones, and mechanical mechanisms affect LUT. Some biological influencers are shared between DM and its associated phenotypes (obesity, metabolic syndrome, prediabetes). Herein, we introduce the term urological complications of obesity and diabetes (UCOD) to allow the setup of a scientific framework that would encourage investigation of the connections between common biological factors determining the role of DM on the LUT. We focus on the most commonly seen urological complications: UI, bladder dysfunction, and LUTS.

According to International Continence Society definitions, LUTS can be divided into storage, voiding, and postmicturition symptoms (1). The common storage symptoms include increased daytime frequency, nocturia of at least one episode/night, urgency, and UI. Voiding symptoms include slow or intermittent stream during micturition, splitting or spraying of the urine stream, straining, hesitation, and terminal dribble. Feeling of incomplete emptying and postmicturition dribble are the common postmicturition symptoms. UI is the complaint of any involuntary leakage of urine. The bladder dysfunction includes overactive bladder (OAB) and underactive bladder. The symptom of OAB is urgency, with or without urge incontinence, usually with frequency and nocturia. The underactive bladder refers to inability to completely empty the bladder (2). DM and obesity could affect the bladder, prostate, and urethra, and cause bladder dysfunction, UI, or other LUTS.

UCOD are among the most common benign urological diseases affecting both men and women across all ages in the United States (117). Collectively, it is estimated that UCOD, including spectrum of UI and LUTS, could affect up to 87% of patients diagnosed with DM (12, 51). Numerous reports indicate that women with obesity/T2DM are at a much higher risk of developing UI (15, 17, 32, 35, 61, 63, 77, 88, 111). Although few studies have specifically distinguished between types of UI (mixed, urge, or stress), evidence suggests that obesity/T2DM are significant risk factors for all three types of UI (14–16). It has long been known that LUTS is highly prevalent in aging men, with estimates ranging from 25% in men 40–49 yr old to >80% in men 70–79 yr old. Recent reports provide strong support for an association between obesity/T2DM and benign prostatic hyperplasia (BPH) and LUTS (30, 78, 79, 121).

Burden of urological complications of diabetes.

The impact of both types of DM on the LUT has long been recognized. Traditionally, commonly known complications of DM have included LUTS, sexual dysfunction, and urinary tract infection. Compared with other recognized complications, such as retinopathy, cardiovascular, renal, micro- and macrovascular complications, and neuropathy (which could lead to devastating results, such as blindness, heart attacks, renal failure, and infections of the lower extremities, leading to amputations), urological complications occupied a lower rank of priority in research and funding attention, despite the fact that the data indicated urological complications to be among the more common complications of DM. However, with the rapid rise of DM, and the high prevalence of urological complications (up to 87% in some reports), studies of these complications have risen to a higher rank of priority.

UI and its subtypes, such as OAB, with or without urge UI, stress and mixed UI, and LUTS resulting from prostatic enlargement in men (30, 78, 79, 121), are among the leading LUT disorders affecting patients with obesity and DM.

T1DM and UCOD

Impact of T1DM on the bladder.

Over the past few years, we and others have been able to unmask the seemingly complex nature of the impact of T1DM on LUT. Several lines of studies in animal models have demonstrated that the impact of T1DM correlates with the duration and severity of hyperglycemia. Diabetic bladders may undergo a transition from a compensated to a decompensated state. In the early stage, the hyperglycemic-induced polyuria functions as the key mechanism to lead the remodeling of the bladder, whereas, in the late stage and with continuation of hyperglycemia and its downstream effects, such as oxidative stress, the bladder decompensates, with decreased micturition pressure and increased residual urine. Our laboratory has published evidence for time-dependent alterations in functionality (26, 27), morphometry (69), contractility (27, 68), molecules, nerves, and vasculature (70) of the bladder in response to T1DM. Our data revealed a striking temporal change in the bladder from a compensated to a decompensated state (27). Our data indicate that 1) DM causes increases in bladder weight and size of the wall and lumen area, showing marked hypertrophy and dilation (69); and 2) nerve and blood vessel density in bladder wall are decreased at 20 wk after diabetes induction (70). In addition, we have shown that DM impacts the highly differentiated epithelial lining of the urinary bladder, the urothelium (UT) (45), which functions not only as a vital urine-blood barrier, but also as a sensory tissue playing a role in bladder function (29).

In a chronic study (3, 9, and 20 wk after DM induction) using the rat model of streptozotocin (STZ)-induced DM, there was evidence that chronic hyperglycemia, glycosuria, and polyuria impacted UT homeostasis, causing a temporal breach in barrier function (evidenced by desquamation of the highly differentiated surface umbrella cells at 9 wk), and, in addition, a change in UT phenotype (evidenced by alterations in the gene expression of some receptors involved in UT signaling and mechanosensation) (45).

The pathogenesis of bladder dysfunction in T1DM is complicated. Unlike other organs, the bladder in diabetes faces not only hyperglycemia, but also an increased production of urine. To investigate the separate role of polyuria and hyperglycemia on bladder in diabetes, we have developed urinary diversion model in rats and characterized its effects on the bladder in nondiabetic conditions (71). Induction of DM in urinary diversion rats allows us to examine the independent role of hyperglycemia (127). Our findings suggest that polyuria causes significant bladder hypertrophy, whereas chronic hyperglycemia-related oxidative stress may play an important role in the failure of bladder function seen in the late stage of DM (127).

Impact of T1DM on the urethra.

The micturition cycle has two components: a bladder filling/storage phase and a urine voiding phase. During the storage phase, the urethra is actively closed by sympathetic α-adrenergic-induced urethral circular smooth muscle contraction and somatic cholinergic contraction of the external urethral sphincter (EUS) muscle (22, 76). In normal healthy bladders, the voiding phase depends upon synergism between the smooth muscle of the bladder and urethra: the former contracts to empty urine from the bladder, while the latter relaxes to allow urine outflow. Thus, in the voiding phase, the somatic excitatory input to the EUS is inhibited, and the autonomic drive to urethral smooth muscle is reversed with parasympathetic nitric oxide (NO)-induced relaxation of urethral circular smooth muscle, accompanied by the inhibition of sympathetic input (22, 76). Several studies have shown that DM causes urethropathy, leading to increased outlet resistance impacting bladder voiding (22, 72, 115, 129). Diabetes can cause EUS dysfunction as a consequence of impaired urethral smooth muscle relaxation and the responsiveness to NO, with increased responsiveness to α₁-adrenergic agonists (129). In a study using the STZ-DM rat model, ~30% of diabetic rats showed detrusor-sphincter dyssynergia, which was not evidenced in control animals (129). These changes can increase outlet resistance, leading to bladder remodeling and accommodation of larger postvoid residual volume (which can ultimately lead to urine reflux and damage to the upper urinary tract), thereby exacerbating the impact of impaired bladder contractility in diabetic bladder dysfunction (DBD) (129). Recent studies also found a significant increase in urethral pressure during micturition in alloxan-induced female diabetic rats (42, 86). Chen et al. (20) suggested the increase in the expression of α₁-adrenoceptor and the impairment of the nerve growth factor (NGF) pathway in the urethras may be involved in diabetic urethral dysfunction. However, another study showed that increased resistance of the urethral outlet in diabetic animals may not be due to the impairment of nitrergic relaxation and increased sensitivity to adrenergic activation, but to the disruption of neural signaling between the urethra and the central nervous system, either at the level of the spinal cord or in higher centers within the brain (5). On the other hand, Marini et al. (73) found that long-term mild diabetes causes urethral fibrosis and ultrastructural alterations, whereas short-term severe diabetes causes muscle atrophy. The striated fast-twitch type II muscle fibers from both short-term severe diabetes and long-term mild diabetes models decreased, while slow-twitch type I muscle fibers increased. These changes of urethral stiffness, decreased elasticity, and the transition of fiber types may play a role in impairment of the urethral closing.

Impact of T1DM on the prostate.

A number of studies report that induction of diabetes caused a significant reduction in serum testosterone levels and in prostatic weight in rats (19, 54). The lobe response to diabetes varied (92). After 1 wk, diabetes led to an atrophy of ~35% in the ventral prostate and an increase in collagen (41). The mechanisms of diabetes-induced regression of the prostate are not clear. Suthagar et al. (110) found that glucose oxidation and androgen and estrogen receptor levels were decreased in the ventral prostate in STZ-induced diabetic rats, suggesting that insulin is essential for maintaining the function of prostate. Studies have showed that transforming growth factors-β₁ and -β₂ (54), potent inhibitors of cell growth, and endothelin receptors (99) were upregulated, whereas fibroblast growth factor-2 was downregulated (124) in the prostate of the rat with diabetes. Insulin treatment can normalize the altered prostatic weights and serum testosterone levels and molecular changes. These results suggest that the above molecular changes may be involved in the diabetes-induced prostate regression (54, 99, 124), which may affect male sexual response.

Obesity/T2DM and UCOD

Clinical studies on UI in obesity and T2DM.

In both case series and population studies, it has been shown that obesity/DM is increasingly associated with urge and stress incontinence. Although some of the reports stop short of differentiating between the types of DM (types 1 and 2) and types of UI (urge, stress, mixed, or overflow), overall the literature is unequivocal in demonstrating that 1) T2DM is by far the most common type of DM and is increasing in incidence (46, 77, 103, 108); and 2) obesity, higher BMI, and DM are independent risk factors beyond all others for manifestation of UI clinical phenotypes among women (15, 17, 32, 35, 61, 63, 77, 88, 111). Table 1 summarizes the findings of the major recent clinical and epidemiological studies on the phenotypes of UI seen in women with obesity, with or without T2DM. These studies are unanimous in indicating that obesity and T2DM are risk factors for development of UI.

Table 1.

Summary of the findings of the major recent clinical and epidemiological studies

Study	Case No.	Characteristics	UI Findings
HERS (15)	2,763	44–79 yr old (mean ± SD 67 ± 7)	Weekly UUI prevalence risk factors: higher age (OR 1.2/5 yr, 95% CI 1.1, 1.3); DM (OR 1.5, 95% CI 1.1, 2.0); ≥2 urinary tract infections in the prior year (OR 2.0, 95% CI 1.1, 3.6).
			Weekly SUI prevalence risk factors: higher BMI (OR 1.1/5 units, 95% CI 1.0, 1.3); higher waist-to-hip ratio (OR 1.2/0.1 unit, 95% CI 1.0, 1.4).
Look AHEAD (baseline) (88)	2,994	45–74 yr old with BMI >25 kg/m2 and T2DM	Weekly incontinence (27%) was greater than other DM-associated complications.
			BMI >35 kg/m2 had higher odds of overall UI & SUI (55–85% higher; P < 0.03) than nonobese.
			Risk factor for UI, SUI, & UUI was urinary tract infection in the prior year (55–90% more risk; <0.001).
Look AHEAD (87)	2,739 of 2,994	45–76 yr old with BMI >36.5 kg/m2; randomized into intensive weight loss intervention, or DM support and education	After 1 yr, less UI in weight loss group than in DM support group (25.3 vs. 28.6%, P < 0.05).
			Each kg of weight lost was associated with 3% reduction in odds of UI developing (P < 0.01), and weight losses of 5–10% reduced these odds by 47% (P < 0.002).
PRIDE (109)	338	Overweight & obese; minimum 10 UI episodes/wk: intensive 6-mo weight loss or structured education program	Intervention group had greater decrease in frequency of SUI (P = 0.02), but not of UUI (P = 0.14).
			A higher proportion of the intervention group had a clinically relevant reduction of ≥70% in the frequency of all UI episodes (P < 0.001), SUI episodes (P = 0.009), and UUI episodes (P = 0.04).
KP CARES (63)	3,962	25–84 yr old; 10% with T2DM	Obese/diabetic: highest likelihood of SUI (OR 3.67, 95% CI 2.48, 5.43).
			Obese, obese/diabetic, and obese/nondiabetic: same OAB likelihood [2.97 (2.08–4.36)] & [2.93 (2.33–3.68)].
			Nonobese/diabetic vs. nonobese nondiabetic: increased odds of SUI [1.90 (1.15–3.11)], but not OAB [1.45 (0.88–2.38)].
Bariatric surgery (62)	201	Consecutive candidates for bariatric surgery	65 Patients (32%) reported UI.
			Surgically induced weight loss improved or resolved UI in 82% of patients.
NHS (31)	36,843	54–79 yr old	Strongest risk factors for UI: higher BMI [OR 3.14 (2.95–3.33)] or age [OR 2.75 (2.54–2.98)].

NHS, Nurses’ Health Study; UUI, urge urinary incontinence; SUI, stress urinary incontinence; OR, odds ratio; CI, confidence interval.

Clinical studies on OAB in T2DM.

OAB is related to a disturbance of the filling/storage phase of the micturition cycle and can significantly impact on quality of life. Lawrence et al. (63) demonstrated that, in 3,962 female patients, 21.4% of diabetic women have OAB compared with only 12.5% of nondiabetic women. Another study showed that mean OAB questionnaire scores were significantly higher in the T2DM patients compared with the healthy subjects. OAB was diagnosed in 35.7% of the DM group and 4.8% of the healthy subjects based on the OAB questionnaire and voiding diaries (85). Increased HbA1c levels were contributed to the increased risk of OAB symptoms (21). In a prospective study based on urodynamic and bladder sensory function assessments, including a total of 86 T2DM women, Lee et al. (64) found 14% patients presented signs of detrusor overactivity and 12.8% had bladder outlet obstruction. In another study, Ho et al. (53) found that, among the 94 diabetic women, 36.2% were diagnosed as OAB based on urodynamic tests. Increased bladder sensation is the most frequent urodynamic finding of OAB, followed by detrusor overactivity. These studies indicated the possible connection between OAB and DM. However, the pathogenesis is not clear.

Animal studies on bladder dysfunction in obesity.

Leiria et al. (65–67) fed 4-wk-old male C57BL6/J mice with a high-fat diet (HFD, 29% carbohydrate, 16% protein, and 55% fat) for 10–12 wk to induce obesity. They found the mice fed with HFD exhibited higher body weight, epididymal fat mass, and insulin resistance. Cystometry measurement showed symptoms of OAB, such as: increased frequency and nonvoid contractions in obese mice. The mechanisms of functional changes may involve the upregulation of protein kinase C, thus enhancing the contractile response in obese mice (67). Impaired bladder relaxation in obese mice may be associated with insulin resistance via affecting the activation of the phosphatidylinositol 3-kinase/Akt/endothelial NO synthase pathway (66), or inducing reactive oxygen species (ROS) generation and downregulation of soluble guanylate cyclase-cyclic guanosine monophosphate signaling (6, 65), whereas Aizawa et al. (3) found the bladder function was not affected in HFD-feeding male C57BL/6J mice for 20 wk, even though it induced diabetes, hyperlipidemia, and tachycardia. The different results may be due to the different diets used in two studies. Recently, our laboratory examined the bladder function in male obese B6.V-Lepob/J mice (48). We found B6.V-Lepob/J mice presented higher levels of total cholesterol (CHO) and free fatty acid, which correlated with frequency, lower average urine volume, and other urinary voiding dysfunctions, suggesting obesity contributes to LUTS.

Animal studies on bladder dysfunction in T2DM.

As T1DM represents a plausibly simpler manifestation of insulin deficiency related to destruction of β-cells of the pancreas, T2DM presents a very challenging manifestation in humans, which has to be the goal for creation of translational animal models of T2DM incorporating a mixture of insulin resistance to insulin deficiency, with or without phenotypes of obesity, metabolic syndrome, and prediabetes. Thus the complexities related to the T2DM phenotype and its natural history creates a challenge in the creation of animal models that could fully represent the full spectrum of T2DM seen in humans. Therefore, it is not surprising to see that a plethora of animal models of T2DM have been used by investigators. These models could be divided into categories of genetic models or diet-induced models. The genetic models have included monogenetic and polygenetic models, including 1) insulin receptor hepatic-specific insulin receptor substrate 1 and 2 deletions [double knockout (DKO)] (33, 123); 2) leptin knockout ob/ob mice (34, 48); 3) leptin receptor knockout db/db mice (23, 126); 4) TallyHo mice (60, 114); 5) spontaneous mutation of the leptin receptor gene (fa gene) (89, 116); 6) Zucker fatty fa/fa rats (24, 25); and 7) spontaneous nonobese Goto-Kakizaki (GK) rats (91). In addition, the diet-induced obesity (47, 96) model has been widely used. In the majority of these studies, however, the role or even description of the sex is ignored.

Wang et al. (123) found bladders of hepatic-specific insulin receptor substrate 1 and 2 deletions (DKO) mice exhibited detrusor overactivity at an early stage (12 wk old), including increased frequency of nonvoiding contractions, decreased voided volume during cytometric test, and dispersed urine spot patterns in spontaneous micturition pattern measurement, but detrusor hypoactivity in older animals (20-wk-old). Tumor necrosis factor (TNF) and Rho kinase were upregulated in DKO mice bladders. Systemic treatment of DKO animals with soluble TNF receptor 1 did not affect the level of blood glucose, but prevented upregulation of Rho kinase and partially reversed the bladder dysfunction (123). Kendig et al. (57) observed the voiding behavior in male Zucker diabetic fatty (ZDF) rats, a T2DM model. They found ZDF rats presented decreased void volume, but increased number of voids over the 6-h period compared with control rats at 16 wk of age, whereas, at 27 wk of age, both void volume and number of voids increased significantly in ZDF rats compared with control rats. These data suggested increased bladder sensation at 16 wk of age, but not 27 wk of age. For the temporal functional change in an obese/T2DM model, FVB^db/db mice were examined recently (126). The blood glucose and HbA1c levels were significantly higher in FVB^db/db mice compared with controls at 12 and 24 wk, but not at 52 wk. This is probably due to an compensated expansion of β-cell number in response to excessive food intake (23). Bladder capacity, voided volume, and peak micturition pressure increased in cystometry measurement in FVB^db/db mice compared with control FVB/NJ mice. Most interestingly, some FVB^db/db mice, especially males at 12 and 24 wk, presented small-volume voiding pattern during 24-h urination behavior measurement and detrusor overactivity in the cystometry test. This study demonstrated that the FVB^db/db mice display not only classical symptoms, including increased bladder capacity, void volume, and micturition pressure, but also detrusor overactivity. The GK rat is an animal model of spontaneous T2DM (91), despite the fact that this diabetic rat is nonobese. Bladder function in GK rats did not change obviously at 12 wk of age (98). However, the rats displayed detrusor overactivity with increased frequency/amplitude of nonvoiding contractions in cystometry measurement at 18 wk old (83), bladder underactivity at 46 wk old (4), and an increased residual volume at 70 wk old (98). Male ZDF rats (30–42 wk old) showed symptoms of detrusor underactivity, including increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate (112). A previous study showed that DM decreased the activity of Aδ- and C-fiber bladder afferent pathways, in association with decreased NGF production in the bladder and decreased transport of NGF to bladder afferent pathways (101), which may be one of the reasons for bladder underactivity.

Impact of obesity and T2DM on the urethra.

A previous study examined the urethra function in female obese ZDF rats without diabetes (fed a low-fat diet) or obese ZDF rats with diabetes (fed a HFD) compared with Zucker lean rats (39). Leak-point pressure (LPP) refers to the bladder pressure at which the urine leaks from the urethra in the absence of a bladder contraction. LPP is generally used to evaluate continence function of the urethra and to determine the etiology of urine leakage (58). They found that LPP in both obese groups was lower than that in control rats, but the difference was not statistically significant. Histological examination revealed fibrosis and edema of the periurethral muscularis in both obese groups. The collagen infiltration may lead to disruption of the striated muscular structures (39). This study demonstrates that obesity affect the structure of the urethra. In male obese C57BL/6 mice induced by feeding with a HFD for 12 wk, impaired urethral smooth muscle relaxation was observed and correlated with ROS generation and downregulation of soluble guanylate cyclase-cyclic guanosine monophosphate signaling (6). Therefore, the conclusions are not consistent in different studies. More studies are needed to illustrate the changes and the underlined mechanisms.

Impact of obesity on the prostate.

Clinical research has shown that the prostates of obese men are larger than the prostates of normal-weight men (43, 44, 49, 84, 128). Recent studies determined a relationship between obesity and LUTS (44, 84). Transrectal ultrasound-guided prostate biopsy was performed in a total of 211 patients (131). The authors found the mean prostate volume was 30, 50, and 70 ml, in the normal, overweight, and obese groups, and the mean International Prostate Symptom Score (IPSS, used to screen for BPH) was 8.0, 16.5, and 20.0, respectively. There is a significant positive correlation between BMI and prostate volume, and BMI and IPSS (131). A study carried out with 465 men in a health promotion center reported a positive correlation between prostate volume and central obesity based on waist circumference and BMI, not based on overall obesity (59). Another study investigated the men who had undergone a radical prostatectomy and showed that there was a positive relationship between BMI and prostate volume in the patients under the age of 63 yr (38). Ochial et al. (82) performed ultrasound-guided extended prostate biopsy in 653 men and found a direct correlation between BMI and prostate volume. In an animal study, Vaněčková et al. (118) found the size of the prostate in HFD-feeding rats increased and presented increased cellular proliferation and enhanced α-adrenoceptor mediated contraction. However, the pathogenesis of obesity-related prostate enlargement is not clear. Studies have showed that hyperinsulinemia can stimulate the sympathetic nervous system (10, 118), causing bladder outlet obstruction and LUTS, suggesting that hyperinsulinemia might be one of the mechanisms (36, 105, 119). In addition, chronic, low-level inflammation might be another mechanism (50, 106). Weisberg et al. (125) found obesity induces adipose cell enlargement and chemokine release, attracting macrophage infiltration of adipose tissue. Obese adipose tissue can release adipokines, such as adiponectin, leptin, resistin, visfatin, chemerin, TNF-α, interleukin (IL)-1, IL-6, IL-8, IL-10, plasminogen activator inhibitor 1, monocyte chemoattractant protein-1, and retinol binding protein-4 (18, 75, 80). The prostate from the patients with BPH/LUTS contain ~70% T lymphocytes, 15% B cells, and 15% macrophages, as well as a smaller subpopulation of mast cells (107, 113). It looks like the proinflammatory microenvironment contributes to BPH stromal hyperproliferation and tissue remodeling (13, 37).

Impact of T2DM on the prostate.

The studies on the impact of T2DM on the prostate are not consistent. Multiple studies have indicated T2DM is an independent risk factor for increased LUTS (9). A case-control study of T2DM patients compared with non-T2DM controls showed that T2DM is a risk factor for worse IPSS and OAB symptom scores (9). However, Sarma et al. (100) examined whether diabetes correlated with clinical markers of BPH in white and black men aged 40–79 yr. They did not find strong evidence for an association between diabetes and BPH across measures (i.e., prostate volume, prostate-specific antigen, and peak urinary flow rate). On the other hand, Hammarsten et al. (44) found that men with non-insulin-dependent DM, treated hypertension, obesity, low high-density lipoprotein-CHO levels, and high insulin levels had a larger prostate gland than the men without those conditions. The systolic blood pressure, obesity, and fasting insulin positively, but high-density lipoprotein-CHO negatively, correlated with the prostate gland volume (44). These studies suggested the enlarged prostate in T2DM could be due to the concurrent obesity and hyperinsulinemia (81), not hyperglycemia itself. A recent study demonstrated obesity/T2DM induced by HFD feeding in mice developed voiding dysfunction, which was associated with chronic inflammation-related prostate fibrosis (40), suggesting inflammation is an important pathogenesis.

Holistic Approach Explores the Potential Mechanisms of UCOD

The treatments of the UCOD are limited, since the pathogenic mechanisms are not very clear. Recently, several groups have examined the molecular changes of the bladder (52, 55, 114, 122, 132) and prostate (130) in DM and prostate (93, 104) in HFD-induced obesity using holistic approaches. The results from these studies have the potential to provide mechanistic insight into the development of UCOD.

Gene ontology analysis of detrusor muscle in rats 1 wk after DM induction showed significant increases in biological pathways involved in cell proliferation, metabolism, and contractile components, including myosin, myosin regulatory and binding proteins, tropomyosin, myosin regulatory light chain, calmodulin 3, and calreticulin (52). Using two-dimensional gel techniques, Yohannes et al. (132) identified that proteins that are involved in cell adhesion, cell shape control, and motility, such as vinculin, intermediate filaments, Ppp2r1a, and extracellular matrix proteins, were downregulated in rat detrusor muscle 2 mo after DM induction, whereas some proteins involved in muscle contraction, glycolysis, mRNA processing, inflammatory response, and chromosome segregation and migration were upregulated (132). The above two studies indicated DM causes the structural and molecular responses in the bladder in the early stage, which may help the bladder adapt to the increased urine production. Recently, metabolomic analysis was performed on detrusor and urothelial tissue in 1-mo-old diabetic and control rats (122). The results showed that DM caused the altered levels of glucose, lactate, 2-hydroxybutyrate, branched-chain amino acid degradation products, 1,5-anhydroglucitol, and markers of oxidative stress in both tissues. In addition, they found DM caused activation of the pentose-phosphate and polyol pathways, along with a reduction in the tricarboxylic acid cycle and β-oxidation in the detrusor muscle tissue. These changes can cause the accumulation of sorbitol and advanced glycation end products, which are likely to contribute to the development of DBD. In the diabetic urothelial layer, there was decreased flux of glucose and changes in lipid metabolism, which may affect the sensory function. In another study, microarray analysis of the detrusor smooth muscle tissue in STZ-induced diabetes was performed (55). The results showed the significant changes of the proteins regulating ROS, protein degradation, and apoptosis, suggesting oxidative stress and apoptosis are involved in the DBD.

In addition to the above studies in T1DM, our laboratory recently used a shotgun proteomics approach to identify proteins differentially expressed between type 2 diabetic (male TallyHo aged 21–26 wk) and age-matched control (SWR/J) mice in the detrusor muscle and UT, separately (114). We found diabetes-induced increased tissue remodeling-type events, such as actin cytoskeleton signaling and signaling by Rho family GTPases in the detrusor muscle samples, whereas the diabetic UT samples exhibited oxidative stress responses, as seen in the suppression of protein expression for key players in the nuclear factor erythroid 2-related factor 2-mediated oxidative stress response pathway. These results suggested that diabetes-induced elevated oxidative stress and tissue remodeling are involved in the development of DBD. The network analysis indicated that the ERK1/2 signaling might be a key regulatory node in the pathophysiological process.

The molecular impact of DM on prostate gland has been examined using a whole genome cDNA microarray analysis (130). The gene expression, particularly that related to cell proliferation and differentiation, oxidative stress, DNA damage repair, cell cycle checkpoints, angiogenesis, and apoptosis, changed significantly in prostate in STZ-induced diabetic rats. Oxidative stress and defects of anti-oxidant DNA damage repair in the prostate may increase the risk of prostate cancer.

Previous studies have suggested that a HFD is a risk factor of BPH and prostate cancer (50, 106). Reyes et al. (93) analyzed the alterations in gene expression in the dorsolateral prostates of ACI rats fed with a high-beef-fat diet for 18 mo. They found the HFD affected the expression of genes involved in inflammation, glucose and fatty acid metabolism, androgen metabolism, potential tumor suppression, and protein kinase activity, as well as intracellular and extracellular matrix molecules, growth factors, and androgen responsive genes. The changes may favor the prostate hyperplasia and the transition to cancer. Recently, microarray analyses were performed to examine the effect of 12-wk HFD feeding on the gene expression in mouse ventral prostate and dorsolateral prostate (104). Pathways analysis revealed that oxidative stress, glutathione metabolism, nuclear factor erythroid 2-related factor-mediated oxidative stress response, and NF-κB were all differentially regulated by the HFD. These results suggested inflammation and oxidative stress may play important roles in HFD-related changes of prostate.

Conclusions

T1DM, obesity, and T2DM have significant yet different impacts on the physiology of the bladder, urethra, and prostate; however, all impact the LUT. The holistic approach helps to reveal the potential molecular mechanisms of the development of UCOD. As most studies focus on STZ-induced T1DM due to the animal models that are easy to produce, it is vital that more translational studies be conducted on the effects of obesity and T2DM on bladder, urethra, and prostate physiology. To reach this goal, the appropriate animal model is important. In addition, the role of sex in UCOD needs to be emphasized due to the following reasons:1) effects of prostate on men; 2) differences in urethral anatomy and physiology between men and women and impact of that on UI; 3) differences in patterns of obesity in association with T2DM among men and women; and 4) the variation in sex hormones and their impact on LUT organs.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

F.D. and G.L. conceived and designed research; F.D. and G.L. drafted manuscript; F.D., G.L., and A.T.H.-M. edited and revised manuscript; F.D., G.L., and A.T.H.-M. approved final version of manuscript.