| Summary: | 博士 === 中原大學 === 醫學工程研究所 === 98 === Background and Hypothesis
Diabetes Mellitus and diabetic bladder dysfunction are very common health problems that markedly increase in prevalence and incidence with advancing age around the world. Over 50% of patients with diabetes exhibiting bladder dysfunction characterized by large bladder capacity, diminished bladder sensation or detrusor overactivity, poor contractility and elevated post-residual urine. Diabetic bladder dysfunction might be induced by the diabetic neuropathy and/or diuresis associated with diabetes. However, the effect of diabetes and diuresis at the tissue and organ levels on specific functional and mechanical changes in the bladder remains uncharacterized. The time-course changes of the tissue compositions, important determinants of mechanical properties, and associated regulated genes of diabetic bladders have not been fully understood. Thus, to achieve a better understanding of the pathophysiology of diabetic cystopathy, it is necessary to elucidate the biomechanical changes that underlie the progression of diabetic cystopathy. In addition, although clinically diabetes was associated with increased severity of lower urinary tract symptoms in elderly men with benign prostate hyperplasia, the mean age of the diabetic patients was over 50 years old and the patients often had multiple medical confounding problems in these studies. The main interest of the present study arises from our clinical observation that urologists often manage patients with advanced stage diabetic cystopathy referred from other physicians. Thus to reduce or prevent the complication of late diabetic cystopathy, it is important to identify lower urinary tract dysfunction and its associated factors in the early stage of diabetes.
First, we hypothesize that the changes in the mechanical properties of the bladder wall are an important indicator of the bladder dysfunction induced by diabetes. Second, we hypothesize that physiologic changes associated with diabetes trigger alternation of select gene and extracellular matrix protein in the urinary bladder. Finally, we hypothesize that diabetes and metabolic syndrome are associated with lower urinary tract symptoms, lower urinary tract function and erectile dysfunction in the early stage of diabetes.
Materials and Methods
In animal study, female Sprague-Dawley rats were injected with streptozotocin (65mg/kg intraperitoneally). Rats were fed with 5% sucrose served as diuretic controls, in addition to normal control rats. Cystometry was performed at the end of 2, 4, and 8 weeks. At each point, the biaxial mechanical properties of 10 x 10 mm tissue specimens obtained from the posterior part of bladder wall were quantified. The changes in overall tissue compliance and mechanical anisotropy as a function of time were examined. Total ribonucleic acid (RNA) isolated from the detrusor layer of the bladders was reverse transcribed, and then complementary deoxyribonucleic acid was amplified with polymerase chain reaction primer sets for type I collagen, type III collagen, tropoelastin, and transforming growth factor beta 1 (TGF-beta-1). Collagen and elastin contents of the bladders were quantified with commercial available assays. A novel semi-automated image analysis method was developed to quantify smooth muscle bundle orientation and mass fraction in the bladder wall tissues.
In clinical study, lower urinary tract symptoms, voiding and erectile function in 226 men aged less than 45 years with type 2 diabetes at a single diabetes clinic and 183 healthy men with normal fasting blood glucose were compared. Subjects were evaluated using the International Prostate Symptom Score questionnaire (IPSS), five-item version of the International Index of Erectile Function questionnaire (IIEF-5), flow rate and post-void residual urine measurement. The association of metabolic syndrome with lower urinary tract symptoms and erectile dysfunction was also evaluated.
Results
In our streptozotocin induced diabetic and sucrose fed diuretic rat models, diuresis alone may explain many of early diabetic effects, including bladder hypertrophy, increase bladder compliance and elevated bladder capacity. Using biaxial mechanical test, we demonstrated that both diabetic and diuretic rat bladder exhibited non-linear stress-strain relationship and mechanical anisotropy, with a greater compliance in the circumferential direction than in the longitudinal direction. The alternations in the mechanical behavior may be a manifestation of morphological adaptation of the bladder from prolate to oblate spheroid to achieve greater compliance.
The changes of biomechanical properties were further confirmed by the methods of molecular biology, biochemical assay and quantitative image analysis. The bladder tissue remodeling was associated with downregulation of transformation growth factor beta 1 and collagen mRNA levels. The increase of the bladder compliance observed in diabetic cystopathy resulted from both diuresis-driven reduction of collagen synthesis and increased elastin synthesis. Semi-automatic image analysis of histological section of rat bladder tissue showed there were significant increase in smooth muscle and decrease in collagen area fractions in the diabetic and diuretic groups compared to normal control. In addition, the diuretic and diabetic bladders exhibited smooth muscles oriented in both circumferential and longitudinal directions, but the normal bladder exhibited predominant smooth muscle orientation only in the longitudinal direction. All these studies provided the evidence about the link between the tissue microstructure and time-dependent alternations of mechanical properties of the bladder.
In clinical studies, the mean age was 38.9 ± 6.1 years (range 20-45) and the mean duration of diabetes was 2.8 ± 3.1 years (range 0.5-20). Compared with controls, men with diabetes had a significantly higher IPSS score (6.1± 5.8 vs 4.1 ± 4.6, p<0.001), an increased of odds ratio of having moderate to severe LUTS (OR=1.78, 95% CI 1.12, 2.84, p=0.01), greater voiding volume (376 ± 177 vs 326 ± 102, p=0.04), worse IIEF-5 score (17.3 ± 6.4 vs 20.0 ± 3.8, p<0.001), an increased of odds ratio of having moderate to severe ED (OR=3.5, 95% CI 2.1, 5.8, p<0.001) but similar maximal flow rate (22.8 ± 7.9 vs 22.6 ± 8.1, p =0.84) and post-voiding residual (20 ± 20 vs 23 ± 35, p =0.82). IIEF-5 score was negatively correlated with IPSS score (p=0.0004, coefficient = －0.23, 95%CI－0.35 to －0.11) and HbA1c (p=0.02, coefficient= －0.14, 95% CI －0.26 to －0.01). A total of 156 (69%) patients met the criteria for metabolic syndrome. The mean age, duration of diabetes, HbA1c, IPSS, voided volume, maximal urinary flowrate and IIEF-5 score were similar between diabetic patients with and without metabolic syndrome.
Conclusions
The results of these cystometry and mechanical testing have suggested that diuresis mainly contributes to the “early” changes of the bladder wall, with diabetes induced additional “late” changes in the mechanical properties of the bladder. The time-course changes in genes, extracellular matrix proteins and bladder smooth muscle oreintation that are pertinent to bladder tissue remodeling associated with diabetic cystopathy. Clinically, type 2 diabetic male patients aged less than 45 years old have more lower urinary tract symptoms but similar bladder emptying function. Age and voiding symptoms are independent risk factors of weak urinary flow rate. Diabetes associated with diuresis seemed to have a more predominate effect on lower urinary tract symptoms than other component of metabolic syndrome in the early stage of diabetes. Thus, our study suggest that need for increased attention to bladder function in the early stage of diabetes (e.g. less than 45 years old). In addition, controlling serum glucose levels with adequate diet and fluid intake might be an important step to prevent the progressive bladder dysfunction caused by diuresis in the early stage of diabetes. Controlling the extracellular matrix proteins levels and attaining normal mechanical properties of the bladder wall might be an important step in treatment of diabetic cystopathy to restore healthy bladder function.
|
|---|
