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.

NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

“…These mice were then assessed for DBD. Mechanistically, DBD results, in part, from peripheral neuropathy (20,21). Therefore, we also evaluated a role for NLRP3 in the variation of nerve cell populations that could explain functional deficits in patients with diabetes, specifically diminished sensation (Ad-fibers) and bladder overactivity (C-fibers).…”

Chronic high‐fat diet decreased detrusor mitochondrial respiration and increased nerve‐mediated contractions

“…However, novel scavenging compounds, such as elamipretide, which are targeted and permeable to mitochondria are showing promise . Our mice demonstrate increase frequency and EFS‐mediated contractions which are representative of the compensatory phase of bladder dysfunction or overactive bladder dysfunction . Our future studies will assess mitochondrial‐targeted antioxidants to determine if restoring mitochondrial function can recover bladder function in diseased states such as obesity or diabetes.…”

“…Alterations in the physiology of the mucosal layer (lamina propria, urothelium) or the detrusor smooth muscle layer as well as changes to innervation can contribute to bladder dysfunction. The symptoms of obesity‐induced bladder dysfunction range from overactive bladder to stress and/or urge incontinence . While it is speculated that obesity increases abdominal pressure and contributes to incontinence, the mechanisms underlying the pathological changes leading to bladder dysfunction remain unknown.…”

Oxidative stress and its possible relation to lower urinary tract functional pathology

“…Diabetes and obesity often occur together and share common urological complications , and clinically obesity may be a major contributing factor for LUTS . Obese animals exhibit cystometric alterations such as increases in the frequency of voiding and non‐voiding contractions , but the link between obesity‐associated bladder dysfunction and oxidative stress has not been widely studied.…”