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Crosstalk between Metabolic Syndrome and Voiding Dysfunction

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 9645

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Special Issue Editors

Dr. Lysanne Campeau

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Guest Editor

Division of Urology, Department of Surgery, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC H3T 1E2, Canada
Interests: physiology and pharmacology of lower urinary tract; urinary incontinence; neurogenic lower urinary tract dysfunction; female elvic medicine; voiding dysfunction; urogenital reconstruction
Special Issues, Collections and Topics in MDPI journals

Dr. Philippe G. Cammisotto

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Guest Editor

Lady Davis Institute for Medical Research, Montreal, Canada
Interests: metabolic disorders; cell and molecular biology; urinary system; pharmacotherapy

Special Issue Information

Dear Colleagues,

Metabolic syndrome and its associated diseases—hypertension, diabetes, and dyslipidemia, among others—have been a matter of public health for decades. Similarly, voiding dysfunction and lower urinary tract symptoms (LUTS) increase in prevalence with aging and affect a significant share of the population. Clinical studies have clearly established a link between both conditions, but so far, shared biological and cellular mechanisms are lacking. Nevertheless, significant progress has been made thanks to several cutting-edge techniques relying on metabolomics, proteomics, new biomarker identification in body fluids, as well as gene knockout mice, laser microdissection, and analyses of gene expression.

This Special Issue of Metabolites, "Crosstalk between Metabolic Syndrome and Voiding Dysfunction", will be dedicated to the most recent discoveries unraveling the relationship between bladder dysfunction and systemic metabolic parameters. These encompass gene expression, urinary and plasma metabolites, hormones and biomarkers, and non-invasive discovery of new clinical biomarkers.

Dr. Lysanne Campeau
Dr. Philippe G. Cammisotto
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

lower urinary tract symptoms
metabolic syndrome
urinary biomarkers
metabolomics
proteomics
translational research
diagnosis
men/women disorders
micturition
pharmacologic treatment
symptoms

Published Papers (6 papers)

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Research

13 pages, 2122 KiB

Open AccessArticle

Decrease in the Ratio proBDNF/BDNF in the Urine of Aging Female Patients with OAB

by Claudia Covarrubias, Philippe G Cammisotto, Samer Shamout and Lysanne Campeau

Metabolites 2023, 13(6), 723; https://doi.org/10.3390/metabo13060723 - 3 Jun 2023

Viewed by 1161

Abstract

Imbalance in the levels of neurotrophins, growth factors crucial in the development, function, and survival of neurons is commonly observed in many pathological states. Concentrations of brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) were measured in the urine of a cohort of aging female patients with overactive bladder disease (OAB). When reported to creatinine, levels were similar between OAB patients and healthy controls. However, the ratio proBDNF/BDNF was significantly decreased in the OAB group. Receiver operating characteristic (ROC) curve analysis of the ratio proBDNF/BDNF displayed a good diagnostic value for OAB (AUC = 0.729). Clinical questionnaires of symptom severity (OABSS and IIQ-7) were negatively correlated with this ratio. On the other hand, microRNAs (miRNA) involved in proBDNF gene translation were expressed at comparable levels between groups. However, urinary enzymatic activity of matrix metalloproteinase-9 (MMP-9), the enzyme that cleaves proBDNF into BDNF, was increased in OAB compared to controls. Levels of miR-491-5p, the main miRNA that downregulates MMP-9 synthesis, were greatly decreased in urine from OAB patients. These results suggest that the ratio proBDNF/BDNF could be useful in the phenotyping of OAB in an aging population, and the difference could originate from enhanced MMP-9 enzymatic activity rather than translational control. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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18 pages, 9720 KiB

Open AccessArticle

A Spectrum of Age- and Gender-Dependent Lower Urinary Tract Phenotypes in Three Mouse Models of Type 2 Diabetes

by Bryce MacIver, Erica M. Bien, Mariana G. de Oliveira and Warren G. Hill

Metabolites 2023, 13(6), 710; https://doi.org/10.3390/metabo13060710 - 31 May 2023

Viewed by 1073

Abstract

Lower urinary tract symptoms are extremely common in people with diabetes and obesity, but the causes are unclear. Furthermore, it has proven difficult to reliably demonstrate bladder dysfunction in diabetic mouse models, thus limiting the ability to gain mechanistic insights. Therefore, the main objective of this experimental study was to characterize diabetic bladder dysfunction in three promising polygenic mouse models of type 2 diabetes. We performed periodic assessments of glucose tolerance and micturition (void spot assay) for eight to twelve months. Males and females and high-fat diets were tested. NONcNZO10/LtJ mice did not develop bladder dysfunction over twelve months. TALLYHO/JngJ males were severely hyperglycemic from two months of age (fasted blood glucose ~550 mg/dL), while females were moderately so. Although males exhibited polyuria, neither they nor the females exhibited bladder dysfunction over nine months. KK.Cg-A^y/J males and females were extremely glucose intolerant. Males exhibited polyuria, a significant increase in voiding frequency at four months (compensation), followed by a rapid drop in voiding frequency by six months (decompensation) which was accompanied by a dramatic increase in urine leakage, indicating loss of outlet control. At eight months, male bladders were dilated. Females also developed polyuria but compensated with larger voids. We conclude KK.Cg-A^y/J male mice recapitulate key symptoms noted in patients and are the best model of the three to study diabetic bladder dysfunction. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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26 pages, 6088 KiB

Open AccessArticle

Urinary ATP Levels Are Controlled by Nucleotidases Released from the Urothelium in a Regulated Manner

by Alejandro Gutierrez Cruz, Mafalda S. L. Aresta Branco, Brian A. Perrino, Kenton M. Sanders and Violeta N. Mutafova-Yambolieva

Metabolites 2023, 13(1), 30; https://doi.org/10.3390/metabo13010030 - 24 Dec 2022

Cited by 7 | Viewed by 1950

Abstract

Adenosine 5′-triphosphate (ATP) is released in the bladder lumen during filling. Urothelial ATP is presumed to regulate bladder excitability. Urinary ATP is suggested as a urinary biomarker of bladder dysfunctions since ATP is increased in the urine of patients with overactive bladder, interstitial cystitis or bladder pain syndrome. Altered urinary ATP might also be associated with voiding dysfunctions linked to disease states associated with metabolic syndrome. Extracellular ATP levels are determined by ATP release and ATP hydrolysis by membrane-bound and soluble nucleotidases (s-NTDs). It is currently unknown whether s-NTDs regulate urinary ATP. Using etheno-ATP substrate and HPLC-FLD detection techniques, we found that s-NTDs are released in the lumen of ex vivo mouse detrusor-free bladders. Capillary immunoelectrophoresis by ProteinSimple Wes determined that intraluminal solutions (ILS) collected at the end of filling contain ENTPD3 > ENPP1 > ENPP3 ≥ ENTPD2 = NT5E = ALPL/TNAP. Activation of adenylyl cyclase with forskolin increased luminal s-NTDs release whereas the AC inhibitor SQ22536 had no effect. In contrast, forskolin reduced and SQ22536 increased s-NTDs release in the lamina propria. Adenosine enhanced s-NTDs release and accelerated ATP hydrolysis in ILS and lamina propria. Therefore, there is a regulated release of s-NTDs in the bladder lumen during filling. Aberrant release or functions of urothelial s-NTDs might cause elevated urinary ATP in conditions with abnormal bladder excitability. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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9 pages, 1284 KiB

Open AccessArticle

A Feasibility Study to Evaluate Changes in Urinary Metabolites after OnabotulinumtoxinA Injection for Refractory Overactive Bladder

by Laura M. Tellechea, Samantha Freeman, Ilir Agalliu, Melissa A. Laudano, Sylvia O. Suadicani and Nitya Abraham

Metabolites 2022, 12(9), 880; https://doi.org/10.3390/metabo12090880 - 19 Sep 2022

Viewed by 1751

Abstract

Metabolomics analysis of urine before and after overactive bladder (OAB) treatment may demonstrate a unique molecular profile, allowing predictions of responses to treatment. This feasibility study aimed to correlate changes in urinary metabolome with changes in OAB symptoms after intravesical onabotulinumtoxinA (BTX-A) injections for refractory OAB. Women 18 years or older with non-neurogenic refractory OAB were recruited to complete OAB-V8 questionnaires and submit urine samples before and after 100 units intravesical BTX-A injection. Samples were submitted to CE-TOFMS metabolomics profiling. Data were expressed as percent of change from pre-treatment and were correlated with OAB-V8 score improvement. Urinary metabolite changes in the OAB-V8 groups were compared using the Kruskal–Wallis test, and associations between metabolites and OAB-V8 scores were examined using quantile regression analysis. Of 61 urinary metabolites commonly detected before and after BTX-A, there was a statistically significant decrease in adenosine and an increase in N8-acetylspermidine and guanidinoacetic acid levels associated with OAB score improvement, suggesting that intravesical BTX-A injection modifies the urinary metabolome. These urinary metabolites could provide insight into OAB pathophysiology and help identify patients who would benefit most from chemodenervation. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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11 pages, 762 KiB

Open AccessArticle

Urinary Levels of miR-491-5p and miR-592 as Potential Diagnostic Biomarkers in Female Aging Patients with OAB: A Pilot Study

by Philippe G. Cammisotto, Abubakr H. Mossa, Samer Shamout and Lysanne Campeau

Metabolites 2022, 12(9), 820; https://doi.org/10.3390/metabo12090820 - 31 Aug 2022

Viewed by 1293

Abstract

Women with overactive bladder syndrome (OAB) have a lower urinary ratio of nerve growth factor (NGF) to its precursor (proNGF) compared to healthy controls. MicroRNAs related to NGF and proNGF metabolism and to their receptors may be present in urine and may possess diagnostic value. Urine and blood samples from 20 control and 20 OAB women (50–80 years) were obtained, together with validated questionnaires and other clinical parameters. The relative expression of urinary microRNAs was measured with RT-qPCR. MiR-491-5p, which negatively controls the translation of the matrix metalloproteinase-9 (MMP-9), the main enzyme degrading NGF, was significantly decreased in OAB. Similarly, miR-592, which represses p75^NTR receptor synthesis, was down-regulated in OAB. Age, renal function and insulin resistance did not affect these results. ROC curves confirmed the high sensitivity of miR-491-5p and miR-592 for diagnosis. On the other hand, miRNAs involved in the expression of proNGF, of survival receptor TrkA and of markers of nerve integrity were similar between groups. The detection of miR-491-5p and miR-592 in urine could be a useful and non-invasive tool for the diagnosis of OAB syndrome in aging women. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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9 pages, 679 KiB

Open AccessArticle

Higher Levels of Serum Uric Acid Have a Significant Association with Lower Incidence of Lower Urinary Tract Symptoms in Healthy Korean Men

by Jiwon Hwang, Seungho Ryu and Joong Kyong Ahn

Metabolites 2022, 12(7), 649; https://doi.org/10.3390/metabo12070649 - 14 Jul 2022

Cited by 5 | Viewed by 1386

Abstract

Gout has been correlated with the risk of incident benign prostatic hyperplasia. In line with increasing prevalence of hyperuricemia, the aim of this study was to investigate the relationship between serum uric acid (SUA) level and the incidence of lower urinary tract symptoms (LUTS) among clinically healthy middle-aged men. We performed a cohort study in 101,091 Korean men without LUTS at baseline who completed health checkups between 2011 and 2016. LUTS were evaluated using the International Prostate Symptom Score, where a score ≥ 8 was defined as significant LUTS. Men were divided into six groups according to their SUA levels in mg/dL (<5.5, 5.5–6.4, 6.5–7.4, 7.5–8.4, 8.5–9.4, and ≥9.5). Throughout the follow-up—encompassing a total of 358,982.6 person years—13,424 people had significant LUTS (37.3 per 1000 person years for incidence rate). The multivariable models demonstrated that the highest level of SUA (≥9.5 mg/dL) was related to the lowest risk of significant LUTS compared with the reference category (<5.5 mg/dL) (0.77 (95% CI 0.59–0.99) for adjusted HR). In this large cohort composed of middle-aged men, higher SUA levels were related to a reduced risk of LUTS. This result suggests another potential role of SUA in restraining LUTS. Additional studies are needed to explain the underlying biological mechanisms of this phenomenological relationship. Full article

(This article belongs to the Special Issue Crosstalk between Metabolic Syndrome and Voiding Dysfunction)

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