The new gestational triad: hyperglycemia, urinary incontinence (UI) and biomolecular profile as a long-term predictor for UI: a prospective cohort study: translational research with biodevice with stem cells for muscle regeneration in diabetic rats

• Grant number: 16/01743-5
• Support Opportunities: Research Projects - Thematic Grants
• Duration: April 01, 2017 - March 31, 2023
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Marilza Vieira Cunha Rudge
• Grantee: Marilza Vieira Cunha Rudge
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Pesquisadores principais: Adonis Khezaee Hijas ; Angélica Mércia Pascon Barbosa ; Fátima Pereira de Souza ; Iracema de Mattos Paranhos Calderon ; Luis Alberto Sobrevia Luarte
• Associated researchers: Álvaro Nagib Atallah ; Carlos Frederico de Oliveira Graeff ; Carlos Izaias Sartorão Filho ; Caroline Baldini Prudencio ; Daisy Maria Favero Salvadori ; Edson Assunção Mareco ; Fabiane Affonso Pinheiro ; Fernanda Piculo ; Gabriela Andrade Piemonte Lopes ; Gabriela Marini Prata ; Giovana Vesentini ; Heber Lombardi de Carvalho ; Juliana Ferreira Floriano ; Maeli Dal Pai ; Manoel João Batista Castello Girão ; Mario Sergio Palma ; Patrícia de Souza Rossignoli ; Paul Hodges ; Raghuvir Krishnaswamy Arni ; Roberto Antonio de Araujo Costa ; Rondinelli Donizetti Herculano ; Selma Maria Michelin Matheus ; Sérgio Luis Felisbino ; Silvana Andrea Molina Lima ; Sofia Beatriz Carolina Vega Quiroz ; Spencer Luiz Marques Payão ; Sthefanie Kenickel Nunes ; Tawana Pascon ; Walnei Fernandes Barbosa
• Associated grant(s): 18/22406-2 - Exosomes in gestational Diabetes Mellitus, AP.R SPRINT
• Associated scholarship(s): 22/10570-8 - Prevalence and characterization of urinary incontinence of pregnancy in hyperglycemic pregnant women: New clinical entity?, BP.IC; 22/10036-1 - Repercussions of gestational diabesity on the anthropometric variables of the newborn: prospective cohort nested in the DIAMATER project., BP.IC; 22/07680-6 - Training and improvement in the execution of the preparation and analysis of ex vivo contractility of the rectus abdominis muscle of pregnant women., BP.TT; + associated scholarships 22/05916-2 - Association of biochemical variables with gestational diabetic pelvic floor myopathy assessed by electromyography as a biomarker of pregnancy-specific urinary incontinence in pregnant women with gestational diabetes mellitus, BP.TT; 21/14295-9 - Training and improvement in the performance of electromyography in pregnant women with pregnancy-specific hyperglycemia and urinary incontinence as a predictor of UI 6-12 months post-cesarean delivery, BP.TT; 21/10665-6 - Effectiveness of the pelvic floor muscle training in aquatic ambient on pelvic floor muscle function and pregnancy specific urinary incontinence in pregnant women with Gestational Diabetes Mellitus: a feasibility study to randomized controlled trial, BP.PD; 18/26305-6 - Skeletal muscle organoid of pregnant women with Gestational Hyperglycemia and pregnancy-specific Urinary Incontinence as funcional 3D model to research biomarkers of Gestational Hyperglycemic Myopathy, BP.DR; 21/08616-7 - Training and improvement in the performance of electromyography in pregnant women with pregnancy-specific hyperglycemia and urinary incontinence as a predictor of UI 6-12 months post-cesarean delivery, BP.TT; 18/07342-8 - Development of microfluidic devices/organ on a chip using xurography, poliester-toner and gelatin methacryloyl (GelMA), BE.PQ; 21/08617-3 - Association of biochemical variables with gestational diabetic pelvic floor myopathy assessed by electromyography as a biomarker of pregnancy-specific urinary incontinence in pregnant women with gestational diabetes mellitus, BP.TT; 21/03678-4 - Training and improvement in the execution of the preparation and analysis of ex vivo contractility in the rectus abdominis muscle of pregnant women, BP.TT; 21/04221-8 - Train and perfect techniques for capturing and folow-up women to identify Specific Pregnancy and Postpartum Urinary Incontinence, BP.TT; 21/04296-8 - TRAINING TO ASSESS BY BIDIMENSIONAL ULTRASONOGRAPHY THE DIASTASIS OF THE RECTUS ABDOMINIS MUSCLE OF WOMEN WITH PREGNANCY-SPECIFIC URINARY INCONTINENCE, BP.TT; 20/09040-9 - Diastasis of the rectus abdominis muscle in women with gestational diabetes mellitus measured by two-dimensional ultrasonography, BP.IC; 20/15629-5 - Effectiveness of pelvic floor muscle exercises on muscular dysfunction and specific urinary incontinence of gestation in women with Gestational Diabetes Mellitus or Gestational Hyperglycemia: systematic review and meta-analysis, BP.DD; 18/22905-9 - Changes in the assessment of nutritional status and levels of micronutrients/expression of their receptors in women with gestational Diabetes Mellitus and Urinary Incontinence of gestation at two moments of gestation, BP.DR; 20/03666-3 - Training and improvement in the performance of electromyography pregnant women with hyperglycemia and pregnancy-specific urinary incontinence as a predictor of UI 6-12 months after cesarean delivery, BP.TT; 20/03343-0 - Training and improvement in the execution of the preparation and ultrastructural analysis of the urethral and rectus muscle abdominal rats, BP.TT; 20/04292-0 - Training and improvement in the execution of the preparation and analysis of transcriptome of the rectus abdominis muscle of pregnant women, BP.TT; 19/04424-6 - The new gestational triad: hyperglycemia, urinary incontinence (UI) and biomolecular profile as a long-term predictor for ui: a prospective cohort study: translational research with biodevice with stem cells for muscle regeneration in rats, BP.IC; 18/25153-8 - Gestational triad hyperglycemia cohort urinary incontinence and clinical molecular and omic profile of hyperglycemic myopathy in the prediction of incontinence and muscle dysfunction and translational research with biodevic for muscle regeneration in rats, BP.IC; 19/05710-2 - Prospective cohort of the omic biomarkers of the abdominal rectus muscle of pregnant women with hyperglycemia and pregnancy-specific urinary incontinence as predictors of urinary incontinence 6-12 months postpartum., BP.PD; 18/25222-0 - The new gestational triad: hyperglycemia, urinary incontinence (UI) and biomolecular profile as a long-term predictor for UI: a prospective cohort study: translational research with biodevice with stem cells for muscle regeneration in diabetic rats, BP.IC; 19/04278-0 - Training and improvement in the preparation, installation and monitoring of latex membrane biodevic as a support for post-pregnancy mesenchymal stem cells of diabetic rats, BP.TT; 18/14136-5 - Cohort study of the gestational triad hyperglycemia, urinary incontinence and clinical, molecular and omic profile of the hyperglycemic myopathy in the prediction of incontinence, BP.IC; 18/17534-1 - Training and improvement in the implementation of standards for systematic review of Collaboration Cochrane on exercise effectiveness on pelvic floor muscle dysfunction and pregnancy-specific urinary incontinence of hyperglycemic pregnant women, BP.TT; 18/02979-8 - Prospective cohort of biochemical, protein and immunohistochemical markers of muscle fiber and extracellular matrix of the rectus abdominis muscle of Hyperglycemia and gestational-specific urinary incontinence as predictor of UI 6-12 months post-cesarean, BP.PD; 18/10661-8 - Gestational triad hyperglycemia cohort, urinary incontinence and clinical profile, molecular and omic of hyperglycemic myopathy in the prediction of incontinence and muscle dysfunction and translational research with biodevic for muscle regeneration in ra, BP.PD; 18/03361-8 - Morphological analysis of rectus abdominis and urethral striated muscles of diabetic pregnant rats submitted to exercise in aquatic environment, BP.MS; 18/04736-5 - Prospective cohort study of omics biomarkers of rectus abdominis muscle from hyperglycemic pregnant women with urinary incontinence as predictive of urinary incontinence 6-12 months after postpartum, BP.PD; 18/01687-3 - To train and improve techniques for biochemical determination of the levels of relaxin, calcium, calcitonin, parathyroid hormone, vitamin D, glucose and insulin in pregnant women, BP.TT; 18/01686-7 - Training and improvement in the preparation, installation and monitoring of latex membrane biodevic as a support for post-pregnancy mesenchymal stem cells of diabetic rats, BP.TT; 17/02518-8 - Development of polymer blends of latex-alginate and latex-collagen for tissue engineering application, BP.DR; 17/21783-4 - Gestational triad cohort: hyperglycemia, urinary incontinence and clinical, molecular and omic profile of hyperglycemic myopathy in predicting incontinence and muscle dysfunction and translational research with biodevice for muscle regeneration in rats, BP.PD; 17/11076-9 - The new gestational triad: hyperglycemia, urinary incontinence (UI) and biomolecular profile as a long-term predictor for UI: a prospective cohort study: translational research with biodevice with stem cells for muscle regeneration in rats, BP.IC; 17/11077-5 - A gestational triad cohort study: hyperglycemia, urinary incontinence and biomolecular profile as a long-term predictor for incontinence and muscular disfunction and translational research with biodevice for muscle regeneration in rats, BP.IC; 17/09179-4 - The new gestational triad: hyperglycemia, urinary incontinence (UI) and biomolecular profile as a long-term predictor for UI: a prospective cohort study: translational research with biodevice with stem cells for muscle regeneration in rats, BP.IC - associated scholarships

Abstract

The research group "Diabetes and pregnancy - clinical and experimental", in the Botucatu Medical School, has investigated since 2006 the pathophysiology of Gestational Diabetes (GDM) and Mild Gestational Hyperglycemia (MGH) and their relationships with Pelvic Floor Muscle Dysfunction (PFMD) and Urinary Incontinence (UI) in clinical and experimental studies. After critical analysis with national and international partners, it was observed that there were some gaps that need to be filled with pre-clinical and clinical complex studies. Objectives: To analyze the influence of the association between Gestational Hyperglycemia (HG) considering GDM and MGH, "Pregnacy-Specific UI (PSUI)" and profile (morphological, functional, biochemical, molecular and OMICs) of Gestational Hyperglycemic Myopathy (GHM) in the Rectus Abdominis Muscles (RAM) and Pelvic Floor Muscles (PFM); analyze the triad, HG, "PSUI" and profile of the GHM, the incidence of UI 6-12 months postpartum and morphological, functional and biochemical profile, within the four cohorts formed by the combination of HG and "PSUI"; to evaluate the effect of a latex biodevice coated with mesenchymal stem cells in the regeneration of urethral muscle and RAM after cesarean section in pregnant rats with moderate diabetes in morphological profile, microvascular, molecular and OMICs; and determine the scientific evidence through systematic review of the effectiveness of exercise on the PFMD and "PSUI" in pregnant women with HG. Materials and Methods: In the clinical study, participants will be selected from January 2016 to December 2019 in the Perinatal Diabetes Research Center of UNESP, at the Maternal Hospital - FAMEMA and the Regional Hospital of Assis City. The total number of participants will be 160, considering the four cohorts that will be constituted. Biochemical analysis will be performed on blood samples obtained from the study participants, to ascertain the levels of CCL7, Relaxin, Ca, PTH, calcitonin, vitamin D, glucose and insulin. In terms of the PFMs, the following evaluations will be conducted: functional assessment of pelvic floor, Electromyography (EMG) and Ultrasound (US). In terms of the RAM, the following evaluations will be conducted: EMG and US, at the time of cesarean ex vivo contractility obtained by myograph, and morphological profiles (ultrastructure of muscle fibers and extracellular matrix), molecular (gene and protein expression in muscle fibers and extracellular matrix) and OMICs (transcriptomics, proteomics and metabolomics). For the experimental study, pregnant Wistar rats divided into groups will be used (n=20 each), non-diabetic and diabetic, to undergo the the installation of a biodevice of latex membrane coated mesenchymal stem cells implanted into the urethral striated muscle and RAM. The systematic review study will follow the accepted rules and be registered with the Cochrane Collaboration. For statistical analysis, associations will be considered statistically significant at p <0.05. Analysis will be done with SPSS v21.0 software. Expected Results: To characterize the GHM; that the proposed triad is a predictor of UI and PFMD after 6-12 months post-partum; to establish markers for diagnosis and future therapies; to highlight the first line of preventive or rehabilitative intervention for muscle dysfunction and "PSUI"; that "PSUI" in pregnant women with GH be included and considered a public health problem as well as a clinical complication, and thus represent a new tool in defining the long-term maternal impact; and that the biodevice be considered for muscle regeneration in future clinical trials; and that this proposed translational approach will bring this research to the forefront of knowledge in Women's Health, once as yet unpublished analysis methodologies can be applied in areas that complement the problematic approach of medical/social interest. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARBOSA, ANGELICA MERCIA PASCON; ENRIQUEZ, EUSEBIO MARIO AMADOR; RODRIGUES, MELINE ROSSETTO KRON; PRUDENCIO, CAROLINE BALDINI; ATALLAH, ALVARO NAGIB; REYES, DAVID RAFAEL ABREU; HALLUR, RAGHAVENDRA LAKSHMANA SHETTY; NUNES, STHEFANIE KENICKEL; PINHEIRO, FABIANE AFFONSO; SARTORAO FILHO, CARLOS ISAIAS; et al. Effectiveness of the pelvic floor muscle training on muscular dysfunction and pregnancy specific urinary incontinence in pregnant women with gestational diabetes mellitus: A systematic review protocol. PLoS One, v. 15, n. 12, DEC 7 2020. (16/01743-5, 18/17534-1)

CUNHA RUDGE, MARILZA VIEIRA; PASCON BARBOSA, ANGELICA MERCIA; SOBREVIA, LUIS; GELALETI, RAFAEL BOTTARO; SHETTY HALLUR, RAGHAVENDRA LAKSHMANA; CASTRO MARCONDES, JOAO PAULO; FAVERO SALVADORI, DAISY MARIA; PRUDENCIO, CAROLINE BALDINI; MAGALHAES, CLAUDIA GARCIA; COSTA, ROBERTO; et al. Altered maternal metabolism during mild gestational hyperglycemia as a predictor of adverse perinatal outcomes: A comprehensive analysis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1866, n. 2, FEB 1 2020. (16/01743-5)

BARROS, NATAN ROBERTO; AHADIAN, SAMAD; TEBON, PEYTON; CUNHA RUDGE, MARILZA VIEIRA; PASCON BARBOSA, ANGELICA MERCIA; HERCULANO, RONDINELLI DONIZETTI. Highly absorptive dressing composed of natural latex loaded with alginate for exudate control and healing of diabetic wounds. Materials Science & Engineering C-Materials for Biological Applications, v. 119, FEB 2021. (17/19603-8, 17/02518-8, 16/01743-5)

BORATTO, MIGUEL H.; NOZELLA, NATAN L.; RAMOS, JR., ROBERTO A.; DA SILVA, RAFAEL APARECIDO; GRAEFF, CARLOS F. O.. Flexible conductive blend of natural rubber latex with PEDOT:PSS. APL Materials, v. 8, n. 12, DEC 1 2020. (19/18481-1, 16/01743-5, 13/07296-2, 17/20809-0)

SARTORAO FILHO, I, CARLOS; PINHEIRO, FABIANE A.; PRUDENCIO, CAROLINE B.; NUNES, STHEFANIE K.; TAKANO, LUIZ; ENRIQUEZ, EUSEBIO M. A.; ORLANDI, MAIARA I. G.; JUNGINGER, BAERBEL; HALLUR, RAGHAVENDRA L. S.; RUDGE, MARILZA V. C.; et al. Impact of gestational diabetes on pelvic floor: A prospective cohort study with three-dimensional ultrasound during two-time points in pregnancy. NEUROUROLOGY AND URODYNAMICS, v. 39, n. 8, AUG 2020. (16/01743-5)

LUANA FÁVARO IAMUNDO; GUILHERME THOMAZ DE AQUINO NAVA; PAULO ROBERTO ROCHA JÚNIOR; CAROLINE BALDINI PRUDENCIO; ANGÉLICA MÉRCIA PASCON BARBOSA. Prevalência e fatores associados à disfunção do assoalho pélvico em mulheres universitárias: um estudo transversal. Fisioter. mov., v. 35, 2022-09-23. (21/10665-6, 16/01743-5)

PRUDENCIO, CAROLINE B.; RUDGE, MARILZA V. C.; PINHEIRO, FABIANE A.; SARTORAO FILHO, I, CARLOS; NUNES, STHEFANIE K.; PEDRONI, CRISTIANE R.; JUNGINGER, BAERBEL; BARBOSA, ANGELICA M. P.. Negative impact of gestational diabetes mellitus on progress of pelvic floor muscle electromyography activity: Cohort study. PLoS One, v. 14, n. 11, NOV 7 2019. (16/01743-5)

RUDGE, MARILZA V. C.; SOUZA, FATIMA P.; ABBADE, JOELCIO F.; HALLUR, RAGHAVENDRA L. S.; MARCONDES, JOAO PAULO C.; PICULO, FERNANDA; MARINI, GABRIELA; VESENTINI, GIOVANA; THABANE, LEHANA; WITKIN, STEVEN S.; et al. Study protocol to investigate biomolecular muscle profile as predictors of long-term urinary incontinence in women with gestational diabetes mellitus. BMC PREGNANCY AND CHILDBIRTH, v. 20, n. 1, FEB 19 2020. (16/01743-5)

VESENTINI, GIOVANA; BARBOSA, ANGELICA M. P.; DAMASCENO, DEBORA C.; MARINI, GABRIELA; PICULO, FERNANDA; MATHEUS, SELMA M. M.; HALLUR, RAGHAVENDRA L. S.; NUNES, STHEFANIE K.; CATINELLI, BRUNA B.; MAGALHAES, CLAUDIA G.; et al. Alterations in the structural characteristics of rectus abdominis muscles caused by diabetes and pregnancy: A comparative study of the rat model and women. PLoS One, v. 15, n. 4, APR 3 2020. (16/09710-9, 16/01743-5, 14/26852-6)

BERTINI, AYLEEN; SALAS, RODRIGO; CHABERT, STEREN; SOBREVIA, LUIS; PARDO, FABIAN. sing Machine Learning to Predict Complications in Pregnancy: A Systematic Revie. FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY, v. 9, JAN 19 2022. (16/01743-5)

FLORIANO, JULIANA FERREIRA; EMANUELI, COSTANZA; VEGA, SOFIA; PASCON BARBOSA, ANGELICA MERCIA; DE OLIVEIRA, RAFAEL GUILEN; FERREIRA FLORIANO, EMERSON APARECIDO; DE OLIVEIRA GRAEFF, CARLOS FREDERICO; ABBADE, JOELCIO FRANCISCO; HERCULANO, RONDINELLI DONIZETE; SOBREVIA, LUIS; et al. Pro-angiogenic approach for skeletal muscle regeneration. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1866, n. 2, FEB 2022. (18/22406-2, 17/21783-4, 16/01743-5)

Filed patent(s) as a result of this research project