Unraveling mechanisms of glycemic control and chronic complications of Diabetes mellitus: contributions to human health

• Grant number: 16/15603-0
• Support Opportunities: Research Projects - Thematic Grants
• Duration: June 01, 2017 - November 30, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ubiratan Fabres Machado
• Grantee: Ubiratan Fabres Machado
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Maria Lucia Cardillo Corrêa Giannella ; Marisa Passarelli
• Associated researchers: Beatriz D'Agord Schaan ; Suely Kazue Nagahashi Marie
• Associated scholarship(s): 18/26013-5 - Contribution of lipotoxicity in the development of cognitive deficit in Diabetes mellitus Type 2 (T2D), BP.PD; 19/25306-1 - Study of microRNAs potentially regulators of GLUT4 expression in adipose tissue of type 2 diabetes obese mice, BP.IC; 18/00172-0 - Advanced glycation products, endoplasmic reticulum stress and the modulation of the reverse cholesterol transport in human arteries with different levels Atherosclerotic lesion, BP.PD; + associated scholarships 18/12265-2 - Changes in the glucose transporters expression in central nervous system: correlation between Type 3 Diabetes mellitus and Alzheimer's Disease, BP.PD; 17/19449-9 - MicroRNAs-mediated epigenetic regulation of GLUT4 protein (Slc2a4 gene) in skeletal muscle of mice with type 2 diabetes mellitus, BP.PD; 16/25155-5 - Role of neuroinflammation and histone deacetylases on mechanisms of transcription of the SLC2A4 gene in SH-SY5Y cells and hippocampal neurons of obese humans without and with diabetes, BP.PD; 13/02854-7 - Anti-inflammatory role of apolipoprotein A-IV in diabetes mellitus and its impact on macrophage reverse cholesterol transport: influence of advanced glycation, BP.PD - associated scholarships

Abstract

Diabetes Mellitus (DM) and its chronic complications are the greatest public health problem. It is a must to develop approaches that help to control glycemia and to reduce the incidence of complications. Target territories to develop complications, which will be focused on in this proposal, include kidney, cardiovascular system, brain (Alzheimer's Disease also referred to as DM3) and liver. This project aims to unravel molecular mechanism concerning glycemic control and the development of complications in DM1 and/or in DM2. For that, we will investigate mechanisms contributing to the development or improvement of: 1) glycemic control: GLUT4 regulation in animal models and inspiratory exercise in humans; 2) Diabetic Renal Disease: genetic susceptibility markers and renal tubular disease related to urinary molecular markers (cells from urinary sediment); 3) Cardiovascular Disease: focusing on Atherosclerosis and endothelial progenitor cells migration in humans, and Cardiomyopathy in animal model; 4) Alzheimer's Disease: focusing on glucose disposal for specific brain areas, based on the expression of glucose transporters (post mortem human brain); and 5) Hepatic Diseases: non-alcoholic fatty liver disease in animal model, and Mauriac Syndrome in DM1 subjects. Several methodologies will be adopted: in vivo, in vitro and in silico analyses; Molecular Biology techniques for evaluation of gene expression (transcriptional, translational and epigenetic regulations). We expect to yield a myriad of results capable of remarkably enriching knowledge of the area, and significantly contributing to the health of Diabetes Mellitus patients. (AU)

Scientific publications

(24)

(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)

FERREIRA, GUILHERME DA SILVA; GARCIA BOCHI, ANA PAULA; PINTO, PAULA RAMOS; DEL BIANCO, VANESSA; RODRIGUES, LETICIA GOMES; TEIXEIRA MORAIS, MYCHEL RAONY PAIVA; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CATANOZI, SERGIO; PASSARELLI, MARISA. Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet. NUTRIENTS, v. 13, n. 7, JUL 2021. (16/15603-0)

BARRETO-ANDRADE, JOAO NILTON; DE FATIMA, LUCIANA ALVES; CAMPELLO, RAQUEL SALDANHA; CIPRIANO GUEDES, JOSE AUGUSTO; DE FREITAS, HELAYNE SOARES; UBIRATAN FABRES MACHADO, MARISTELA MITIKO OKAMOTO. Estrogen Receptor 1 (ESR1) Enhances Slc2a4/GLUT4 Expression by a SP1 Cooperative Mechanism. INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, v. 15, n. 12, p. 1320-1328, 2018. (16/15603-0, 15/18715-1)

MORI, ROSANA CRISTINA; SANTOS-BEZERRA, DANIELE PEREIRA; PELAES, TATIANA SOUZA; ADMONI, SHARON NINA; PEREZ, RICARDO VESSONI; MONTEIRO, MARIA BEATRIZ; MACHADO, CLEIDE GUIMARAES; QUEIROZ, MARCIA SILVA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA. Variants inHSD11B1gene modulate susceptibility to diabetes kidney disease and to insulin resistance in type 1 diabetes. DIABETES-METABOLISM RESEARCH AND REVIEWS, v. 37, n. 1, JUN 2020. (16/15603-0)

ESTEVES, V, JOAO; YONAMINE, CAIO Y.; PINTO-JUNIOR, DANILO C.; GERLINGER-ROMERO, FREDERICO; ENGUITA, FRANCISCO J.; MACHADO, UBIRATAN F.. Diabetes Modulates MicroRNAs 29b-3p, 29c-3p, 199a-5p and 532-3p Expression in Muscle: Possible Role in GLUT4 and HK2 Repression. FRONTIERS IN ENDOCRINOLOGY, v. 9, SEP 12 2018. (16/15603-0, 12/20432-0, 12/15514-7, 17/19449-9)

SANTOS-BEZERRA, DANIELE P.; CAVALEIRO, ANA MERCEDES; SANTOS, ARITANIA SOUSA; SUEMOTO, CLAUDIA KIMIE; PASQUALUCCI, CARLOS AUGUSTO; JACOB-FILHO, WILSON; PARAIZO LEITE, RENATA ELAINE; PASSARELLI, MARISA; NAGAHASHI MARIE, SUELY KAZUE; MACHADO, UBIRATAN FABRES; et al. Alcohol Use Disorder is Associated with Upregulation of MicroRNA-34a and MicroRNA-34c in Hippocampal Postmortem Tissue. ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, v. 45, n. 1, p. 64-68, JAN 2021. (18/12265-2, 16/15603-0)

MACHADO-LIMA, ADRIANA; LOPEZ-DIEZ, RAQUEL; IBORRA, RODRIGO TALLADA; PINTO, RAPHAEL DE SOUZA; DAFFU, GURDIP; SHEN, XIAOPING; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA CARDILLO; SCHMIDT, ANN MARIE; et al. RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 19, OCT 2020. (12/19112-0, 15/21072-5, 13/06800-9, 18/00172-0, 13/26256-1, 12/12088-7, 14/05951-6, 16/15603-0)

IBORRA, RODRIGO TALLADA; MACHADO-LIMA, ADRIANA; OKUDA, LIGIA SHIMABUKURO; PINTO, PAULA RAMOS; NAKANDAKARE, EDNA REGINA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA; PICKFORD, RUSSELL; WOODS, TOM; BRIMBLE, MARGARET A.; et al. AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages. JOURNAL OF DIABETES AND ITS COMPLICATIONS, v. 32, n. 1, p. 1-10, JAN 2018. (12/19112-0, 13/26256-1, 16/15603-0, 12/12088-7, 13/02854-7, 15/21072-5)

SANTOS-BEZERRA, DANIELE P.; MACHADO-LIMA, ADRIANA; MONTEIRO, MARIA BEATRIZ; ADMONI, SHARON N.; PEREZ, RICARDO V.; MACHADO, CLEIDE G.; SHIMIZU, MARIA HELOIZA; CAVALEIRO, ANA M.; THIEME, KARINA; QUEIROZ, MARCIA S.; et al. Dietary advanced glycated end-products and medicines influence the expression of SIRT1 and DDOST in peripheral mononuclear cells from long-term type 1 diabetes patients. Diabetes & Vascular Disease Research, v. 15, n. 1, p. 81-89, JAN 2018. (12/04831-1, 16/15603-0, 12/25490-8)

YONAMINE, CAIO Y.; ALVES-WAGNER, ANA B.; ESTEVES, V, JOAO; OKAMOTO, MARISTELA M.; CORREA-GIANNELLA, MARIA L.; GIANNELLA-NETO, DANIEL; MACHADO, UBIRATAN F.. Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control. Molecular and Cellular Endocrinology, v. 481, p. 26-34, FEB 5 2019. (12/20432-0, 16/15603-0, 13/26616-8, 12/04831-1)

YONAMINE, CAIO Y.; PINHEIRO-MACHADO, ERIKA; MICHALANI, MARIA L.; ALVES-WAGNER, ANA B.; ESTEVES, JOAO V.; FREITAS, HELAYNE S.; MACHADO, UBIRATAN F.. Resveratrol Improves Glycemic Control in Type 2 Diabetic Obese Mice by Regulating Glucose Transporter Expression in Skeletal Muscle and Liver. Molecules, v. 22, n. 7, JUL 2017. (16/15603-0)

MORI, ROSANA CRISTINA; DA SILVA, THAIS POCAS; CAMPELLO, RAQUEL SALDANHA; MACHADO, UBIRATAN FABRES. Carbenoxolone enhances peripheral insulin sensitivity and GLUT4 expression in skeletal muscle of obese rats: Potential participation of UBC9 protein. Life Sciences, v. 229, p. 157-165, JUL 15 2019. (16/15603-0)

SANTOS-BEZERRA, DANIELE P.; SANTOS, ARITANIA S.; GUIMARAES, GABRIEL C.; ADMONI, SHARON N.; PEREZ, V, RICARDO; MACHADO, CLEIDE G.; PELAES, TATIANA S.; PASSARELLI, MARISA; MACHADO, UBIRATAN F.; QUEIROZ, MARCIA S.; et al. Micro-RNAs 518d-3p and 618 Are Upregulated in Individuals With Type 1 Diabetes With Multiple Microvascular Complications. FRONTIERS IN ENDOCRINOLOGY, v. 10, JUN 12 2019. (16/15603-0)

DAVID-SILVA, ALINE; ESTEVES, JOAO VICTOR; MORAIS, MYCHEL RAONY P. T.; FREITAS, HELAYNE SOARES; ZORN, TELMA MARIA; CORREA-GIANNELLA, MARIA LUCIA; MACHADO, UBIRATAN FABRES. Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice. DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY, v. 13, p. 739-751, 2020. (16/15603-0, 11/09463-8, 17/19449-9)

FATIMA, LUCIANA A.; CAMPELLO, RAQUEL S.; BARRETO-ANDRADE, JOAO N.; PASSARELLI, MARISA; SANTOS, ROBERTA S.; CLEGG, DEBORAH J.; MACHADO, UBIRATAN F.. Estradiol stimulates adipogenesis and Slc2a4/GLUT4 expression via ESR1-mediated activation of CEBPA. Molecular and Cellular Endocrinology, v. 498, DEC 1 2019. (16/15603-0, 12/24210-1)

DA SILVA, KAROLLINE S.; PINTO, PAULA R.; FABRE, NELLY T.; GOMES, DIEGO J.; THIEME, KARINA; OKUDA, LIGIA S.; IBORRA, RODRIGO T.; FREITAS, VANESSA G.; SHIMIZU, MARIA H. M.; TEODORO, WALCY R.; et al. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats. FRONTIERS IN PHYSIOLOGY, v. 8, SEP 22 2017. (16/15603-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 14/17251-9, 13/02854-7)

MINANNI, CARLOS ANDRE; MACHADO-LIMA, ADRIANA; IBORRA, RODRIGO TALLADA; OKUDA, LIGIA SHIMABUKURO; PINTO, RAPHAEL DE SOUZA; MELLO SANTANA, MONIQUE DE FATIMA; DE ARAUJO LIRA, AECIO LOPES; NAKANDAKARE, EDNA REGINA; CARDILLO CORREA-GIANNELLA, MARIA LUCIA; PASSARELLI, MARISA. Persistent Effect of Advanced Glycated Albumin Driving Inflammation and Disturbances in Cholesterol Efflux in Macrophages. NUTRIENTS, v. 13, n. 10, OCT 2021. (17/18545-4, 12/19112-0, 16/15603-0, 12/12088-7, 18/00172-0, 15/21072-5)

SANTOS-BEZERRA, DANIELE P.; FILGUEIRAS, LUCIANO R.; MONTEIRO, MARIA BEATRIZ; ADMONI, SHARON N.; PEREZ, V, RICARDO; CAVALEIRO, ANA M.; MACHADO, CLEIDE G.; MACHADO, UBIRATAN F.; PASSARELLI, MARISA; JANCAR, SONIA; et al. Leukotriene Pathway Activation Associates with Poor Glycemic Control and with Cardiovascular Autonomic Neuropathy in Type 1 Diabetes. Mediators of Inflammation, v. 2020, MAR 23 2020. (16/15603-0, 13/15719-0)

MONTEIRO, MARIA BEATRIZ; PELAES, TATIANA S.; SANTOS-BEZERRA, DANIELE P.; THIEME, KARINA; LERARIO, ANTONIO M.; OBA-SHINJO, SUELI M.; MACHADO, UBIRATAN F.; PASSARELLI, MARISA; MARIE, SUELY K. N.; CORREA-GIANNELLA, MARIA LUCIA. Urinary Sediment Transcriptomic and Longitudinal Data to Investigate Renal Function Decline in Type 1 Diabetes. FRONTIERS IN ENDOCRINOLOGY, v. 11, APR 30 2020. (16/15603-0, 15/19000-6)

MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE P.; PELAES, TATIANA S.; VAIDYA, VISHAL S.; CORREA-GIANNELLA, MARIA LUCIA. MicroRNAs 1915-3p, 2861, and 4532 Are Associated with Long-Term Renal Function Decline in Type 1 Diabetes. CLINICAL CHEMISTRY, v. 65, n. 11, p. 1458-1459, NOV 2019. (16/04935-2, 16/15603-0, 15/19000-6, 18/12265-2)

PINTO, PAULA R.; DA SILVA, KAROLLINE S.; IBORRA, RODRIGO T.; OKUDA, LIGIA S.; GOMES-KJERULF, DIEGO; FERREIRA, GUILHERME S.; MACHADO-LIMA, ADRIANA; ROCCO, DEBORA D. F. M.; NAKANDAKARE, EDNA R.; MACHADO, UBIRATAN F.; et al. Exercise Training Favorably Modulates Gene and Protein Expression That Regulate Arterial Cholesterol Content in CETP Transgenic Mice. FRONTIERS IN PHYSIOLOGY, v. 9, MAY 8 2018. (12/19112-0, 16/15603-0, 13/11084-0, 12/12088-7, 11/15153-1, 12/18724-2, 13/02854-7, 14/07617-6, 15/21072-5)

PINTO-JUNIOR, DANILO C.; SILVA, KAROLLINE S.; MICHALANI, MARIA L.; YONAMINE, CAIO Y.; ESTEVES, JOAO V.; FABRE, NELLY T.; THIEME, KARINA; CATANOZI, SERGIO; OKAMOTO, MARISTELA M.; SERAPHIM, PATRICIA M.; et al. Advanced glycation end products-induced insulin resistance involves repression of skeletal muscle GLUT4 expression. SCIENTIFIC REPORTS, v. 8, MAY 25 2018. (12/20432-0, 16/15603-0, 16/25155-5, 12/18724-2, 13/00713-7, 14/17251-9)

OKUDA, LIGIA SHIMABUKURO; IBORRA, RODRIGO TALLADA; RAMOS, PAULA; MACHADO, UBIRATAN FABRES; CORREA-GIANNELLA, MARIA LUCIA; PICKFORD, RUSSELL; WOODS, TOM; BRIMBLE, MARGARET ANNE; RYE, KERRY-ANNE; PASSARELLI, MARISA. Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages. Mediators of Inflammation, v. 2020, JAN 14 2020. (13/23392-1, 16/15603-0, 15/21072-5, 13/02854-7, 13/26256-1)

PINTO, PAULA RAMOS; YOSHINAGA, MARCOS Y.; DEL BIANCO, VANESSA; BOCHI, ANA PAULA; FERREIRA, GUILHERME S.; PINTO, ISABELLA F. D.; RODRIGUES, LETICIA G.; NAKANDAKARE, EDNA R.; OKAMOTO, MARISTELA M.; MACHADO, UBIRATAN F.; et al. Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice. Journal of Biological Chemistry, v. 296, JAN-JUN 2021. (16/15603-0, 13/07937-8, 15/21072-5)

THIEME, KARINA; VELOSO PEREIRA, BEATRIZ MARIA; DA SILVA, KAROLLINE S.; FABRE, NELLY T.; CATANOZI, SERGIO; PASSARELLI, MARISA; CORREA-GIANNELLA, MARIA LUCIA. Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro. Life Sciences, v. 270, APR 1 2021. (18/00573-4, 19/10583-0, 16/15603-0, 16/04591-1, 12/04831-1, 12/18724-2, 13/00713-7, 14/17251-9)