New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives

• Grant number: 12/04831-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2012
• End date: December 31, 2016
• 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 scholarship(s): 15/18715-1 - Participation of the transcription factor SP1 in estradiolinduced regulation of Slc2a4/GLUT4 expression in adipocytes 3T3L1, BP.MS; 15/19000-6 - Study of sediment and microRNAs in the urine of patients with Type 1 diabetes to identify pathways associated to the progression of diabetic kidney disease, BP.PD; 14/17251-9 - The effects of chronic administration of albumin modified by advanced glycation (AGE) on renal tissue: characterization of the inflammatory, antioxidant and epigenetic profile, BP.PD; + associated scholarships 14/02219-2 - Effect of resveratrol on hepatic metabolism of glucose in Diabetes, BP.IC; 13/26616-8 - cAMP responsive element (CRE) participation in the SLC2A4 regulation by sympathetic nervous system, BP.PD; 13/00713-7 - Effects of chronic administration of albumin modified by advanced glycation (age) on liver tissue: characterization of histological, inflammatory and antioxidant profile, BP.MS; 13/03343-6 - VEGFA-mediated role of estradiol on angiogenesis/adipogenesis process in the adipose tissue, BP.PD; 12/25490-8 - Lower expression of advanced glycation endproduts receptor-1 (AGER1) in peripheral blood mononuclear cells is associated with renal disease in type 1 diabetes patients, BP.MS; 12/24210-1 - REGULATION OF Slc2a4/GLUT4 EXPRESSION BY 17²-ESTRADIOL, BP.PD; 12/20432-0 - INVESTIGATION OF miRNAS POTENTIALLY INVOLED IN THE SLC2A4-GLUT4 EXPRESSION REGULATION IN SKELETAL MUSCLE OF DIABETIC RATS, BP.DR; 12/18724-2 - Advanced glycated albumin and insulin resistance in rats: focus on periepididimal adipose tissue and N-acetylcysteine actions, BP.DR; 12/15514-7 - Effect of advanced glycated albumin upon Slc2a4 gene in skeletal muscle, BP.DR; 12/12088-7 - Glycemic control and the removal of macrophage cholesterol by ABCA-1: role of modified albumin by advanced glycation, BP.PD; 08/09194-4 - Cannabinoid receptor CB1 modulation of glucose transporter protein GLUT4 in adipocytes 3T3-L1 and visceral adipose tissue of obese mice, BP.PD - associated scholarships

Abstract

Diabetes mellitus is a growing public health problem. In order to combat this disease, it is necessary to have deep knowledge of its pathophysiological mechanisms. The present project attempts to investigate features related to the development/progression of DM, seeking to expand preventive and therapeutic approaches for the control of glycemia and the development of chronic complications. In experimental models, the following will be investigated: 1) the effects of inflammatory mediators, endoplasmic reticulum stress pathway, sympathetic blockers, corticosteroids, estrogen, glycated albumin and AGEs upon glucose uptake and glucose transporter expression in muscle and adipose tissue, glucose efflux and proteins related to glucose metabolism in liver, and insulin secretion by pancreatic islets; 2) the relationship between nephropathy development and GLUTs, SGLTs, RAGE and AGE-R1 expression in kidney; 3) the effect of glycotoxicity, cAMP, AGEs and inflammatory mediators on renal HEK-293 cells; and 4) the role of GLUT4, lipid content, inflammatory activity, AGEs, oxidative stress and endoplasmic reticulum stress in the cardiomyopathy. As new therapeutic players, the effects of diacerein, estrogen receptor alpha agonist, cannabinoid receptor CB1 inhibitor, benfotiamine and sirtuin will be investigated. Furthermore, we will also investigate: 5) in human type 2 DM, the effect of acute exercise on glycemic control (by CGMS) and markers of oxidative stress and inflammatory activity, and the impact of resistance exercise on glycemic control and cardiovascular function; and 6) in human type 1 DM, the correlation between polymorphisms (SNPs) in genes related to glucose transport, AGEs production and oxidative stress and nephropathy; the correlation between polymorphonuclear cells RAGE/AGE-R1 and nephropathy; and the expression of GLUTs/RAGE/AGE-R1 in urinary sediment, as a marker of intra-renal activity of pathways related to the development/progression of nephropathy. We hope to characterize new preventive and therapeutic approaches, which will contribute to the health of diabetic subjects. (AU)

Scientific publications

(29)

(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)

SANTOS-BEZERRA, DANIELE PEREIRA; ADMONI, SHARON NINA; MORI, ROSANA CRISTINA; PELAES, TATIANA SOUZA; PEREZ, RICARDO VESONI; MACHADO, CLEIDE GUIMARAES; MONTEIRO, MARIA BEATRIZ; PARISI, MARIA CANDIDA; PAVIN, ELIZABETH JOAO; QUEIROZ, MARCIA SILVA; et al. Genetic variants in DNMT1 and the risk of cardiac autonomic neuropathy in women with type 1 diabetes. JOURNAL OF DIABETES INVESTIGATION, v. 10, n. 4, p. 985-989, JUL 2019. (12/04831-1)

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)

GERLINGER-ROMERO, FREDERICO; YONAMINE, CAIO YOGI; PINTO JUNIOR, DANILO CORREA; DELCONTI ESTEVES, JOAO VICTOR; MACHADO, UBIRATAN FABRES. Dysregulation between TRIM63/FBXO32 expression and soleus muscle wasting in diabetic rats: potential role of miR-1-3p,-29a/b-3p, and-133a/b-3p. Molecular and Cellular Biochemistry, v. 427, n. 1-2, p. 187-199, MAR 2017. (12/04831-1)

FABRE, NELLY T.; THIEME, KARINA; SILVA, KAROLLINE S.; CATANOZI, SERGIO; CAVALEIRO, ANA MERCEDES; PINTO, JR., DANILO A. C.; OKAMOTO, MARISTELA M.; MORAIS, MYCHEL RAONY P. T.; FALQUETTO, BARBARA; ZORN, TELMA M.; et al. Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products. Molecular and Cellular Endocrinology, v. 447, n. C, p. 116-124, MAY 15 2017. (12/04831-1, 12/18724-2, 13/00713-7, 14/17251-9)

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)

ALVES-WAGNER, ANA BARBARA; MORI, ROSANA CRISTINA; SABINO-SILVA, ROBINSON; FATIMA, LUCIANA ALVES; ALVES, ADILSON DA SILVA; BRITTO, LUIZ ROBERTO; SCHAAN, BEATRIZ D'AGORD; MACHADO, UBIRATAN FABRES. Beta-adrenergic blockade increases GLUT4 and improves glycemic control in insulin-treated diabetic Wistar rats. AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL, v. 193, p. 108-116, DEC 2015. (12/04831-1)

PINTO, PAULA RAMOS; FERRARETTO MOURA ROCCO, DEBORA DIAS; OKUDA, LIGIA SHIMABUKURO; MACHADO-LIMA, ADRIANA; CASTILHO, GABRIELA; DA SILVA, KAROLLINE SANTANA; GOMES, DIEGO JUVENAL; PINTO, RAPHAEL DE SOUZA; IBORRA, RODRIGO TALLADA; FERREIRA, GUILHERME DA SILVA; et al. Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta. LIPIDS IN HEALTH AND DISEASE, v. 14, SEP 16 2015. (12/19112-0, 11/04631-0, 12/12088-7, 11/15153-1, 12/04831-1, 12/18724-2, 13/02854-7)

DA COSTA-PESSOA, JULIANA MARTINS; DAMASCENO, ROSELIA SANTOS; MACHADO, UBIRATAN FABRES; BELOTO-SILVA, OLIVIA; OLIVEIRA-SOUZA, MARIA. High Glucose Concentration Stimulates NHE-1 Activity in Distal Nephron Cells: the Role of the Mek/Erk1/2/p90(RSK) and p38MAPK Signaling Pathways. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 33, n. 2, p. 333-343, 2014. (12/04831-1)

ALVES-WAGNER, ANA BARBARA; SABINO-SILVA, ROBINSON; CAMPELLO, RAQUEL S.; MORI, ROSANA C.; MACHADO, UBIRATAN F.. Decreased diabetes-induced glycemic impairment in WKY and SHR involves enhanced skeletal muscle Slc2a4/GLUT4 expression. DIABETOLOGY & METABOLIC SYNDROME, v. 6, SEP 10 2014. (12/04831-1)

MORAES, PAULO ALEXANDRE; YONAMINE, CAIO YOGI; PINTO JUNIOR, DANILO CORREA; DELCONTI ESTEVES, JOAO VICTOR; MACHADO, UBIRATAN FABRES; MORI, ROSANA CRISTINA. Insulin acutely triggers transcription of Slc2a4 gene: Participation of the AT-rich, E-box and NFKB-binding sites. Life Sciences, v. 114, n. 1, p. 36-44, SEP 26 2014. (12/04831-1)

SANTOS-BEZERRA, D. P.; SANTOS, A. S.; GUIMARAES, G. C.; ADMONI, S. N.; PEREZ, R. V.; PELAES, T. S.; MACHADO, C. G.; PASSARELLI, M.; MACHADO, U. F.; QUEIROZ, M. S.; et al. Increased serum expression of miR-518d-3p and miR-618 in individuals with type 1 diabetes with microvascular chronic complications. Diabetologia, v. 61, p. 1-pg., 2018-10-01. (12/04831-1, 16/15603-0)

CAMPELLO, RAQUEL S.; FATIMA, LUCIANA A.; BARRETO-ANDRADE, JOAO NILTON; LUCAS, THAIS F.; MORI, ROSANA C.; PORTO, CATARINA S.; MACHADO, UBIRATAN F.. Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation. JOURNAL OF MOLECULAR ENDOCRINOLOGY, v. 59, n. 3, p. 257-268, OCT 2017. (12/04831-1, 12/24210-1)

FATIMA, L. A.; CAMPELLO, R. S.; SANTOS, R. DE SOUZA; FREITAS, H. S.; FRANK, A. P.; MACHADO, U. F.; CLEGG, D. J.. Estrogen receptor 1 (ESR1) regulates VEGFA in adipose tissue. SCIENTIFIC REPORTS, v. 7, DEC 1 2017. (15/13652-1, 12/04831-1, 13/03343-6)

GREGORIO, KAREN CRISTINA REGO; LAURINDO, CAROLINE PANCERA; MACHADO, UBIRATAN FABRES. Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation. CELLS, v. 10, n. 1, JAN 2021. (02/07384-4, 12/04831-1)

LEHNEN, TATIANA EDERICH; LEHNEN, ALEXANDRE MACHADO; VICENTE TAVARES, ANGELA MARIA; BELLO-KLEIN, ADRIANE; MARKOSKI, MELISSA MEDEIROS; MACHADO, UBIRATAN FABRES; SCHAAN, BEATRIZ. Atorvastatin administered before myocardial infarction in rats improves contractility irrespective of metabolic changes. Clinical and Experimental Pharmacology and Physiology, v. 41, n. 12, p. 986-994, DEC 2014. (12/04831-1)

MONTEIRO, MARIA BEATRIZ; THIEME, KARINA; SANTOS-BEZERRA, DANIELE PEREIRA; QUEIROZ, MARCIA SILVA; WORONIK, VIKTORIA; PASSARELLI, MARISA; MACHADO, UBIRATAN FABRES; GIANNELLA-NETO, DANIEL; OLIVEIRA-SOUZA, MARIA; CORREA-GIANNELLA, MARIA LUCIA. Beta-2-microglobulin (B2M) expression in the urinary sediment correlates with clinical markers of kidney disease in patients with type 1 diabetes. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 65, n. 6, p. 816-824, JUN 2016. (12/04831-1, 12/05583-1, 12/02003-4, 13/19569-3)

YONAMINE, CAIO YOGI; PINHEIRO-MACHADO, ERIKA; MICHALANI, MARIA LUIZA; FREITAS, HELAYNE SOARES; OKAMOTO, MARISTELA MITIKO; CORREA-GIANNELLA, MARIA LUCIA; MACHADO, UBIRATAN FABRES. Resveratrol improves glycemic control in insulin-treated diabetic rats: participation of the hepatic territory. NUTRITION & METABOLISM, v. 13, JUN 29 2016. (12/04831-1)

POLETTO, ANA CLAUDIA; DAVID-SILVA, ALINE; DE MELO YAMAMOTO, ALINE PEDRO; MACHADO, UBIRATAN FABRES; FURUYA, DANIELA TOMIE. Reduced Slc2a4/GLUT4 expression in subcutaneous adipose tissue of monosodium glutamate obese mice is recovered after atorvastatin treatment. DIABETOLOGY & METABOLIC SYNDROME, v. 7, MAR 14 2015. (13/18841-1, 12/04831-1, 14/10007-5)

MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE PEREIRA; THIEME, KARINA; PASSARELLI, MARISA; MACHADO, UBIRATAN FABRES; LIN, CHIN JIA; CORREA-GIANNELLA, MARIA LUCIA. Optimization of total RNA isolation from human urinary sediment. Clinica Chimica Acta, v. 462, p. 158-161, NOV 1 2016. (12/04831-1, 15/19000-6)

THIEME, KARINA; DA SILVA, KAROLLINE S.; FABRE, NELLY T.; CATANOZI, SERGIO; MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE PEREIRA; COSTA-PESSOA, JULIANA MARTINS; OLIVEIRA-SOUZA, MARIA; MACHADO, UBIRATAN F.; PASSARELLI, MARISA; et al. N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 40, n. 3-4, p. 608-620, 2016. (13/00713-7, 12/04831-1, 14/17251-9, 12/18724-2)

MONTEIRO, MARIA BEATRIZ; SANTOS-BEZERRA, DANIELE PEREIRA; THIEME, KARINA; ADMONI, SHARON NINA; PEREZ, RICARDO VESSONI; MACHADO, CLEIDE GUIMARAES; QUEIROZ, MARCIA SILVA; NERY, MARCIA; OLIVEIRA-SOUZA, MARIA; WORONIK, VIKTORIA; et al. Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes. Free Radical Research, v. 50, n. 1, p. 101-110, JAN 2 2016. (12/25490-8, 13/19569-3, 12/05583-1, 12/04831-1, 12/02003-4)

MARQUES, T.; PATENTE, T. A.; MONTEIRO, M. B.; CAVALEIRO, A. M.; QUEIROZ, M. S.; NERY, M.; DE AZEVEDO, M. J.; CANANI, L. H.; PARISI, M. C.; MOURA-NETO, A.; et al. Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus. Clinica Chimica Acta, v. 444, p. 170-175, APR 15 2015. (12/04831-1, 09/09276-3)

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)

DAVID-SILVA, ALINE; FREITAS, HELAYNE S.; OKAMOTO, MARISTELA M.; SABINO-SILVA, ROBINSON; SCHAAN, BEATRIZ D.; MACHADO, UBIRATAN F.. Hepatocyte nuclear factors 1 alpha/4 alpha and forkhead box A2 regulate the solute carrier 2A2 (Slc2a2) gene expression in the liver and kidney of diabetic rats. Life Sciences, v. 93, n. 22, p. 805-813, NOV 19 2013. (12/04831-1)

ZANQUETTA, MELISSA MOREIRA; ALVES-WAGNER, ANA BARBARA; MORI, ROSANA CRISTINA; CAMPELLO, RAQUEL SALDANHA; MACHADO, UBIRATAN FABRES. Recovery of insulin sensitivity and Slc2a4 mRNA expression depend on T3 hormone during refeeding. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 63, n. 3, p. 328-334, MAR 2014. (12/04831-1)

DA SILVA, ARIEL S.; DIAS, LUCINARA D.; BORGES, JULIA F.; MARKOSKI, MELISSA M.; DE SOUZA, MARTINA S.; IRIGOYEN, MARIA C.; MACHADO, UBIRATAN F.; SCHAAN, BEATRIZ D.. Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats. Life Sciences, v. 92, n. 24-26, p. 1174-1179, JUL 10 2013. (12/04831-1)

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)

GUEDES, J. A. C.; ESTEVES, J. V.; MORAIS, M. R. T.; ZORN, T. M. T.; MACHADO, U. F.; FURUYA, D. T.. MECHANISMS FOR OSTEOCALCIN-IMPROVED INSULIN RESISTANCE. DIABETES TECHNOLOGY & THERAPEUTICS, v. 20, p. 1-pg., 2018-02-01. (14/10007-5, 13/18841-1, 12/04831-1, 15/01576-9)

THIEME, KARINA; FABRE, NELLY TAKASHIMA; DA SILVA, KAROLLINE SANTANA; CATANOZI, SERGIO; MONTEIRO, MARIA BEATRIZ; MACHADO, UBIRATAN FABRES; PASSARELLI, MARISA; CARDILLO CORREA-GIANNELLA, MARIA LUCIA. CHRONIC ADMINISTRATION OF ALBUMIN MODIFIED BY ADVANCED GLYCATION (AGE) INDUCES EXPRESSION OF PRO-FIBROTIC, PRO-APOPTOTIC AND RENIN-ANGIOTENSIN SYSTEM GENES ON RENAL TISSUE. FASEB JOURNAL, v. 30, p. 2-pg., 2016-04-01. (12/04831-1, 14/17251-9)