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Glucose transporters and diabetes mellitus: contribution to the knowledge of glycemic control and chronic diseases development


Diabetes mellitus (DM) is an important public health trouble, and despite enormous efforts to control it, the DM incidence is growing up. Although the main characteristic of DM is the loss of glycemic homeostasis, which is related with impaired body glucose fluxes, its morbid-mortality is related to chronic degenerative diseases in kidney, eyes, and autonomic nervous and cardiovascular systems, which are related to impaired cellular glucose disposal. Thus, the glucose transport is a key mechanism in the development of impaired glucose homeostasis and chronic degenerative diseases. Glucose transport occurs by facilitative diffusion or by sodium glucose co transport, involving two families of transporter carriers the GLUTs and the SGLTs, respectively. One and a half decade of glucose transporter studies in DM have given us enough data to conclude that: 1) changes in muscle and adipose tissues GLUT4 expression are related to impaired glycemic homeostasis; and 2) changes in GLUTs or SGLTs expression in specific tissues are related to the degenerative diseases. By studying the role of GLUT4 in the glycemic homeostasis as well as the role of GLUT1, GLUT2 and SGLT2 in the diabetic nephropathy, we have contributed to the knowledge in this field. To know the mechanisms that regulate the expression of these genes may provide us with the way to control these genes and to establish preventive or therapeutic approaches. The aim of the present project is to investigate mechanisms involved in diabetes-induced changes of glucose transporters gene expression, and their relationship with glycemic homeostasis and chronic diseases (mainly in kidney and in the sympathetic nervous system). Specific purposes include the investigation of: 1) mechanisms involved in GLUT4 expression changes (heart, muscle and adipose tissue) and its relationship with the glycemic control; 2) sympathetic nervous system and renin-angiotensin system effects upon glucose transporter gene expression changes related to glycemic control and nephropathy; 3) transcriptional and post-transcriptional mechanisms involved in the observed gene expression changes, focusing on transcriptional factors MEF2/D, HIF-1α, TRα, PPAR-y, NF-kB, HNF-3β e HNF-1α; and 4) in diabetic humans, the correlation between nephropathy and T22999 and T-22841polymorphisms of GLUT1 gene. According to specific objectives, our study includes: 1) animal models of diabetes (mice and rats) treated or not with drug, hormones and diets; 2) isolated muscle (L6), adipose and tubule-renal (HEK-H and IRPTC) cells, cultivated with drugs and hormones; and 3) human patients, diabetic for > 15 years, with or without nephropathy. Our study will investigate: 1) metabolic-hormonal conditions; 2) mRNA (Northem and real-time PCR) and protein (Westem and immunohistochemistry) expression of glucose transporters; 3) the involvement of transcriptional factor in observed changes of gene expression (Eletroforetic Mobility Shift Assay - EMSA ¬gel-shift and supershift); 4) potential post-transcriptional regulations of the genes (RNAse-H and polyssomal mRNA analysis assays); 5) intracellular transduction path¬way of hormones, substrates and transcriptional factors; and 6) the frequency of GLUT1 polymorphisms in diabetic patients. We hope that establishing mechanisms involved in the glucose transporter expression changes in DM will contribute to achieving ways to develop new preventive and therapeutic approaches for diabetes and its chronic diseases. (AU)

Scientific publications (12)
(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)
SABINO-SILVA, ROBINSON; OKAMOTO, MARISTELA MITIKO; DAVID-SILVA, ALINE; MORI, ROSANA CRISTINA; FREITAS, HELAYNE SOARES; MACHADO, UBIRATAN FABRES. Increased SGLT1 expression in salivary gland ductal cells correlates with hyposalivation in diabetic and hypertensive rats. DIABETOLOGY & METABOLIC SYNDROME, v. 5, OCT 24 2013. Web of Science Citations: 8.
FURUYA, D. T.; NERI, E. A.; POLETTO, A. C.; ANHE, G. F.; FREITAS, H. S.; CAMPELLO, R. S.; REBOUCAS, N. A.; MACHADO, U. F. Identification of nuclear factor-kappa B sites in the Slc2a4 gene promoter. Molecular and Cellular Endocrinology, v. 370, n. 1-2, p. 87-95, MAY 6 2013. Web of Science Citations: 17.
DE OLIVEIRA, UBIRAJARA OLIVEIRA; BELLO-KEIN, ADRIANE; DE OLIVEIRA, ALVARO REISCHAK; KUCHASKI, LUIZ CARLOS; MACHADO, UBIRATAN FABRES; IRIGOYEN, MARIA CLAUDIA; SCHAAN, BEATRIZ D'AGORD. Insulin alone or with captopril: effects on signaling pathways (AKT and AMPK) and oxidative balance after ischemia-reperfusion in isolated hearts. FUNDAMENTAL & CLINICAL PHARMACOLOGY, v. 26, n. 6, p. 679-689, DEC 2012. Web of Science Citations: 6.
SABINO-SILVA, ROBINSON; CERONI, ALEXANDRE; KOGANEZAWA, TADACHIKA; MICHELINI, LISETE C.; MACHADO, UBIRATAN F.; ANTUNES, VAGNER R. Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands. Physiology & Behavior, v. 107, n. 3, p. 390-396, OCT 10 2012. Web of Science Citations: 0.
CAMPELLO, R. S.; ALVES-WAGNER, A. B.; LUCAS, T. F.; MORI, R. C.; FURUYA, D. T.; PORTO, C. S.; MACHADO, U. F. Estrogen Receptor 1 Agonist PPT Stimulates Slc2a4 Gene Expression and Improves Insulin-Induced Glucose Uptake in Adipocytes. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 12, n. 19, p. 2059-2069, OCT 2012. Web of Science Citations: 12.
FURUYA, D. T.; POLETTO, A. C.; FREITAS, H. S.; MACHADO, U. F. Inhibition of cannabinoid CB1 receptor upregulates Slc2a4 expression via nuclear factor-kappa B and sterol regulatory element-binding protein-1 in adipocytes. JOURNAL OF MOLECULAR ENDOCRINOLOGY, v. 49, n. 2, p. 97-106, OCT 2012. Web of Science Citations: 15.
CAMPELLO, RAQUEL SALDANHA; TEIXEIRA ALVES-WAGNER, ANA BARBARA; ABDULKADER, FERNANDO; TIEKO MORI, ROSANA CRISTINA; MACHADO, UBIRATAN FABRES. Carbohydrate- and lipid-enriched meals acutely disrupt glycemic homeostasis by inducing transient insulin resistance in rats. Canadian Journal of Physiology and Pharmacology, v. 90, n. 5, p. 537-545, MAY 2012. Web of Science Citations: 7.
SABINO-SILVA, ROBINSON; ALVES-WAGNER, ANA B. T.; BURGI, KATIA; OKAMOTO, MARISTELA M.; ALVES, ADILSON S.; LIMA, GUILHERME A.; FREITAS, HELAYNE S.; ANTUNES, VAGNER R.; MACHADO, UBIRATAN F. SGLT1 protein expression in plasma membrane of acinar cells correlates with the sympathetic outflow to salivary glands in diabetic and hypertensive rats. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 299, n. 6, p. E1028-E1037, DEC 2010. Web of Science Citations: 14.
POLETTO, ANA CLAUDIA; ANHE, GABRIEL FORATO; EICHLER, PAULA; TAKAHASHI, HILTON KENJI; FURUYA, DANIELA TOMIE; OKAMOTO, MARISTELA MITIKO; CURI, RUI; MACHADO, UBIRATAN FABRES. Soybean and sunflower oil-induced insulin resistance correlates with impaired GLUT4 protein expression and translocation specifically in white adipose tissue. Cell Biochemistry and Function, v. 28, n. 2, p. 114-121, MAR 2010. Web of Science Citations: 7.
SABINO-SILVA, R.; FREITAS, H. S.; LAMERS, M. L.; OKAMOTO, M. M.; SANTOS, M. F.; MACHADO, U. F. Na plus -Glucose Cotransporter SGLT1 Protein in Salivary Glands: Potential Involvement in the Diabetes-Induced Decrease in Salivary Flow. Journal of Membrane Biology, v. 228, n. 2, p. 63-69, MAR 2009. Web of Science Citations: 24.
LIMA, GUILHERME ALVES; ANHE, GABRIEL FORATO; GIANNOCCO, GISELE; NUNES, MARIA TEREZA; CORREA-GIANNELLA, MARIA LUCIA; MACHADO, UBIRATAN FABRES. Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TR alpha transcriptional factors. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 296, n. 1, p. E132-E138, JAN 2009. Web of Science Citations: 23.

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