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Regulation of glucose transporters gene expression in Diabetes Mellitus: Pathophysiological role and potential preventive and therapeutical approaches

Grant number: 02/07384-4
Support type:Research Projects - Thematic Grants
Duration: December 01, 2002 - July 31, 2007
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Ubiratan Fabres Machado
Grantee:Ubiratan Fabres Machado
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Maria Tereza Nunes

Abstract

Regulation of glucose transporters gene expression in Diabetes Mellitus: Pathophysiogical role and potential preventive and therapeutical approaches. In the nineties, several glucose transporter proteins were characterized as responsible for both the facilitated diffusion (GLUTs) and the sodium-coupled transport (SGL Ts). Subsequent1y, the participation of glucose transporters in several pathophysiological mechanisms of Diabetes Mellitus (DM) was reported. Our studies in DM have contributed to clarify the following: (1) the reduction of the GLUT4 protein content in skeletal and cardiac muscles, and in white and brown adipose tissues is involved in insulin resistance; (2) the increase in GLUT2 and SGL T2 and the reduction of GLUT1, respectively in S1 and S2 segments of renal proximal tubule, are involved in the diabetic tubulopathy; and (3) the increase in cortical GLUT1 (mesangial cells) is involved in the diabetic glomerulosclerosis. To avoid or to reverse these gene expression changes represents to establish preventive or therapeutical approaches for the pathophysiological alterations of DM. For that, it is very important to deeply know the regulatÍon of glucose transporters gene expression mechanisms. Thus, the aim of the present study is to investigate the changes in the gene expression, as well as the involved mechanisms, present in DM, focusing on GLUT4 in insulin sensitive tissues, and on GLUT2, GLUT1, SGLT2 and SGLT1 in kidney. We propose, then: (1) to investigate mechanisms involved in GLUT 4 gene expression on increased and reduced insulin sensitivity conditions; (2) to investigate the potential role of T3 and E2 hormones as modulators of GLUT4 gene expression; (3) to investigate the glucose transporters in kidney and its relationship with tubular and mesangial damages; and (4) to screen (by macroarray analysis) transcriptional factors genes responsible for the transporters gene expression detected. According to each specific study we will investigate: (1) monosodium glutamate-treated mice as model of obesity and DM2; (2) fasted and refed rats as model of acute decrease and increase of insulin sensitivity, respectively; (3) thiroidectomized rats treated or not with T3, and ooforectomized remate rats treated or not with E2, as models to investigate the role of these lipophilic hormones; (4) aloxan-treated rats as model of diabetic rats with tubulopathy; (5) streptozotocin-treated and renal denervated rats as model of diabetic rats with nephropathy and autonomic neuropathy. Also in accordance with each study: (1) the metabolic and hormonal condition will be characterized; (2) the abundance of transporter proteins and their mRNAs will be analyzed by Western and Northern blotting, respectively; (3) the involved transcriptional factors will be screened by macroarrays; and (4) occasional post-transcriptional modulations will be investigated, concerning the mRNA poly-A tail by analysis of mRNA migration, in order to determine the poly-A tail size by RNase-H assay.We hope that the knowledge about glucose transporters gene expression mechanisms will help to provide scenery, which may contribute to the development of new pharmacological approaches to DM. (AU)

Scientific publications (8)
(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, THAIS DE CASTRO; NICOLETTI DE CARVALHO, JOSE EDGAR; POYARES, LEONICE LOURENCO; BORDIN, SILVANA; MACHADO, UBIRATAN FABRES; NUNES, MARIA TEREZA. Potential Role of Growth Hormone in Impairment of Insulin Signaling in Skeletal Muscle, Adipose Tissue, and Liver of Rats Chronically Treated with Arginine. Endocrinology, v. 150, n. 5, p. 2080-2086, MAY 2009. Web of Science Citations: 14.
DE ALMEIDA BARROS, RODRIGO PALAZZO; MORANI, ANDREA; MORISCOT, ANSELMO; MACHADO, UBIRATAN FABRES. Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4. Molecular and Cellular Endocrinology, v. 295, n. 1-2, p. 24-31, NOV 25 2008. Web of Science Citations: 41.
FREITAS‚ HS; ANHE‚ GF; MELO‚ KFS; OKAMOTO‚ MM; OLIVEIRA-SOUZA‚ M.; BORDIN‚ S.; MACHADO‚ UF. Na+-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1α expression and activity. Endocrinology, v. 149, n. 2, p. 717-724, 2008.
MORI‚ RCT; HIRABARA‚ SM; HIRATA‚ AE; OKAMOTO‚ MM; MACHADO‚ UF. Glimepiride as insulin sensitizer: increased liver and muscle responses to insulin. DIABETES OBESITY & METABOLISM, v. 10, n. 7, p. 596-600, 2008.
DE CASTRO BARBOSA‚ T.; LOURENÇO POYARES‚ L.; FABRES MACHADO‚ U.; NUNES‚ M.T. Chronic oral administration of arginine induces GH gene expression and insulin resistance. Life Sciences, v. 79, n. 15, p. 1444-1449, 2006.
FREITAS, HELAYNE SOARES; SCHAAN, BEATRIZ D’AGORD; SERAPHIM, PATRICIA MONTEIRO; NUNES, MARIA TEREZA; MACHADO, UBIRATAN FABRES. Acute and short-term insulin-induced molecular adaptations of GLUT2 gene expression in the renal cortex of diabetic rats. Molecular and Cellular Endocrinology, v. 237, n. 1/2, p. 49-57, Jun. 2005.
TOMIE FURUYA‚ D.; BINSACK‚ R.; EMY ONISHI‚ M.; MONTEIRO SERAPHIM‚ P.; FABRES MACHADO‚ U. Low ethanol consumption induces enhancement of insulin sensitivity in liver of normal rats. Life Sciences, v. 77, n. 15, p. 1813-1824, 2005.
A.M. VARGAS; R.P.A. BARROS; R.A. ZAMPIERI; M.M. OKAMOTO; P. DE CARVALHO PAPA; U.F. MACHADO. Abnormal subcellular distribution of GLUT4 protein in obese and insulin-treated diabetic female dogs. Brazilian Journal of Medical and Biological Research, v. 37, n. 7, p. 1095-1101, Jul. 2004.

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