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

Abstract

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)