Regulation of renal brush-border glucose transport in response to metabolic dysregulation.
Doctoral thesis, UCL (University College London).
Diabetic nephropathy is a consequence of hyperglycaemia-induced renal cell damage and a major contributor to end-stage renal disease in later stages of diabetes. Previous studies, in type I diabetes, observed PKC-βI-dependent GLUT2 recruitment to the proximal tubule brush-border membrane (BBM) as a direct result of elevated plasma glucose. The up-regulation of glucose transporters at the proximal tubule BBM causes a rise in intracellular glucose concentration; tubular injury in diabetic nephropathy is postulated to be a result of increased GLUT-mediated glucose entry into the proximal tubule cell. Augmented glucose transport across the proximal tubule BBM is likely to elevate glucose reabsorption and exacerbate hyperglycaemia during diabetes. Thus identification of regulators of this process may offer novel therapeutic targets to reduce renal glucose handling during hyperglycaemia. Studies described in this thesis were designed to elucidate the modulation of glucose transporters in models of metabolic syndrome associated with diabetes. Type II diabetes, the prevalent form of the disease, was found to elevate both SGLT- and GLUT-mediated glucose transport across the proximal tubule BBM, with an accompanying increase in glucose transporter expression. In rodent models of metabolic syndrome, induced by feeding studies, an elevation in PKC-βI-dependent GLUT2 recruitment to the proximal tubule BBM was also observed. However SGLT1 expression at the proximal tubule BBM did not consistently mirror that of GLUT2. In studies presented in this thesis, the sweet taste receptor heterodimer (T1R2/3) was identified at the proximal tubule BBM and this sweet taste sensor exhibited a tight correlation with SGLT1 in all models of metabolic dyregulation studied. Furthermore, stimulation of T1R2/3, by the artificial sweetener saccharin, resulted in an increase in SGLT-mediated glucose transport across the proximal tubule BBM. The data reported in this thesis provide evidence that GLUT2 expression at the proximal tubule BBM is not solely a response to hyperglycaemia but also a renal response to whole-body metabolic dysregulation. From these studies it is hypothesised that PKC-βI-mediated GLUT2 recruitment to the proximal tubule BBM occurs via a SGLT-T1R2/3-dependent and –independent pathway.
|Title:||Regulation of renal brush-border glucose transport in response to metabolic dysregulation|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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