Marks, Joanne; (2004) Renal brush border membrane glucose transport: Regulatory mechanisms and adaption to diabetic hyperglycaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There is now substantial evidence that implicates hyperglycaemia in the progression of diabetic nephropathy. Studies using mesangial cells have demonstrated that overexpression of the facilitative glucose transporter, GLUT1, is a key factor that predisposes this cell type to glucose-induced damage. Diabetes is also reported to evoke changes in proximal tubule function, yet the underlying mechanisms involved have not been studied in detail. The studies described in this thesis were designed to investigate the effect of streptozotocin-induced diabetes on proximal tubular glucose transport and to determine the cellular mechanisms involved in its regulation. Streptozotocin-induced diabetes was found to increase facilitative glucose transport across the proximal tubule brush border membrane (BBM), a response that could be abolished by normalisation of the blood glucose levels. Changes in transport rate correlated with expression of GLUT2 at the proximal tubule BBM. Experiments investigating the regulation of renal glucose transport demonstrated that sodium-dependent and facilitative glucose transport, are regulated by different intracellular signaling events. The regulation of sodium-dependent glucose transport was found to occur via cAMP-induced insertion of SGLT1 protein into the proximal tubule BBM. In contrast, a pathway involving both protein kinase C and intracellular calcium was demonstrated to regulate facilitative glucose transport. The data reported herein provided evidence that GLUT2 expression at the proximal tubule BBM provides a dominant low affinity/high capacity route for glucose reabsorption during hyperglycaemia, which may culminate in glucose-induced damage of this nephron segment. The adaptation of renal glucose transport to experimentally-induced diabetes and the mechanisms involved in the regulation of renal glucose transport display striking similarities to those reported for the small intestine.

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