Diabetes Increases Facilitative Glucose Uptake and GLUT2 Expression at the Rat Proximal Tubule Brush Border Membrane

Abstract

The mechanism of renal glucose transport involves the reabsorption of filtered glucose from the proximal tubule lumen across the brush border membrane (BBM) via a sodium‐dependent transporter, SGLT, and exit across the basolateral membrane via facilitative, GLUT‐mediated, transport. The aim of the present study was to determine the effect of streptozotocin‐induced diabetes on BBM glucose transport. We found that diabetes increased facilitative glucose transport at the BBM by 67.5 % (P < 0.05) – an effect that was abolished by overnight fasting. Western blotting and immunohistochemistry demonstrated GLUT2 expression at the BBM during diabetes, but the protein was undetectable at the BBM of control animals or diabetic animals that had been fasted overnight. Our findings indicate that streptozotocin‐induced diabetes causes the insertion of GLUT2 into the BBM and this may provide a low affinity/high capacity route of entry into proximal tubule cells during hyperglycaemia.

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

“…Moreover, our previous study demonstrated that in STZ-induced diabetes the sodium-dependent component of renal glucose transport was unchanged, whereas the facilitative (GLUT-mediated) component was significantly enhanced. Western blotting showed an increase in both GLUT2 and GLUT5 protein at the BBM, with no change in GLUT1 protein levels; and that the upregulation of GLUT2, but not of GLUT5, could be abolished by overnight fasting [9]. Similar findings were reported by Freitas et al, who concluded that plasma glucose concentration was the key regulator of the gene encoding GLUT2 [24].…”

“…We have reported previously that STZ-induced diabetes results in translocation of GLUT2 protein to the BBM and that this is likely to be due to hyperglycaemia [9]. The present study aimed to determine whether more modest changes in plasma glucose concentration had any effect on GLUT2 levels at the BBM.…”

“…Therefore, since GLUT5 is considered to be a fructose transporter in vivo, with only a low affinity for glucose [25], and GLUT1 protein levels in the renal tubule are generally considered to be reduced [26,27] or unchanged in diabetes [9], it is reasonable to hypothesise that GLUT2 might be responsible for glucose-induced tubular cell hypertrophy in diabetes. Indeed, two indirect findings also suggest a potential pathophysiological link between GLUT2 function and the kidney: one is the finding of renal hypertrophy and glomerulopathy in patients with GLUT2 mutations in the Fanconi-Bickel syndrome [28]; the other is the recent observation that flavonoids, which are known to ameliorate the changes of diabetic nephropathy in experimental models [29], inhibit GLUT2 production [30].…”

“…Brush border membrane vesicle preparation The methods used to prepare renal BBM vesicles have been described previously [9]. In brief, animals were anaesthetised with an i.p.…”

“…There is less evidence to support a similar process occurring in the proximal tubule BBM, but because the basic glucose transport mechanisms are similar in both tissues, it seems likely that the same model may apply. Indeed, we have demonstrated that GLUT2 is translocated to the proximal tubule BBM in streptozotocin (STZ)-induced diabetes and that overnight fasting, which reduces plasma glucose concentrations to normal levels, reverses the BBM targeting of GLUT2 [9].…”