Increased Renal Metabolism in Diabetes: Mechanism and Functional Implications

Abstract

The coupling between the Na+/glucose cotransporter and Na(+)-K(+)-ATPase (NKA) described for epithelial cells (1) prompted us to study in rats with streptozocin-induced diabetes the effect of increased tubular glucose load on tubular Na+ reabsorption, NKA-dependent O2 consumption (QO2), and NKA activity. Filtered glucose is mainly reabsorbed in the proximal tubuli via the phlorizin-sensitive Na+/glucose cotransporter. In this study, the diabetic rats had a significantly higher renal blood flow (RBF), glomerular filtration rate (GFR), and Na+ reabsorption than the control rats. Total renal QO2 as well as QO2 in cortical tissue, which consists mainly of proximal tubular cells, was significantly higher in diabetic than in control rats. The increase in tissue QO2 was entirely caused by increased NKA-dependent QO2. NKA activity, measured as rate of ATP hydrolysis, was increased in cortical tubular but not glomerular tissue from diabetic rats. Phlorizin treatment abolished the increase in NKA activity, Na+ reabsorption, and QO2, as well as the increase in RBF and GFR in diabetic rats. We conclude that diabetes is associated with increased renal O2 metabolism secondary to the increase in coupled Na+ reabsorption via the Na+/glucose cotransporter and NKA. The increased oxygen consumption might contribute to the hyperperfusion and hyperfiltration in the diabetic kidney.

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…A perhaps more plausible explanation is therefore that the in-creased glucose load to the proximal tubular cells enhances the flux through the Na + /glucose co-transporters [17]. As a result, Na + /K + -ATPase up-regulates and thus increases oxygen consumption [17,27]. This explanation is also supported by results showing that the ouabain-sensitive inhibition of oxygen consumption was increased in the medullary cells of the diabetic animals.…”

“…However, an increased renal cellular oxygen consumption has previously been reported in vitro during the early onset of diabetes mellitus [8,17]. This was partly ascribed to increased tubular load of sodium, as a result of glomerular hyperfiltration [17]. In the present work, however, we chose to study diabetic animals when the initial diabetes-induced glomerular hyperfiltration, known to exist in this rat strain [26], was no longer present.…”

“…The reduced renal oxygen tension and increased renal cellular oxygen consumption were also independent of GFR [8]. A perhaps more plausible explanation is therefore that the in-creased glucose load to the proximal tubular cells enhances the flux through the Na + /glucose co-transporters [17]. As a result, Na + /K + -ATPase up-regulates and thus increases oxygen consumption [17,27].…”

“…One potential mechanism is a change in oxygen-haemoglobin dissociation, occurring as a result of increased lactate concentration and concomitant decreased pH in the renal medulla in diabetic animals (see above). However, an increased renal cellular oxygen consumption has previously been reported in vitro during the early onset of diabetes mellitus [8,17]. This was partly ascribed to increased tubular load of sodium, as a result of glomerular hyperfiltration [17].…”

“…For non-diabetic rats, the buffer contained 5.8 mmol/l glucose, and for diabetic animals the buffer contained 23.2 mmol/l glucose (similar to the blood glucose concentrations in the latter animals). The renal cells were isolated as previously described [8,17,18]. In brief, the rats were anaesthetised with thiobutabarbital, the kidneys were excised and the renal capsule was removed.…”