The kidney contributes to glucose homeostasis through processes of gluconeogenesis, glucose filtration, glucose reabsorption, and glucose consumption. Each of these processes can be altered in patients with type-2 diabetes (T2DM), providing potential targets for novel therapies. Recent studies have indicated that the kidney is responsible for up to 20% of all glucose production via gluconeogenesis. In patients with T2DM, overall glucose production increases by as much as 300%, with equal contributions from hepatic and renal sources. This increased production contributes not only to increased fasting glucose in T2DM patients but also to raised postprandial glucose because, in contrast to the liver, glucose ingestion increases renal gluconeogenesis. Under normal circumstances, up to 180 g/day of glucose is filtered by the renal glomerulus and virtually all of it is subsequently reabsorbed in the proximal convoluted tubule. This reabsorption is effected by two sodium-dependent glucose cotransporter (SGLT) proteins. SGLT2, situated in the S1 segment, is a low-affinity high-capacity transporter reabsorbing up to 90% of filtered glucose. SGLT1, situated in the S3 segment, is a high-affinity low-capacity transporter reabsorbing the remaining 10%. In patients with T2DM, renal reabsorptive capacity maladaptively increases from a normal level of 19.5 to 23.3 mmol/l/min. Once glucose has been reabsorbed into the tubular epithelial cells, it diffuses into the interstitium across specific facilitative glucose transporters (GLUTs). GLUT1 and GLUT2 are associated with SGLT1 and SGLT2, respectively.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC), leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml) in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB) and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-κB suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression through phosphorylated smad3.

Although there have been major advances in the understanding of the molecular mechanisms that contribute to the development of diabetic nephropathy, current best practice still leaves a significant treatment gap. The incidence of diabetes and associated nephropathy is increasing, with the main cause of mortality being related to cardiovascular causes. Novel therapies which are both 'cardio-renal'-protective seem the logical way forward. In the present review, we discuss the GLP-1 (glucagon-like peptide-1) receptor agonists and DPP-4 (dipeptidyl peptidase-4) inhibitors (incretin-based therapies), which are novel antidiabetic agents used in clinical practice and their role in diabetic nephropathy with specific focus on renoprotection and surrogate markers of cardiovascular disease. We discuss the pleiotropic effects of the incretin-based therapies apart from glucose-lowering and highlight the non-GLP-1 effects of DPP (dipeptidyl peptidase) inhibition. Large-scale clinical studies with cardiovascular end points are underway; however, studies with renal end points are lacking but much needed.

The available clinical evidence shows consistent reduction in glycaemic parameters and some evidence suggests additional effects including weight loss and mild blood pressure reduction. There are some side effects that warrant further investigation and establishing whether SGLT2 inhibition provides a renal benefit relies on future long-term studies with specific renal end-points.

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Background and ObjectiveSodium glucose cotransporter 2 (SGLT2) is the main luminal glucose transporter in the kidney. SGLT2 inhibition results in glycosuria and improved glycaemic control. Drugs inhibiting this transporter have recently been approved for clinical use and have been suggested to have potential renoprotective benefits by limiting glycotoxicity in the proximal tubule. We aimed to determine the renoprotective benefits of empagliflozin, an SGLT2 inhibitor, independent of its glucose lowering effect.Research Design and MethodsWe induced diabetes using a low dose streptozotocin protocol in 7–8 week old endothelial nitric oxide (eNOS) synthase knockout mice. We measured fasting blood glucose on a monthly basis, terminal urinary albumin/creatinine ratio. Renal histology was assessed for inflammatory and fibrotic changes. Renal cortical mRNA transcription of inflammatory and profibrotic cytokines, glucose transporters and protein expression of SGLT2 and GLUT1 were determined. Outcomes were compared to diabetic animals receiving the angiotensin receptor blocker telmisartan (current best practice).ResultsDiabetic mice had high matched blood glucose levels. Empagliflozin did not attenuate diabetes-induced albuminuria, unlike telmisartan. Empagliflozin did not improve glomerulosclerosis, tubular atrophy, tubulointerstitial inflammation or fibrosis, while telmisartan attenuated these. Empagliflozin did not modify tubular toll-like receptor-2 expression in diabetic mice. Empagliflozin did not reduce the upregulation of macrophage chemoattractant protein-1 (MCP-1), transforming growth factor β1 and fibronectin mRNA observed in the diabetic animals, while telmisartan decreased transcription of MCP-1 and fibronectin. Empagliflozin increased GLUT1 mRNA expression and telmisartan increased SGLT2 mRNA expression in comparison to untreated diabetic mice. However no significant difference was found in protein expression of GLUT1 or SGLT2 among the different groups.ConclusionHence SGLT2 inhibition does not have renoprotective benefits independent of glucose lowering.

The naturally occurring substance phlorizin has long been recognized to block the reabsorption of glucose from the glomerular ultrafiltrate into the systemic circulation. The poor oral bioavailability and adverse effects associated with this agent, however, have prevented its use in clinical practice and restricted its use to that of a physiological tool. The development of novel agents that are able to block the principal glucose transporter in the kidney has allowed the inhibition of renal glucose reabsorption to be re-evaluated as a therapeutic tool in patients with diabetes mellitus. This Perspectives article summarizes current knowledge pertaining to glucose transport in the kidney and describes the evidence regarding glucose transport blockade as a novel target for the management of hyperglycemia in the context of existing treatment strategies.

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