Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon

Disclosures

Curr Opin Nephrol Hypertens. 2016;25(1):50-58. 

In This Article

Molecular Regulation of Sodium Glucose Cotransporter 2 Expression and Activity

Studies in mice have shown that pharmacological SGLT2 inhibition itself also increases renal SGLT2 protein expression, that is, under conditions when the physiologic uptake of glucose into the early proximal tubule is inhibited.[14] The mechanisms involved in SGLT2 upregulation under these conditions and in response to diabetes (see above) remain poorly understood. Studies in human embryonic kidney (HEK-293 T) cells indicated that insulin phosphorylates SGLT2 on Ser624, thereby increasing its activity.[16] Studies in cultured human proximal tubular cells reported that insulin, but not high glucose, enhanced SGLT2 protein expression. The insulin-induced increase in SGLT2 expression was associated with an increased reactive oxygen species content and attenuated by N-acetylcysteine.[17] Insulin binding in the kidney corresponds to sites of SGLT2 expression, and therefore the insulin release following ingestion of a glucose-rich meal may activate SGLT2 to retain the ingested glucose in the body.[18] Although hyperinsulinemia may contribute to the increased SGLT2 protein expression and activity in T2DM db/db mice, it cannot explain the increased renal SGLT2 expression in hypoinsulinemic T1DM Akita mice.[13,14] Other molecules implicated in the upregulation of SGLT2 activity include protein kinase C and protein kinase A, whereas angiotensin II AT1 receptors and hepatocyte nuclear factor HNF-1α have been proposed to increase SGLT2 expression in the diabetic state (for review see[12,19]). More studies are needed to better understand the nuances of the regulation of SGLT2 expression and activity.

Is there relevant extrarenal expression of SGLT2? This question is important for the clinical use of SGLT2 inhibitors, and, consistent with previous reports in humans and mice,[4] a recent study could not detect SGLT2 mRNA in human small intestine, liver, heart, lung, fat tissue, and brain.[9] Obviously, negative results cannot exclude small amounts of SGLT2 mRNA expression, and, as discussed below, new studies indicated that SGLT2 is expressed and functionally active in glucagon-secreting alfa cells of the pancreatic islets.[20]

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