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Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy – published online 22/08/2020

Giuseppe Daniele, Carolina Solis-Herrera, Angela Dardano, Andrea Mari, Andrea Tura, Laura Giusti, Jancy J. Kurumthodathu, Beatrice Campi, Alessandro Saba, Anna Maria Bianchi, Carla Tregnaghi, Maria Francesca Egidi, Muhammad Abdul-Ghani, Ralph DeFronzo, Stefano Del Prato

The expected reduction in plasma glucose concentration mediated by sodium–glucose cotransporter 2 (SGLT2) inhibitors is partially offset by a concomitant increase in endogenous glucose production. The signal mediating such a paradoxical response to SLT2-inhibition is currently unknown. In this issue, Daniele, Solis-Herrera et al (https://doi.org/10.1007/s00125-020-05254-w) demonstrate that SGLT2 inhibition in non-diabetic individuals who have undergone kidney transplantation with removal of native kidneys is associated with attenuation of the paradoxical stimulation of endogenous glucose production. They explain that these results suggest the existence of a neuronal axis linking the kidney and the liver that modulates endogenous glucose production in response to urinary glucose loss induced by SGLT2 inhibition. Based on these findings, the authors propose that SGLT2 inhibition can activate efferent renal nerves, generating a signal that augments endogenous (hepatic) glucose production to compensate for the urinary glucose loss.

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