Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transp
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ARTICLE
Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy Giuseppe Daniele 1 & Carolina Solis-Herrera 2 & Angela Dardano 1 & Andrea Mari 3 & Andrea Tura 3 & Laura Giusti 1 & Jancy J. Kurumthodathu 1 & Beatrice Campi 1 & Alessandro Saba 1 & Anna Maria Bianchi 1 & Carla Tregnaghi 1 & Maria Francesca Egidi 1 & Muhammad Abdul-Ghani 2 & Ralph DeFronzo 2 & Stefano Del Prato 1 Received: 31 January 2020 / Accepted: 30 May 2020 # The Author(s) 2020
Abstract Aims/hypothesis The glucosuria induced by sodium–glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA1c. We hypothesised that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys. Methods This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30–65 years old, with a BMI of 25–35 kg/m2 and stable body weight (±2 kg) over the preceding 3 months, and HbA1c 60 ml min−1 [1.73 m]−2 (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) were recruited from the Nephrology Unit of the Department of Clinical and Experimental Medicine at the University of Pisa, Italy. All participants underwent renal transplantation because of autosomal dominant polycystic renal disease. Inclusion criteria were: age 30–65 years; BMI 25–35 kg/m2 with stable body weight (±2 kg) over the preceding 3 months; and HbA1c 140/90 mmHg were excluded. The Institutional Review Board of the University of Pisa and the Italian Medicines Agency (AIFA) approved the study in accordance with principles described in the Declaration of Helsinki. All participants gave written informed consent before participating in the study. The study was registered at ClinicalTrials.gov (registration no. NCT03168295). Study design This was a randomised, double-blind, placebocontrolled, single-centre study evaluating the effect of dapagliflozin on glucose metabolism in two groups of renal transplant participants: ten individuals with residual native kidneys and ten individuals who had undergone pretransplant bilateral nephrectomy. At baseline, all participants had their medical history taken and underwent physical
examination and routine laboratory tests to exclude major organ system disease other than polycystic kidney disease. Participants underwent two identical study procedures at a 5to 14-day interval, with the administration of 10 mg dapagliflozin or placebo in randomised double-blind fashion. Dapagliflozin and matching placebo were packaged in bulk bottles and delivered to the hospital pharmacy, which managed
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