Increase in endogenous glucose production with SGLT2 inhibition is unchanged by renal denervation and correlates strongly with the increase in urinary glucose excretion

Carolina Solis-Herrera, Giuseppe Daniele, Mariam Alatrach, Christina Agyin, Curtis Triplitt, John Adams, Rupal Patel, Amalia Gastaldelli, Henri Honka, Xi Chen, Muhammad Abdul-Ghani, Eugenio Cersosimo, Stephano Del Prato, Ralph DeFronzo

Research output: Contribution to journalArticle

Abstract

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation. RESEARCH DESIGN AND METHODS Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 6 0.1%] and eight non-DM [A1C 5.6 6 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. RESULTS Following placebo in T2D, fasting plasma glucose (FPG) (143 6 14 to 124 6 10 mg/dL; P 5 0.02) and fasting plasma insulin (12 6 2 to 10 6 1.1 mU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 6 15 to 112 6 9 mg/dL; P 5 0.01) and fasting plasma insulin (14 6 3 to 11 6 2 mU/mL; P 5 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 6 0.19 vs. 1.96 6 0.14 mg/kg/ min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 6 0.10 to 1.78 6 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r 5 0.824; P < 0.001) was observed. CONCLUSIONS Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.

Original languageEnglish (US)
Pages (from-to)1065-1069
Number of pages5
JournalDiabetes care
Volume43
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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    Solis-Herrera, C., Daniele, G., Alatrach, M., Agyin, C., Triplitt, C., Adams, J., Patel, R., Gastaldelli, A., Honka, H., Chen, X., Abdul-Ghani, M., Cersosimo, E., Prato, S. D., & DeFronzo, R. (2020). Increase in endogenous glucose production with SGLT2 inhibition is unchanged by renal denervation and correlates strongly with the increase in urinary glucose excretion. Diabetes care, 43(5), 1065-1069. https://doi.org/10.2337/dc19-2177