TY - JOUR
T1 - Increase in endogenous glucose production with SGLT2 inhibition is unchanged by renal denervation and correlates strongly with the increase in urinary glucose excretion
AU - Solis-Herrera, Carolina
AU - Daniele, Giuseppe
AU - Alatrach, Mariam
AU - Agyin, Christina
AU - Triplitt, Curtis
AU - Adams, John
AU - Patel, Rupal
AU - Gastaldelli, Amalia
AU - Honka, Henri
AU - Chen, Xi
AU - Abdul-Ghani, Muhammad
AU - Cersosimo, Eugenio
AU - Prato, Stephano Del
AU - DeFronzo, Ralph
N1 - Funding Information:
This protocol was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01-DK-107680-03 (to R.D.).
Funding Information:
Funding. This protocol was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01-DK-107680-03 (to R.D.). Duality of Interest. C.T. is on the speakers’ bureaus of Janssen Pharmaceuticals, Eli Lilly and Company, and AstraZeneca. E.C. receives research support from AstraZeneca and Janssen Pharmaceuticalsandisonthespeakers’bureausof Janssen Pharmaceuticals, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca, and Sanofi. S.D.P. has received honoraria from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi Pharmaceutical Co., Merck Sharp & Dohme, Mundipharma, Novartis, Novo Nordisk, Sanofi, Servier, and Takeda Pharmaceutical Company and research support from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, and Novartis. R.D. is on the advisory boards of AstraZeneca, Novo Nordisk, Janssen Pharmaceuticals, Intarcia Therapeutics, and Boehringer Ingelheim; has received research support from Bristol-Myers Squibb, Boehringer Ingelheim, and AstraZeneca; and is on the speakers’ bureaus of Novo Nordisk and AstraZeneca. Author Contributions. C.S.-H., G.D., C.T., E.C., S.D.P., and R.D. contributed to the study concept and design, analysis and interpretation of data, drafting and revision of the manuscript, statistical analysis, and study supervision. C.S.-H., M.A., C.A., C.T., J.A., and R.P. contributed to the study recruitment, experiments, and data acquisition and analysis. A.G. and M.A.-G. contributed to the study concept and analysis. H.H. and X.C. contributed to acquisition and data analysis. R.D. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
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U2 - 10.2337/dc19-2177
DO - 10.2337/dc19-2177
M3 - Article
C2 - 32144165
AN - SCOPUS:85083833625
SN - 0149-5992
VL - 43
SP - 1065
EP - 1069
JO - Diabetes care
JF - Diabetes care
IS - 5
ER -