SGLT2 抑制导致内源性葡萄糖生成增加，而肾去神经支配对此无影响，并与尿葡萄糖排泄增加密切相关。
Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion.
机构信息
Division of Diabetes, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
出版信息
Diabetes Care. 2020 May;43(5):1065-1069. doi: 10.2337/dc19-2177. Epub 2020 Mar 6.
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 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-H]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 ± 14 to 124 ± 10 mg/dL; = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; = 0.02) decreased, and plasma glucagon increased (all < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D ( < 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 ± 0.10 to 1.78 ± 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 ( = 0.824; < 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.
目的
钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂可导致内源性葡萄糖生成（EGP）增加。然而，其机制尚不清楚。我们研究了 SGLT2 抑制剂在接受肾去神经支配的肾移植受者中 2 型糖尿病（T2D）和非糖尿病（非 DM）患者中的 EGP 影响。
研究设计和方法
14 名接受肾移植的受试者（6 名 T2D[A1C7.2±0.1%]和 8 名非 DM[A1C5.6±0.1%]）接受[3-H]葡萄糖输注，测量 EGP 后给予达格列净（DAPA）10mg 或安慰剂。测量血浆葡萄糖、胰岛素、C 肽、胰高血糖素和葡萄糖特异性活性。
结果
在 T2D 中，给予安慰剂后，空腹血糖（FPG）（143±14 至 124±10mg/dL；P=0.02）和空腹血浆胰岛素（12±2 至 10±1.1μU/mL；P<0.05）下降；血浆胰高血糖素无变化，EGP 下降。在 T2D 中，给予 DAPA 后，FPG（143±15 至 112±9mg/dL；P=0.01）和空腹血浆胰岛素（14±3 至 11±2μU/mL；P=0.02）下降，血浆胰高血糖素增加（均 P<0.05 与安慰剂相比）。T2D 中 EGP 与基线相比无变化（2.21±0.19 与 1.96±0.14mg/kg/min；P<0.001 与安慰剂相比）。在非 DM 中，给予 DAPA 后，FPG 和空腹血浆胰岛素下降，而血浆胰高血糖素无变化。DAPA 后 EGP 与基线相比无变化（1.85±0.10 至 1.78±0.10mg/kg/min），而安慰剂时 EGP 显著下降。当所有患者 DAPA 与安慰剂相比 EGP 生成增加时，与 UGE 差异进行比较，观察到强烈的相关性（r=0.824；P<0.001）。
结论
肾移植受者的肾去神经支配未能阻止 DAPA 介导的 T2D 和非 DM 患者 EGP 的刺激。DAPA 刺激的 EGP 升高与 UGE 的增加密切相关，从而削弱了 FPG 的下降。
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