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 [3-3H]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 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 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 ± 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 (r = 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.

中文翻译：

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具有SGLT2抑制作用的内源性葡萄糖产量的增加不受肾脏去神经作用的影响，并且与尿葡萄糖排泄物的增加强烈相关。

目的钠葡萄糖共转运蛋白2（SGLT2）抑制导致内源性葡萄糖生成（EGP）增加。但是，机制尚不清楚。我们研究了SGLT2抑制剂对患有肾失神经的肾移植接受者的2型糖尿病（T2D）和无糖尿病（非DM）受试者的EGP的影响。研究设计和方法14例接受肾脏移植的受试者（6例接受T2D [A1C 7.2±0.1％]和8例非DM [A1C 5.6±0.1％]的患者接受达格列净（DAPA）的输注[3-3H]葡萄糖测量EGP ）10毫克或安慰剂。测量血浆葡萄糖，胰岛素，C肽，胰高血糖素和滴定的葡萄糖比活性。结果在T2D中使用安慰剂后，空腹血浆葡萄糖（FPG）（143±14至124±10 mg / dL； P = 0.02）和空腹血浆胰岛素（12±2至10±1.1μU/ mL； P <0.05）降低。血浆胰高血糖素未改变，EGP下降。在T2D中进行DAPA后，FPG（143±15至112±9 mg / dL; P = 0.01）和空腹血浆胰岛素（14±3至11±2μU/ mL; P = 0.02）降低，血浆胰高血糖素升高（全部与安慰剂相比，P <0.05）。在T2D中，EGP与基线相比不变（2.21±0.19 vs. 1.96±0.14 mg / kg / min）（P <0.001 vs.安慰剂）。在DAPA后的非DM中，FPG和空腹血浆胰岛素降低，血浆胰高血糖素未改变。在DAPA后，EGP与基线无变化（1.85±0.10至1.78±0.10 mg / kg / min），而安慰剂使EGP显着下降。当针对所有患者绘制DAPA与安慰剂后EGP产生的增加对比尿葡萄糖排泄（UGE）的差异时，观察到很强的相关性（r = 0.824; P <0.001）。结论接受肾脏移植的患者的肾脏去神经支配不能阻止TPA和非DM患者的DAPA介导的EGP刺激。DAPA刺激的EGP上升与UGE的上升密切相关，从而抑制了FPG的下降。