Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.

中文翻译：

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反对血浆胰岛素和胰高血糖素浓度在 SGLT2 抑制剂引起的 EGP 增加中的重要作用的证据

钠-葡萄糖共转运 2 抑制剂 (SGLT2i) 降低血浆葡萄糖但刺激内源性葡萄糖产生 (EGP)。目前的研究检查了达格列净对 EGP 的影响，同时将血浆葡萄糖、胰岛素和胰高血糖素浓度限制在空腹水平。38 名 2 型糖尿病患者接受了 3 次 8 小时的 EGP（[3-3H]-葡萄糖）测量。3 小时示踪剂平衡后，受试者接受 1) dapagliflozin 10 mg (n = 26) 或安慰剂 (n = 12)；2) 将血糖浓度固定在空腹水平，重复 EGP 测量；和 3) 重复 EGP 测量，同时用生长抑素输注抑制胰岛素和胰高血糖素分泌并替代基础血浆胰岛素和胰高血糖素浓度。在研究 1 中，接受达格列净的受试者的 EGP（基线至 EGP 测量的最后一小时）的变化比接受安慰剂的受试者大 22%（+0.66 ± 0.11 mg/kg/min，P < 0.05），并且与显着增加有关与安慰剂相比，血浆胰高血糖素和血浆胰岛素浓度降低。在葡萄糖钳夹条件下（研究 2），接受达格列净和安慰剂的受试者血浆胰岛素和胰高血糖素浓度的变化相当，但达格列净和安慰剂之间的 EGP 差异仍然存在（+0.71 ± 0.13 mg/kg/min，P < 0.01 ）。在胰腺钳夹条件下（研究 3），dapagliflozin 最初使 EGP 大幅下降（比安慰剂低 8%），随后在最后一小时内 EGP 逐渐增加，比安慰剂高 10.6%。总的来说，