Department of Medicine, Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, University Health System, San Antonio, TX 78229, USA.
J Clin Endocrinol Metab. 2023 Dec 21;109(1):161-170. doi: 10.1210/clinem/dgad438.
This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria.
To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. Our hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion and glucagon suppression.
Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug.
In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Δ = 42 ± 1 mg/dL) than DAPA (Δ = 72 ± 3), and lower in DAPA/EXE (Δ = 11 ± 3) than EXE and DAPA. EGP decrease was lower in DAPA (Δ = -0.65 ± 0.03 mg/kg/min) than EXE (Δ = -0.96 ± 0.07); in DAPA/EXE (Δ = -0.84 ± 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2, DAPA/EXE, Δ = 27 ± 1) and EGP decreases (DAPA, Δ = -0.60 ± 0.05 mg/kg/min; EXE, Δ = -0.77 ± 0.04; DAPA/EXE, Δ = -0.72 ± 0.03) were observed. At 4 months, PG elevations (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6; DAPA/EXE, Δ = 46 ± 2) and lower EGP decrease in DAPA (Δ = -0.66 ± 0.04 mg/kg/min) vs EXE (Δ = -0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ = -0.65 ± 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min.
Our findings provide strong evidence for the emergence of a new long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy.
本研究旨在探讨 2 型糖尿病（T2D）患者接受 SGLT-2 抑制剂治疗时新的糖调节机制的发展，该机制独立于葡萄糖、胰岛素和胰高血糖素。数据表明，在持续糖尿期间，肾脏中存在一种潜在的触发因素（多个），刺激内源性葡萄糖产生（EGP）。
研究 SGLT-2 抑制剂联合 GLP-1 受体激动剂对 T2D 患者 EGP 和葡萄糖动力学的影响。我们的假设是，SGLT2i 诱导的糖尿后，EGP 增加持续时间长，并且不会被 GLP-1RA 刺激胰岛素分泌和抑制胰高血糖素所消除。
75 例患者接受了 5 小时双示踪口服葡萄糖耐量试验（OGTT）（静脉 3-[3H]-葡萄糖口服[1-14C]-葡萄糖）：（1）在达格列净（DAPA）；艾塞那肽（EXE）或两者治疗前后 1 次，DAPA/EXE（急性研究），和（2）每种药物治疗 1 和 4 个月后。
在急性研究中，在 OGTT 期间，EXE 时的血浆葡萄糖（PG）升高（Δ=42±1mg/dL）低于 DAPA（Δ=72±3），DAPA/EXE（Δ=11±3）低于 EXE 和 DAPA。DAPA 时 EGP 下降（Δ=-0.65±0.03mg/kg/min）低于 EXE（Δ=-0.96±0.07）；在 DAPA/EXE（Δ=-0.84±0.05）中，低于 EXE，高于 DAPA。在 1 个月时，观察到类似的 PG 升高（EXE，Δ=26±1mg/dL；DAPA，Δ=62±2，DAPA/EXE，Δ=27±1）和 EGP 下降（DAPA，Δ=-0.60±0.05mg/kg/min；EXE，Δ=-0.77±0.04；DAPA/EXE，Δ=-0.72±0.03）。在 4 个月时，PG 升高（EXE，Δ=55±2mg/dL；DAPA，Δ=65±6；DAPA/EXE，Δ=46±2）和 DAPA 时 EGP 下降（Δ=-0.66±0.04mg/kg/min）低于 EXE（Δ=-0.84±0.05），也相当；在 DAPA/EXE（Δ=-0.65±0.03）中，与 DAPA 相等，低于 EXE。血浆胰岛素/胰高血糖素的变化不能解释 DAPA/EXE 与 EXE 相比 EGP 升高的原因。
我们的发现为 SGLT2i 诱导的糖尿通过新的、持久的、葡萄糖独立的、胰岛素/胰高血糖素独立的糖调节机制刺激 T2D 患者 EGP 提供了强有力的证据。SGLT2i 加 GLP-1 受体激动剂联合治疗与单药治疗相比，具有更好的血糖控制效果。
