Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
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DOI：
10.1172/jci72227
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Woerle, Hans-Juergen
中科院分区：
文献类型：
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作者：
Ferrannini, Ele;Muscelli, Elza;Woerle, Hans-Juergen
背景。钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂通过增强尿葡萄糖排泄来降低血糖。尚未在人类糖尿病中研究对药物引起的急性或慢性糖尿的生理反应。方法。我们对 66 名 2 型糖尿病患者（62 +/- 7 岁，BMI = 31.6 +/- 4.6 kg/m(2)，HbA(1c) = 55 +/- 8 mmol/mol，平均值 +/- SD）在基线、单次给药后以及恩格列净 (25 mg) 治疗 4 周后进行了评估。在每个时间点，患者接受混合膳食，同时给予双示踪剂葡萄糖和间接量热法。结果。单剂量和长期恩格列净治疗均会在禁食期间（中位数为 7.8 [四分位距 {IQR}, 4.4] g/3 小时和 9.2 [IQR, 5.2] g/3 小时）和餐后摄入（中位数为 29.0 [IQR, 12.5] g/5 小时和 28.2 [IQR, 15.4] g/5 小时）引起糖尿。小时）。禁食 3 小时后，内源性葡萄糖生成 (EGP) 增加 25%，而血糖降低 0.9 +/- 0.7 mmol/l（与基线相比，P < 0.0001）。进餐后，葡萄糖和胰岛素 AUC 下降，而胰高血糖素反应增加（所有 P < 0.001）。虽然口服葡萄糖外观没有变化，但 EGP 有所增加（中位数为 40 [IQR，14] 至 37 [IQR，11] g 与 34 [IQR，11] g，均 P < 0.01）。由于葡萄糖氧化和非氧化葡萄糖处置均减少，长期给药后脂质氧化随之增加（所有 P < 0.01），因此组织葡萄糖处置减少（中位数为 75 [IQR，16] g 和 70 [IQR，21] g vs. 93 [IQR，18] g，P < 0.0001）。 beta 细胞葡萄糖敏感性增加（中位数为 55 [IQR, 35] pmol.min(-1.)-m(-2.)-mM(-1) 和 55 [IQR, 39] pmol.min(-l.)m(-2.)mM(-1) vs. 44 [IQR, 32] pmol.min(-1.)m(-2.)mM(-1)，P < 0.0001），胰岛素敏感性提高。静息能量消耗率和餐后能量消耗率没有变化。结论。在 2 型糖尿病患者中，恩格列净诱导的糖尿改善了 β 细胞功能和胰岛素敏感性，尽管一剂后胰岛素分泌和组织葡萄糖处理下降，且 EGP 上升，从而降低了空腹和餐后血糖。长期给药将底物利用从碳水化合物转变为脂质。
Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes.Methods. We evaluated 66 patients with type 2 diabetes (62 +/- 7 years, BMI = 31.6 +/- 4.6 kg/m(2), HbA(1c) = 55 +/- 8 mmol/mol, mean +/- SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry.Results. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 +/- 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] grand 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). beta Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol.min(-1.)-m(-2.)-mM(-1) and 55 [IQR, 39] pmol.min(-l.)m(-2.)mM(-1) vs. 44 [IQR, 32] pmol.min(-1.)m(-2.)mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged.Conclusions. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved beta cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utiliation from carbohydrate to lipid.