Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes
Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes
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DOI：
10.2337/dc15-2688
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发表时间：
2016-11-01
期刊：
影响因子：
16.2
通讯作者：
Abdul-Ghani, Muhammad
中科院分区：
文献类型：
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作者：
Daniele, Giuseppe;Xiong, Juan;Abdul-Ghani, Muhammad
胰岛素抵抗与线粒体有关！功能障碍和ATP合成减少。葡萄糖转运蛋白2抑制剂钠（SGLT2i）治疗2型糖尿病（T2DM）可改善胰岛素敏感性。然而，最近的报告显示，在接受SGLT2i治疗的T2DM患者中，酮症酸中毒的发生。目前的研究检验了达格列净改善胰岛素敏感性对线粒体的影响。ATP合成和2)底物氧化速率和酮的产生。研究设计和方法18例T2DM患者随机接受达格列净组（n = 9）或安慰剂组（n = 9）。在2周前后，受试者接受胰岛素钳夹、氚化葡萄糖、间接量热法和肌肉活检。结果达格列净降低空腹血糖（167 +/- 13 ~ 128 +/- 6 mg/dL），增加胰岛素刺激下葡萄糖处置36% （P < 0.01）。葡萄糖氧化降低（1.06 ~ 0.80 mg/kg）。min, P < 0.05)，而非氧化性葡萄糖处理（糖原合成）增加（2.74 ~ 4.74 mg/kg）。min, P = 0.03)。达格列净降低了基础葡萄糖氧化，增加了脂质氧化和血浆酮浓度（0.05 ~ 0.19 mmol/L, P < 0.01），升高了空腹血浆胰高血糖素（77 +/- 8 ~ 94 +/- 13,P < 0.01）。达格列净降低ATP合成速率，这与血浆酮浓度升高相关。结论斯帕格列净改善胰岛素敏感性，引起葡萄糖氧化向脂质氧化转变，并增加胰高血糖素与胰岛素比值，为酮生成增加提供了代谢基础。
OBJECTIVEInsulin resistance is associated with mitochondria! dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondria! ATP synthesis and 2) substrate oxidation rates and ketone production.RESEARCH DESIGN AND METHODSThe study randomized 18 individuals with T2DM to dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies.RESULTSDapagliflozin reduced fasting plasma glucose (167 +/- 13 to 128 +/- 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg . min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg . min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 +/- 8 to 94 +/- 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration.CONCLUSIONSDapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.