Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study.
Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study.
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DOI：
10.2337/dc12-2391
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发表时间：
2013-08
期刊：
影响因子：
16.2
通讯作者：
Henry RR
中科院分区：
文献类型：
--
作者：
Polidori D;Sha S;Mudaliar S;Ciaraldi TP;Ghosh A;Vaccaro N;Farrell K;Rothenberg P;Henry RR
卡格列净是一种钠葡萄糖协同转运蛋白（SGLT）2抑制剂，也是一种低效SGLT 1抑制剂。本研究检验了以下假设：给药后肠道卡格列净水平足够高，可短暂抑制肠道SGLT 1，从而延迟肠道葡萄糖吸收。这项两阶段、交叉研究使用双示踪剂方法在20例健康受试者中评价了卡格列净对肠道葡萄糖吸收的影响。在600 kcal混合餐耐受性试验前20分钟给予安慰剂或卡格列净300 mg。经常测量血浆葡萄糖、3 H-葡萄糖、14 C-葡萄糖和胰岛素6 h，以计算血浆中口服葡萄糖（RaO）的出现率、内源性葡萄糖产生率和葡萄糖处置率。与安慰剂相比，卡格列净治疗可降低餐后血糖和胰岛素波动（0至2小时曲线下面积[AUC 0 - 2 h]分别减少35%和43%;两者P < 0.001），0至6小时尿糖排泄增加（UGE 0 - 6 h，18.2 ± 5.6 vs. <0.2g; P < 0.001）和延迟RaO。卡格列净在0至1小时内使AUC RaO降低31%（几何平均值，264与381 mg/kg; P < 0.001），在0至2小时内降低20%（576与723 mg/kg; P = 0.002）。在2至6小时内，卡格列净增加RaO，使得0至6小时内的总AUC RaO比安慰剂低<6%（960对1，018 mg/kg; P = 0.003）。在前2小时内观察到对乙酰氨基酚吸收适度减少（约10%），但这种差异不足以解释RaO的减少。在0至6小时内，各组的总葡萄糖处置相似。卡格列净通过增加UGE（通过肾脏SGLT 2抑制）和延迟RaO（可能由于肠道SGLT 1抑制）降低餐后血糖和胰岛素。
Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.
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DOI：
10.1152/ajpendo.00127.2009
发表时间：
2009-08-01
影响因子：
5.1
作者：
Bonuccelli, Sandra;Muscelli, Elza;Ferrannini, Ele
通讯作者：
Ferrannini, Ele
影响因子：
3.5
作者：
Medhus, AW;Lofthus, CM;Husebye, E
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Husebye, E
DOI：
10.1111/j.1365-2125.1975.tb00568.x
发表时间：
1975-01-01
影响因子：
3.4
作者：
NIMMO, WS;HEADING, RC;PRESCOTT, LF
通讯作者：
PRESCOTT, LF
影响因子：
7.7
作者：
FERRANNINI, E;BJORKMAN, O;DEFRONZO, RA
通讯作者：
DEFRONZO, RA
影响因子：
16.2
作者：
Mudaliar, S;Mohideen, P;Henry, RR
通讯作者：
Henry, RR