Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes
Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes
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DOI：
10.1210/jc.2003-031907
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发表时间：
2004-05-01
影响因子：
5.8
通讯作者：
Schweizer, A
中科院分区：
文献类型：
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作者：
Ahrén, B;Landin-Olsson, M;Schweizer, A
与胰高血糖素样肽-1（GLP-1）的抗糖尿病作用相关的胰岛素刺激vs.胰高血糖素分泌抑制尚未确立。在此，在饮食控制的糖尿病受试者中研究了通过抑制二肽基肽酶-4（DPP-4）使循环GLP-1增加4周对24小时血糖以及胰岛素和胰高血糖素对早餐反应的影响[年龄：65 ± 8岁（SD），体重指数：27.3 ± 3.3 kg/m2，空腹血糖：9.0 +/- 1.3 mmol/L]。与安慰剂（n = 19）相比，特异性DPP-4抑制剂[（1-[[（3-羟基-1-金刚烷基）氨基]乙酰基]-2-氰基-（S）-吡咯烷）（LAF 237）;每日100 mg，n = 18]空腹血糖降低0.70 mmol/L（P = 0.037），4小时餐时血糖波动1.45 mmol/L（P < 0.001），24小时平均血糖波动0.93 mmol/L（P < 0.001）。LAF 237使基线和餐后活性GLP-1升高。LAF 237降低了胰高血糖素对早餐的反应（治疗前60分钟时的胰高血糖素水平为88 +/- 8 pg/ml，治疗后为77 +/- 5 pg/ml; P = 0.001）。相比之下，总体胰岛素水平没有改变。4周胰高血糖素降低与2小时血糖降低相关（r = 0.61; P = 0.008）。未观察到胰岛素存在这种相关性。因此，在2型糖尿病中，通过DPP-4抑制改善代谢控制与胰高血糖素水平降低相关，尽管胰岛素水平较低，但胰岛素水平不变。
The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.