二肽基肽酶 4 抑制对健康受试者肠促胰岛素效应、葡萄糖耐量和胃肠道介导的葡萄糖处置的影响。

The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects.

机构信息

Center for Diabetes ResearchGentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkCenter for Diabetes ResearchGentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

出版信息

Eur J Endocrinol. 2014 Sep;171(3):353-62. doi: 10.1530/EJE-14-0314. Epub 2014 Jun 16.

DOI:10.1530/EJE-14-0314

PMID:24935932

Abstract

OBJECTIVE

Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects.

DESIGN

A randomised, controlled and open-labelled study.

METHODS

Ten healthy subjects (six women; age, 40±5 years (mean±s.e.m.); BMI, 24±3 kg/m(2); fasting plasma glucose, 5.1±0.2 mmol/l and HbA1c, 34±1 mmol/mol (5.3±0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A1+B1) and without (A2+B2) preceding administration of the DPP4 inhibitor sitagliptin.

RESULTS

Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1±0.1 vs 4.9±0.1 mmol/l, P=0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151±35 vs 137±26 mmol/l×min, P=0.7) or peak plasma glucose during OGTT (8.5±0.4 vs 8.1±0.3 mmol/l, P=0.3) was observed. Neither incretin effect (40±9% (without DPP4 inhibitor) vs 40±7% (with DPP4 inhibitor), P=1.0), glucagon responses (1395±165 vs 1223±195 pmol/l×min, P=0.41), GIGD (52±4 vs 56±5%, P=0.40) nor gastric emptying (Tmax for plasma paracetamol: 86±9 vs 80±12 min, P=0.60) changed following DPP4 inhibition.

CONCLUSIONS

These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.

摘要

目的

二肽基肽酶 4（DPP4）的抑制被认为可以增强肠降血糖素激素的生理效应。我们研究了 DPP4 抑制对健康受试者的血糖依赖性胰岛素促分泌多肽（GIP）、胰高血糖素样肽 1（GLP1）、肠降血糖素效应、葡萄糖耐量、胃肠道葡萄糖处置（GIGD）和胃排空的影响。

设计

一项随机、对照和开放标签研究。

方法

10 名健康受试者（6 名女性；年龄，40±5 岁（均值±标准差）；BMI，24±3kg/m2；空腹血糖，5.1±0.2mmol/l，HbA1c，34±1mmol/mol（5.3±0.1%））随机分为两组配对研究日，包括 4 小时 50g 口服葡萄糖耐量试验（OGTT）和对乙酰氨基酚（A）和等血糖静脉（i.v.）葡萄糖输注（B），用（A1+B1）和不（A2+B2）在前服用 DPP4 抑制剂西他列汀。

结果

所有受试者在配对研究日均获得等血糖。DPP4 抑制后，空腹水平和 OGTT 诱导的活性 GLP1 和 GIP 反应显著增加。DPP4 抑制对空腹血糖（5.1±0.1 与 4.9±0.1mmol/l，P=0.3）、葡萄糖耐量（血浆葡萄糖 AUC，151±35 与 137±26mmol/l×min，P=0.7）或 OGTT 期间的峰值血糖（8.5±0.4 与 8.1±0.3mmol/l，P=0.3）均无显著影响。肠降血糖素效应（无 DPP4 抑制剂时为 40±9%（无 DPP4 抑制剂）与有 DPP4 抑制剂时为 40±7%（有 DPP4 抑制剂），P=1.0）、胰高血糖素反应（1395±165 与 1223±195pmol/l×min，P=0.41）、GIGD（52±4 与 56±5%，P=0.40）或胃排空（血浆对乙酰氨基酚 Tmax：86±9 与 80±12min，P=0.60）均未因 DPP4 抑制而改变。