SEARCH

SEARCH BY CITATION

Keywords:

  • diabetes;
  • exendin-4;
  • obesity;
  • omeprazole
  • 糖尿病,唾液素-4,肥胖,奥美拉唑

Abstract

Background:  In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti-obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes.

Methods:  The effects repeated dose treatment for 14 days with exendin-4 (8 μg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity.

Results:  Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content.

Conclusions:  Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity.

摘要

背景: 除了具有葡萄糖调节作用之外,唾液素-4,一种稳定的胰升糖素样肽-1受体激动剂,还具有胰腺保护作用与减肥作用。为了使这些额外的疗效最佳化,适当地联合使用其他的减肥或者胰腺保护药物将是一个有效的方法。在本研究中,我们考察了唾液素-4联合质子泵抑制剂奥美拉唑对一种2型糖尿病且肥胖的实验模型db/db小鼠的影响。

方法: 在肥胖的高血糖db/db小鼠中使用唾液素-4(8 μg/kg,皮下注射)与奥美拉唑(30 mg/kg,皮下注射)重复治疗14天后测定其对血糖控制、食物摄入以及体重的影响。测定该治疗对血浆胃泌素、胃促生长素以及瘦素水平的影响,以及它们对恶心样症状的影响。通过测定循环中的%HbA1c、胰腺内的胰岛素与胰升糖素含量以及葡萄糖激酶活性来评估重复治疗对胰腺的影响。

结果: 重复给药后,联合治疗可导致血浆瘦素与胃促生长素水平显著下降。奥美拉唑可以改善厌食与体重减轻作用,并且逆转唾液素-4对胃泌素水平的抑制作用。14天的联合治疗显著减少血糖波动,胰岛素水平也有改善,并伴随着%HbA1c水平的下降。它还改善了葡萄糖激酶的活性以及胰腺内的胰岛素含量,胰升糖素的含量则显著减少。

结论: 联合使用奥美拉唑与唾液素-4治疗后可减少食物摄入以及减少体重增加,最有可能的机制是通过改变血浆中的胃促生长素与瘦素水平,以及通过增加葡萄糖激酶的活性来改善胰腺内的胰岛素与胰升糖素含量。