Long-Term Administration of Omeprazole-Induced Hypergastrinemia and Changed Glucose Homeostasis and Expression of Metabolism-Related Genes

Abstract

Introduction: PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice.

Methods: Healthy adult male BALB/c mice were randomly divided into three equal groups (n = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 μl saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of Sirt1, Pparg, Nfκb1 (p105), Nfe2l2, Cxcl5, Smad3, H2a.z, and H3f3b were measured by RT-PCR.

Result: The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in Sirt1, Pparg, and Cxcl5 mRNA expression. There were no differences in β-cell numbers between groups.

Conclusion: Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of Sirt1, Pparg, and Cxcl5 in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced Cxcl5 mRNA expression and its association with pancreatic cancer risk should be investigated.

Figure 1

Effects of OZ treatment on (a) body weight, (b) serum glucose levels, (c) oral glucose, (d) and insulin tolerance tests in male BALB/c mice. Comparison of data in the group at different time points: ^∗P < 0.05; ^∗∗P < 0.01; ^∗∗∗P < 0.001. P₁: comparison of experimental and intact groups; P₂: comparison of control and intact groups; P₃: comparison of experimental and control groups.

Figure 2

Effects of OZ treatment on (a) basal insulin resistance (HOMA-IR), (b) serum gastrin, (c) and insulin levels in male BALB/c mice and (d) cluster analysis of serum insulin and gastrin concentrations in experimental, control, and intact groups.

Figure 3

Effects of OZ treatment on the mRNA expression of inflammation-related genes: (a) Sirt1, (b) Pparg, (c) Nfκb1, (d) Nfe2l2, (e) and Cxcl5 in the mouse pancreas.

Figure 4

Effects of OZ treatment on the mRNA expression of chromatin-modifying genes: (a) Smad3, (b) H2a.z, (c) H3f3b.

Figure 5

Comparison of β-cell counts between groups depending on islet diameters: (a) one-way ANOVA (Kruskal-Wallis statistic) and posthoc Dunn's multiple comparison test, (b, c) representative islets from experimental mouse, and (d, e) representative islets from intact mouse.