NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion.

Hussein Herz,Mohamad Mokadem,Marwa Abu El Haija,Yuanchao Ye,Yang Song,Benjamin Linden,Liping Tian,Justin L Grobe,Randall W Lengeling,Yi Chu

doi:10.3390/nu14010120

Abstract

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Highlights

Thereafter, we examined if the administration of a glucagonlike peptide-1 (GLP-1) agonist corrects this NSAIDinduced disruption in glucose metabolism
To further investigate the association between non-steroidal anti-inflammatory drugs (NSAIDs) and glucose metabolism through GLP-1 signaling, we examined the effect of the GLP-1 receptor antagonist (Exendin-9) on glucose tolerance test (GTT) in ibuprofen vs. placebo-treated mice
Our study demonstrates that replacement with GLP-1 receptor agonist (Exendin-4) improves hepatic insulin sensitivity in NSAID-treated mice by having a similar glucose appearance rate to the control group but at a lower insulin level

Summary

Introduction

Nonsteroidal anti-inflammatory drug (NSAID) damage to the small intestine was first described in a rat model using indomethacin in 1969, while a case report of small bowel creativecommons.org/licenses/by/ 4.0/). Though NSAID damage occurs throughout the small bowel, distal small intestinal damage may be more severe for several reasons. These include colonic reflux of bacteria into the terminal ileum (as bacteria have been suggested to play a role in this drug-induced insult), as well as the ileal brake and enterohepatic circulation of the drug [9]. Non-aspirin NSAIDs were available by prescription since the middle of the past century, but it was not until 1984 that they became available OTC in the United

Results

Discussion

Conclusion