Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2024; 15(8): 1764-1777
Published online Aug 15, 2024. doi: 10.4239/wjd.v15.i8.1764
Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice
Fang-Xin Jin, Yan Wang, Min-Ne Li, Ru-Jiang Li, Jun-Tang Guo
Fang-Xin Jin, Yan Wang, Min-Ne Li, Ru-Jiang Li, Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, Weifang 261053, Shandong Province, China
Jun-Tang Guo, Department of Pathological Physiology, Shandong Second Medical University, Weifang 261053, Shandong Province, China
Co-corresponding authors: Ru-Jiang Li and Jun-Tang Guo.
Author contributions: Li RJ and Jin FX designed the research study and prepared the manuscript; Guo JT, Li RJ, and Jin FX participated in the data analysis, interpretation of the results, and preparation of the draft manuscript; Jin FX, Wang Y, and Li MN performed the research and participated in the animal work and sample collection. All authors have read and approved the final manuscript. Both Li RJ and Guo JT have played important and indispensable roles in the experimental design, data interpretation, and manuscript preparation as the co-corresponding authors. Li RJ applied for and obtained the funds for this research project. Li RJ proposed and designed the established the animal model of type 1 diabetes mellitus with impaired hypoglycaemic counterregulation, performed data analysis, and prepared the first draft. Guo JT was responsible for mouse grouping and specimen collection. Guo JT was instrumental and responsible for data re-analysis and re-interpretation, and figure preparation, and participated in data analysis and interpretation. This collaboration between Li RJ and Guo JT is crucial for the publication of this manuscript.
Supported by National Natural Science Foundation of China, No. 81471048.
Institutional animal care and use committee statement: All animal studies in this article were approved by the Ethics Committee of Shandong Second Medical University (No. 2019SDL029) and conducted according to the animal care and use procedures of Shandong Second Medical University.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The raw data are available upon reasonable request from the corresponding author at nuliluck@163.com.
ARRIVE guidelines statement: The authors have read and the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ru-Jiang Li, MD, Professor, Department of Histology and Embryology, Key Laboratory of Universities in Shandong Province, Shandong Second Medical University, No. 7166 Baotong West Street, Weifang 261053, Shandong Province, China. nuliluck@163.com
Received: March 1, 2024
Revised: June 3, 2024
Accepted: July 5, 2024
Published online: August 15, 2024
Processing time: 146 Days and 21.7 Hours
Abstract
BACKGROUND

Impaired hypoglycaemic counterregulation has emerged as a critical concern for diabetic patients who may be hesitant to medically lower their blood glucose levels due to the fear of potential hypoglycaemic reactions. However, the patho-genesis of hypoglycaemic counterregulation is still unclear. Glucagon-like peptide-1 (GLP-1) and its analogues have been used as adjunctive therapies for type 1 diabetes mellitus (T1DM). The role of GLP-1 in counterregulatory dys-function during hypoglycaemia in patients with T1DM has not been reported.

AIM

To explore the impact of intestinal GLP-1 on impaired hypoglycaemic counterregulation in type 1 diabetic mice.

METHODS

T1DM was induced in C57BL/6J mice using streptozotocin, followed by intraperitoneal insulin injections to create T1DM models with either a single episode of hypoglycaemia or recurrent episodes of hypoglycaemia (DH5). Immunofluorescence, Western blot, and enzyme-linked immunosorbent assay were employed to evaluate the influence of intestinal GLP-1 on the sympathetic-adrenal reflex and glucagon (GCG) secretion. The GLP-1 receptor agonist GLP-1(7-36) or the antagonist exendin (9-39) were infused into the terminal ileum or injected intraperitoneally to further investigate the role of intestinal GLP-1 in hypoglycaemic counterregulation in the model mice.

RESULTS

The expression levels of intestinal GLP-1 and its receptor (GLP-1R) were significantly increased in DH5 mice. Consecutive instances of excess of intestinal GLP-1 weakens the sympathetic-adrenal reflex, leading to dysfunction of adrenal counterregulation during hypoglycaemia. DH5 mice showed increased pancreatic δ-cell mass, cAMP levels in δ cells, and plasma somatostatin concentrations, while cAMP levels in pancreatic α cells and plasma GCG levels decreased. Furthermore, GLP-1R expression in islet cells and plasma active GLP-1 levels were significantly increased in the DH5 group. Further experiments involving terminal ileal infusion and intraperitoneal injection in the model mice demonstrated that intestinal GLP-1 during recurrent hypoglycaemia hindered the secretion of the counterregulatory hormone GCG via the endocrine pathway.

CONCLUSION

Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia.

Keywords: Glucagon-like peptide-1; Impaired hypoglycaemic counterregulation; Type 1 diabetes; Intestine; Pancreas

Core Tip: Glucagon-like peptide-1 (GLP-1) is an incretin hormone primarily produced by specific enteroendocrine L-cells in the intestines. The role of GLP-1 in impaired hypoglycaemic counterregulation in type 1 diabetes mellitus (T1DM) has not been reported. In this study, a model of recurrent hypoglycaemia in T1DM mice was established, and it was found that excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and glucagon during hypoglycaemia.