{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:42:13Z","timestamp":1791916933099,"version":"4.3.4"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation.<\/jats:p>","DOI":"10.3390\/ph15070904","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:38:50Z","timestamp":1658443130000},"page":"904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bolus Injection of Liraglutide Raises Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1 Receptor in the Brain"],"prefix":"10.3390","volume":"15","author":[{"given":"Chia-Chen","family":"Hsu","sequence":"first","affiliation":[{"name":"Graduate Institute of Gerontology and Health Care Management, Chang Gung University of Science and Technology, Taoyuan City 33303, Taiwan"},{"name":"Department of Otorhinolaryngology, Taipei City Hospital, Taipei City 10341, Taiwan"},{"name":"Department of Exercise and Health Sciences, University of Taipei, Taipei City 11153, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juei-Tang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Chi-Mei Medical Center, Tainan City 71004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping Hao","family":"Hsu","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nursing, Tzu Chi University of Science and Technology, Hualien 970302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Chun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Tajen University, Pingtung 90741, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/dom.13129","article-title":"Incretin hormones: Their role in health and disease","volume":"20","author":"Nauck","year":"2018","journal-title":"Diabetes Obes. 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