Tags

Type your tag names separated by a space and hit enter

Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice.
Am J Physiol Gastrointest Liver Physiol. 2018 11 01; 315(5):G671-G684.AJ

Abstract

Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct β-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice. NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale , Toulouse , France. Université Paul Sabatier, Unité Mixte de Recherche 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse Cedex, France.Institut National de la Santé et de la Recherche Médicale , Toulouse , France. Université Paul Sabatier, Unité Mixte de Recherche 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse Cedex, France.Institut National de la Santé et de la Recherche Médicale , Toulouse , France. Université Paul Sabatier, Unité Mixte de Recherche 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse Cedex, France.Sorbonne Paris Cité, Université Denis Diderot, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8251, Paris , France.Sorbonne Paris Cité, Université Denis Diderot, Unité de Biologie Fonctionnelle et Adaptative, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8251, Paris , France.Physiology and Behavior Laboratory, Institute of Food, Nutrition, and Health, Eidgenössische Technische Hochschule Zürich, Switzerland.Institut National de la Santé et de la Recherche Médicale , Toulouse , France. Université Paul Sabatier, Unité Mixte de Recherche 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse Cedex, France.Institut National de la Santé et de la Recherche Médicale , Toulouse , France. Université Paul Sabatier, Unité Mixte de Recherche 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse Cedex, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30070580

Citation

Charpentier, Julie, et al. "Lixisenatide Requires a Functional Gut-vagus Nerve-brain Axis to Trigger Insulin Secretion in Controls and Type 2 Diabetic Mice." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 315, no. 5, 2018, pp. G671-G684.
Charpentier J, Waget A, Klopp P, et al. Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice. Am J Physiol Gastrointest Liver Physiol. 2018;315(5):G671-G684.
Charpentier, J., Waget, A., Klopp, P., Magnan, C., Cruciani-Guglielmacci, C., Lee, S. J., Burcelin, R., & Grasset, E. (2018). Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice. American Journal of Physiology. Gastrointestinal and Liver Physiology, 315(5), G671-G684. https://doi.org/10.1152/ajpgi.00348.2017
Charpentier J, et al. Lixisenatide Requires a Functional Gut-vagus Nerve-brain Axis to Trigger Insulin Secretion in Controls and Type 2 Diabetic Mice. Am J Physiol Gastrointest Liver Physiol. 2018 11 1;315(5):G671-G684. PubMed PMID: 30070580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice. AU - Charpentier,Julie, AU - Waget,Aurélie, AU - Klopp,Pascale, AU - Magnan,Christophe, AU - Cruciani-Guglielmacci,Céline, AU - Lee,Shin Jae, AU - Burcelin,Rémy, AU - Grasset,Estelle, Y1 - 2018/08/02/ PY - 2018/8/3/pubmed PY - 2019/8/17/medline PY - 2018/8/3/entrez KW - GLP-1 analogs KW - GLP-1 receptor agonist KW - autonomic nervous system KW - incretin KW - vagus nerve SP - G671 EP - G684 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 315 IS - 5 N2 - Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct β-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice. NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/30070580/Lixisenatide_requires_a_functional_gut_vagus_nerve_brain_axis_to_trigger_insulin_secretion_in_controls_and_type_2_diabetic_mice_ L2 - http://journals.physiology.org/doi/full/10.1152/ajpgi.00348.2017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -