Metformin Improves Autonomic Nervous System Imbalance and Metabolic Dysfunction in Monosodium L-Glutamate-Treated Rats.

Camila Cristina Ianoni Matiusso,Juliane Rocha De Sant Anna,Carina Previate,Vander Silva Alves,Tatiane Aparecida Ribeiro,Ana Maria Praxedes De Moraes,Ananda Malta,Elaine Vieira,Claudinéia Conationi Da Silva Franco,Lucas Paulo Jacinto Saavedra,Júlio Cézar De Oliveira ,Luiz F Barella ,Laize Peron Tófolo ,Veridiana Mota Moreira ,Paulo Cézar De Freitas Mathias ,Amanda Bianchi Trombini,Marialba Avezum Alves De Castro Prado,Rosiane Aparecida Miranda,Rodrigo Mello Gomes,Kelly Valério Prates,Audrei Pavanello,Flávio Andrade Francisco,Isabela Peixoto Martins

doi:10.3389/fendo.2021.660793

Abstract

Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21–100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.

Highlights

The incidence of non-communicable diseases such as diabetes, obesity, and hypertension has been growing in the last five decades, reaching high prevalence in developing countries, with serious consequences to the future of human beings [1, 2]
The present study shows that superior vagal electrical activity decreases and sympathetic activity increases upon metformin treatment, leading to improvement of the autonomic nervous system (ANS) imbalance
Using agonists and antagonists of parasympathetic neurotransmitters, our work demonstrates that insulin secretion control improved in monosodium L-glutamate (MSG)-rats treated with metformin

Summary

Introduction

The incidence of non-communicable diseases such as diabetes, obesity, and hypertension has been growing in the last five decades, reaching high prevalence in developing countries, with serious consequences to the future of human beings [1, 2] These diseases manifest mostly as common metabolic dysfunctions such as glucose intolerance, insulin resistance, hyperglycemia, hyperinsulinemia, and dyslipidemia, among other. To treat 350 million people with type 2 diabetes worldwide, as estimated by the World Health Organization, private and public institutions follow treatment programs that use drugs to ameliorate disease symptoms One of these antidiabetics drugs is metformin, which is used to treat diabetes worldwide since 1950 [4]. There is evidence that metformin improves hypertension and dyslipidemia [6,7,8]

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