Letter to the Editor
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jan 15, 2022; 13(1): 65-69
Published online Jan 15, 2022. doi: 10.4239/wjd.v13.i1.65
Gut microbiota-derived metabolites are novel targets for improving insulin resistance
Rosana MC Bastos, Érika B Rangel
Rosana MC Bastos, Érika B Rangel, Hospital Israelita Albert Einstein, São Paulo 05652-001, SP, Brazil
Érika B Rangel, Nephrology Division, Federal University of São Paulo, São Paulo 04023-900, SP, Brazil
Author contributions: Bastos RMC and Rangel ÉB wrote the letter; Rangel ÉB revised the letter and gave the final approval.
Supported by São Paulo Research Foundation, No. 2013/19560-6 and No. 2017/23195-2; and EFSD (European Foundation for the Study of Diabetes)/Sanofi (to Rangel ÉB).
Conflict-of-interest statement: The authors declare no conflicts of interest.
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: Érika B Rangel, MD, PhD, Assistant Professor, Senior Scientist, Hospital Israelita Albert Einstein, Av Albert Einstein 627, Building A, 2SS, São Paulo 05652-001, SP, Brazil. erikabr@uol.com.br
Received: July 3, 2021
Peer-review started: July 3, 2021
First decision: July 28, 2021
Revised: August 1, 2021
Accepted: December 31, 2021
Article in press: December 31, 2021
Published online: January 15, 2022
Abstract

The gut microbiota plays a key role in metabolic diseases. Gut-microbiota-derived metabolites are found in different dietary sources, including: Carbohydrate (acetate, propionate, butyrate, also known as short-chain fatty acids, as well as succinate); protein (hydrogen sulfide, indole, and phenylacetic acid); and lipids (resveratrol-, ferulic acid-, linoleic acid-, catechin- and berry-derived metabolites). Insulin resistance, which is a global pandemic metabolic disease that progresses to type 2 diabetes mellitus, can be directly targeted by these metabolites. Gut-microbiota-derived metabolites have broad effects locally and in distinct organs, in particular skeletal muscle, adipose tissue, and liver. These metabolites can modulate glucose metabolism, including the increase in glucose uptake and lipid oxidation in skeletal muscle, and decrease in lipogenesis and gluconeogenesis associated with lipid oxidation in the liver through activation of phosphatidylinositol 3-kinase - serine/threonine-protein kinase B and AMP-activated protein kinase. In adipose tissue, gut-microbiota-derived metabolites stimulate adipogenesis and thermogenesis, inhibit lipolysis, and attenuate inflammation. Importantly, an increase in energy expenditure and fat oxidation occurs in the whole body. Therefore, the therapeutic potential of current pharmacological and non-pharmacological approaches used to treat diabetes mellitus can be tested to target specific metabolites derived from intestinal bacteria, which may ultimately ameliorate the hyperglycemic burden.

Keywords: Insulin resistance, Gut microbiota, Metabolites, Host metabolism, Metabolic organs, Novel targets

Core Tip: The gut-microbiota-derived metabolites play a key role in metabolic diseases. Insulin signaling pathways are directly targeted by these metabolites, as they promote an increase in glucose uptake and lipid oxidation in skeletal muscle; a decrease in lipogenesis and gluconeogenesis associated with an increase in lipid oxidation in the liver; and an improvement in thermogenesis and inflammation in the adipose tissue. Collectively, these findings pave the way for the development of novel drugs or for investigation of the therapeutic potential of drugs currently used to treat insulin resistance, targeting the gut-microbiota-derived metabolites.