The cause of insulin resistance in obesity and type 2 diabetes mellitus (T2DM) is not limited to impaired insulin signalling but also involves the complex interplay of multiple metabolic pathways. The analysis of large data sets generated by metabolomics and lipidomics has shed new light on the roles of metabolites such as lipids, amino acids and bile acids in modulating insulin sensitivity. Metabolites can regulate insulin sensitivity directly by modulating components of the insulin signalling pathway, such as insulin receptor substrates (IRSs) and AKT, and indirectly by altering the flux of substrates through multiple metabolic pathways, including lipogenesis, lipid oxidation, protein synthesis and degradation and hepatic gluconeogenesis. Moreover, the post-translational modification of proteins by metabolites and lipids, including acetylation and palmitoylation, can alter protein function. Furthermore, the role of the microbiota in regulating substrate metabolism and insulin sensitivity is unfolding. In this Review, we discuss the emerging roles of metabolites in the pathogenesis of insulin resistance and T2DM. A comprehensive understanding of the metabolic adaptations involved in insulin resistance may enable the identification of novel targets for improving insulin sensitivity and preventing, and treating, T2DM.
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The authors thank A. Santoro for comments on the manuscript. Q.Y. is supported by US National Institutes of Health (NIH) grant R01 DK100385; B.B.K. is supported by NIH R01 DK43051, R01 DK106210, R01 DK107405 and a grant from the JPB Foundation; A.V. is supported by NIH R01 DK106210.
B.B.K. is an inventor on patents related to the fatty acid esters of hydroxy fatty acids. The other authors declare no competing interests.
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- Toll-like receptors
(TLRs). A family of pattern-recognition receptors with a role in innate immunity. For example, TLR4 is activated upon dimerization with the co-receptor myeloid differentiation protein 2 (MD2); signalling via TLR4–MD2 results in the transcription of pro-inflammatory genes.
- Mendelian randomization
A novel epidemiological study design that uses genetic variants to investigate the causal relationship of a biomarker to the risk of having a phenotype or disease.
Two molecules that have the same molecular formula but differ in the orientation of atoms. Enantiomers are stereoisomers that are mirror images of each other; an enantiomer is labelled ‘R’ in its right-handed configuration and ‘S’ in its left-handed configuration.
- Stereospecific numbering
(sn). The sn position is often used to define the configuration of glycerol-containing metabolites. When the OH group on the second carbon (sn-2) of glycerol is oriented to the left, the top (first) carbon is at the sn-1 position and the bottom (third) carbon is at the sn-3 position.
- Non-alcoholic steatohepatitis
(NASH). Hepatitis caused by excessive fat deposition in the liver that is not related to heavy alcohol use.
- Lands cycle
Cycles to remodel phospholipids by first de-acylating and then re-acylating them, thereby altering the fatty acid moiety to generate mature phospholipids.
- Anaplerotic pathways
Pathways that replenish tricarboxylic acid cycle intermediates, which can then be used for energy production or for gluconeogenesis in the liver.
- Periportal neural system
The nervous system that innervates the liver.
- L cells
A subset of entero-endocrine cells that secrete gut peptides such as glucagon-like peptide 1 (GLP1), incretins, etc.
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Yang, Q., Vijayakumar, A. & Kahn, B.B. Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol 19, 654–672 (2018). https://doi.org/10.1038/s41580-018-0044-8
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