Lipidomics

Biochemistry

Bioinformatics

Biology

Endocrinology

Metabolome

Lipogenesis

Insulin

Metabolism

Metabolomics

Insulin resistance

Lipid metabolism

Insulin receptor

Metabolic pathway

IRS1

Nature Reviews Molecular Cell Biology

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. Metabolomics and lipidomics have enabled the identification of metabolites (such as lipids, amino acids and bile acids) and metabolic pathways that modulate insulin sensitivity both directly and indirectly. Understanding the metabolic adaptations involved in insulin resistance may lead to novel approaches for preventing and treating T2DM.

Metabolites as regulators of insulin sensitivity and metabolism