Metabolites as regulators of insulin sensitivity and metabolism

Abstract

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.

Fig. 1 |. Lipids as signalling molecules that regulate metabolism.

Several signalling lipids, including fatty acids, fatty acid esters of hydroxy fatty acids (FAHFAs), diacylglycerol (DAG) and ceramides, regulate intracellular pathways to influence insulin resistance. a | Fatty acids regulate insulin sensitivity and inflammation. Saturated fatty acids (SFAs) activate Toll-like receptor 4 (TLR4), possibly via its co-receptor, myeloid differentiation protein 2 (MD2), which, through the adaptor proteins TIR-domain-containing adaptor-inducing interferon-β (TRIF) and myeloid differentiation primary response protein MYD88, increases the activity of pro-inflammatory transcription factors. TRIF activation promotes the nuclear translocation of interferon regulatory factor 3 (IRF3) to increase the expression of cytokines. MYD88 activation increases phosphorylation of inhibitor of nuclear factor-κB (NF-κB) kinase (IKKβ), which further phosphorylates inhibitor of NF-κB (IκB), leading to nuclear translocation of NF-κB to increase pro-inflammatory cytokine expression. MYD88 also activates Jun N-terminal kinase (JNK) to increase the activity of transcription factor activator protein 1 (AP1), thereby altering the expression of cytokines. Pro-inflammatory cytokines, through their receptors (not shown), further activate these pro-inflammatory transcription factors to establish a positive feedback loop for sustained inflammation. SFA-activated TLR4 and cytokine production impair insulin signalling through IKKβ and JNK activation, but the direct targets of IKKβ and JNK in the insulin signalling pathway remain to be identified. SFA-mediated activation of endoplasmic reticulum (ER) stress, the SRC–JNK pathway and the incorporation of SFAs into diacylglycerol (DAG) and ceramides also impair insulin signalling by inhibiting phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS1) or AKT. Polyunsaturated fatty acids (PUFAs) exert anti-inflammatory effects by activating G protein-coupled receptor 120 (GPR120), which recruits β-arrestin 2 and sequesters TAK1 binding protein 1 (TAB1) to inhibit the TAK1-mediated activation of JNK and IKKβ. PUFA, FAHFAs and resolvins may exert anti-inflammatory effects by activating G protein-coupled receptors (GPCRs) in antigen-presenting cells such as macrophages to inhibit cytokine production. The dashed lines indicate indirect effects. b | DAG and ceramide may induce insulin resistance. DAG accumulates ectopically in insulin-resistant muscle and liver. In muscle, DAG-activated protein kinase Cθ (PKCθ) promotes the phosphorylation of IRS1 on Ser1101 in mice, impairing IRS1 phosphorylation on tyrosine and attenuating insulin signalling. In liver, DAG-activated PKCε promotes phosphorylation of IR on Thr1160 to suppress insulin signalling. As a result of DAG increase, glucose uptake via insulin responsive glucose transporter 4 (GLUT4) in muscle is reduced, and glucose output via GLUT2 from liver is increased; these changes induce hyperglycaemia. Ceramides contribute to hyperglycaemia by activating protein phosphatase 2 A (PP2A), which dephosphorylates AKT, and stimulating PKCλ and PKCζ, which prevent AKT from associating with the membrane, thereby inhibiting AKT activity.

Fig. 2 |. Alterations in lipid metabolism are associated with insulin-resistant states.

Obesity and type 2 diabetes mellitus are associated with increased lipolysis in adipose tissue owing to the action of, or resistance to, multiple hormones and to the increased production of cytokines (such as tumour necrosis factor (TNF) and interleukin-6 (IL-6)) by adipose tissue macrophages. The release of TNF and IL-6 from macrophages is potentiated by the secretion, from adipocytes, of adipocytokines such as retinol-binding protein 4 (RBP4). Fatty acids including long-chain fatty acids (LCFAs) that are released by lipolysis are taken up by muscle and liver via the fatty acid transporter scavenger receptor class B member 1 (SRB1). In muscle, LCFA thioesters (LCFA-CoAs) are imported into mitochondria for β-oxidation via the carnitine shuttle, in which LCFA-CoAs are converted into long-chain acylcarnitines (LCACs). Incomplete β-oxidation in insulin-resistant states causes accumulation of acylcarnitines (ACs) (shown as a dashed line) of varying lengths, which are associated with insulin resistance and hyperglycaemia. In the liver, LCFAs are imported into the mitochondria and are oxidized to generate acetyl-CoA, which activates pyruvate carboxylase, leading to increased production of phosphoenolpyruvate (PEP) from pyruvate. Glycerol generated from lipolysis, in addition to PEP, is converted into glucose-6-phosphate (G6P), resulting in increased glucose production. Overall, the increased flux of metabolic substrates into liver causes insulin resistance and hyperglycaemia. Although an increase in AC muscle content correlates with insulin resistance, a causative effect has not been established in vivo.

Fig. 3 |. Lipids and metabolites modify proteins to regulate metabolism.

Protein acetylation regulates insulin signalling and glucose metabolism. a | Histone acetyltransferase p300, histone deacetylase 2 (HDAC2) and sirtuin 1 (SIRT1) modulate acetylation of insulin receptor substrate 1 (IRS1) and/or AKT in cancers, causing mitogenesis and vascularization, but their effects on activation of insulin-stimulated metabolic pathways remain to be determined (shown as a dashed line). b | In the nucleus, these acetyltransferases and deacetylases also modulate the activity of transcription factors, including farnesoid X-activated receptor (FXR), CREB-regulated transcription co-activator 2 (CRTC2), forkhead box protein O1 (FOXO1) and peroxisome proliferator-activated receptor-γ (PPARγ), and of PPARγ co-activator 1α (PGC-1α)) to regulate bile acid synthesis, gluconeogenesis, adipogenesis and lipid metabolism. Moreover, the modulation of histone acetylation by histone deacetylase 3 (HDAC3), which interacts with Rev-erbAα, regulates the circadian rhythm of lipid and glucose metabolism. p300 also acetylates glucokinase (GCK) regulatory protein (GKRP), which sequesters GCK in the nucleus to inhibit its participation in glycolysis. c | Protein palmitoylation regulates glucose transport in adipocytes. In adipocytes, glucose transporter 4 (GLUT4), components of the GLUT4 storage vesicle (namely, vesicle-associated membrane protein 2 (VAMP2) and insulin-responsive aminopeptidase (IRAP)) and GLUT4 trafficking proteins (including synaptosomal-associated protein 23 (SNAP23), syntaxin 4 and AKT substrate of 160 kDa (AS160)) are palmitoylated at cysteine residues, which regulates their activity. Decreased palmitoylation is associated with impaired insulin-stimulated GLUT4 translocation.

Fig. 4 |. Increased levels of branched-chain amino acids are associated with insulin resistance.

Several factors may increase serum levels of branched-chain amino acids (BCAAs) in states of insulin resistance and obesity, including increased BCAA production by gut microbiota, decreased expression of BCAA catabolizing enzymes in white adipose tissue (WAT) resulting from increased WAT inflammation and endoplasmic reticulum (ER) stress, and possibly decreased catabolism of hepatic BCAAs, which is linked to impaired hypothalamic insulin signalling. Although elevated serum levels of BCAAs are associated with insulin resistance and cardiovascular disease, whether this is causative needs further investigation. BCAAs increase incomplete lipid oxidation in muscle, resulting in the accumulation of acylcarnitines and mitochondrial dysfunction. Altered valine catabolism in muscle increases the production of 3-hydroxyisobutyrate (3-HIB) and decreases the secretion of β-aminoisobutyric acid (BAIBA), which results in increased lipid oxidation and the accumulation of acylcarnitines. Elevated cardiac BCAAs may cause oxidative stress in heart. In adipose tissue, impaired BCAA catabolism may reduce substrate flux into lipogenesis. All these factors may contribute to metabolic dysfunction in insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Dashed lines indicate possible effects that have not been conclusively validated.