Molecular targets related to inflammation and insulin resistance and potential interventions

Abstract

Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions.

Figure 1

Summary of the main insulin signaling pathways. GLUT-1 and -4: glucose transporter-1 and -4; Grb-2: growth receptor binding-2; GSK-3: glycogen synthase kinase-3; IR: insulin receptor; IRS-1 and -2: insulin receptor substrate-1 and -2; MAPK: mitogen-activated protein kinase; PDK-1: phosphoinositide-dependent kinase-1; PIP2: phosphatidyl-inositol diphosphate; PI3: phosphatidyl-inositol triphosphate; P: phosphate; PKC: protein kinase C; PP-1: phosphoprotein phosphatase-1; p70S6 K: protein 70 S6 kinase; p90rsk: protein 90 ribosomal S6 kinase; Shc: Src homology collagen; SHP-2: phosphatase with Src homology 2 domain; SoS: Son of Sevenless.

Figure 2

Inflammatory pathways activated during obesity and their cross talk with insulin signaling. Different signals act directly through membrane (e.g., toll-like receptors [TLRs] and cytokine receptors) and intracellular proteins (inflammasomes) or indirectly by their effect on cell organelles such as mitochondria and endosomal reticulum and generation of metabolites (e.g., ceramides and other lipid mediators) to activate inflammatory pathways. Transcription factor such as nuclear factor κB (NFκB), activator protein-1 (AP-1), and signal transducers and activators of transcription (STAT) are activated downstream to these pathways and lead to the expression of proteins that inhibit insulin signaling and induce a pro-inflammatory state by recruiting and activating immune cells. AT, adipose tissue; DAMPS, damage associated molecular patterns; ER, endoplasmic reticulum; HIF-1, hypoxia factor-1; IAPP, islet amyloid polypeptide; PAMPS, pathogen associated molecular patterns; ROS, reactive oxygen species; SFAs, saturated fatty acids; SOCS, suppressor of cytokine signaling; TAK, transforming growth factor β-activated kinase.

Figure 3

Potential molecular targets for reducing inflammation in insulin resistance conditions. Circulated proteins and lipid mediators are included as potential targets. Resolvins, protectins, and maresins are lipid mediators generated from n-3 fatty acid metabolism that have potent anti-inflammatory and immunoregulatory actions, promoting decreased inflammatory cytokine expression. Toll-like receptors (TLRs) are transmembrane receptors that are activated by saturated fatty acids (SFAs) and lipopolysaccharides (LPSs) inducing inflammatory responses. TLRs activate intracellular pathways that inhibit the peroxisome proliferator-activated receptor-γ (PPAR-γ activity). This transcriptional factor is involved with decreased inflammatory cytokine expression and increased Treg cell differentiation. Other cytokines, including tumor necrosis factor-α (TNF-α), also promote PPAR-γ inhibition. G-protein coupled receptor (GPCR) activation may attenuate the production of TNF-α, interleucin-6 (IL-6) and macrophage chemoattractant protein-1. GPR120 is a GPCR activated by n-3 fatty acids in insulin resistance models. COX: cyclooxygenase; IKK: IκB kinase; JNK: c-Jun NH(2)-terminal kinase; PI3 K-γ: phosphatidylinositol 3-kinase-γ; PKC: protein kinase C; PLC-β: phospholipase C-β.

Figure 4

MicroRNA (miRNA) biogenesis and gene expression control in human cells. (1) Canonical pathway produces pre-miRNA by Drosha/DGCR8 cleavage of pri-miRNA. (2) Noncanonical pathway mirtrons are produced by spliced introns debranched by debranching enzyme (Dbr), after which they fold into pre-miRNA hairpins. Pre-miRNA hairpins are exported from the nucleus to cytosol by exportin-5 (Expo-5) and cleaved by Dicer to produce 22 nucleotides RNA duplexes. One strand of the duplex is transferred to Argonaute complex (Ago) and guided to base-pair with its target mRNA throughout its seed sequence. TRBP: tar-RNA binding protein.