Epigenetics and Immunometabolism in Diabetes and Aging

Abstract

Significance: A strong relationship between hyperglycemia, impaired insulin pathway, and cardiovascular disease in type 2 diabetes (T2D) is linked to oxidative stress and inflammation. Immunometabolic pathways link these pathogenic processes and pose important potential therapeutic targets. Recent Advances: The link between immunity and metabolism is bidirectional and includes the role of inflammation in the pathogenesis of metabolic disorders such as T2D, obesity, metabolic syndrome, and hypertension and the role of metabolic factors in regulation of immune cell functions. Low-grade inflammation, oxidative stress, balance between superoxide and nitric oxide, and the infiltration of macrophages, T cells, and B cells in insulin-sensitive tissues lead to metabolic impairment and accelerated aging.

Critical issues: Inflammatory infiltrate and altered immune cell phenotype precede development of metabolic disorders. Inflammatory changes are tightly linked to alterations in metabolic status and energy expenditure and are controlled by epigenetic mechanisms.

Future directions: A better comprehension of these mechanistic insights is of utmost importance to identify novel molecular targets. In this study, we describe a complex scenario of epigenetic changes and immunometabolism linking to diabetes and aging-associated vascular disease. Antioxid. Redox Signal. 29, 257-274.

Keywords: diabetes; epigenetics; inflammation; nitric oxide; superoxide; vascular.

FIG. 1.

Vicious cycle of oxidative stress, endothelial dysfunction, and vascular inflammation in the pathogenesis of vascular complications of metabolic disorders. eNOS, endothelial nitric oxide synthase; ET1, endothelin 1; H₂O₂, hydrogen peroxide; NO, nitric oxide; Nox, nonphagocytic NADPH oxidase; O₂⁻, superoxide anion; PGI₂, prostacyclin; ROS, reactive oxygen species; T2D, type 2 diabetes; XO, xanthine oxidase.

FIG. 2.

Schematic representation of metabolic alterations between OXPHOS and anaerobic glycolysis is one of the key determinants of immune cell activation (e.g., macrophage or T cell) from quiescent state. Modified, based on (36) TCA/Krebs cycle; ATP; Modified from ATP, adenosine triphosphate; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid.

FIG. 3.

Interactions between PVAT and vascular wall components “outside to inside” and “inside to outside” theory of interactions in development of vascular pathologies. Both types of inteactions coexist in development of vascular dysfunction and augment each other. EC, endothelial cell; IFN-γ, interferon gamma; IgG, immunoglobulin G; IL, interleukin; PPAR-γ, peroxisome proliferator-activated receptor gamma; PVAT, perivascular adipose tissue; TNF-α, tumor necrosis factor alpha; VSMC, vascular smooth muscle cell.

FIG. 4.

Central role of epigenetic regulation in the pathogenesis of diabetic vascular dysfunction. Epigenetic changes within endothelium, adipocytes, in particular PVAT and inflammatory cells are all contributing to vascular dysfunction and metabolic dysregulation, including insulin resistance. Key genes identified to be regulated epigenetically in each of the discussed organ systems are indicated in gray along with miRNAs implicated. These epigenetic changes lead to oxidative stress, adipocyte and perivascular inflammation, and endothelial dysfunction. CCL, CC chemokine ligand; miRNAs, microRNAs; NF-κB, nuclear factor kappa B.