Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition

Abstract

Diabetes mellitus is increasing at an alarming rate and has become a global challenge. Insulin resistance in target tissues and a relative deficiency of insulin secretion from pancreatic β-cells are the major features of type 2 diabetes (T2D). Chronic low-grade inflammation in T2D has given an impetus to the field of immuno-metabolism linking inflammation to insulin resistance and β-cell dysfunction. Many factors advocate a causal link between metabolic stress and inflammation. Numerous cellular factors trigger inflammatory signalling cascades, and as a result T2D is at the moment considered an inflammatory disorder triggered by disordered metabolism. Cellular mechanisms like activation of Toll-like receptors, Endoplasmic Reticulum stress, and inflammasome activation are related to the nutrient excess linking pathogenesis and progression of T2D with inflammation. This paper aims to systematically review the metabolic profile and role of various inflammatory pathways in T2D by capturing relevant evidence from various sources. The perspectives include suggestions for the development of therapies involving the shift from metabolic stress to homeostasis that would favour insulin sensitivity and survival of pancreatic β-cells in T2D.

Keywords: Adipose tissue; Diabetes mellitus; Inflammation; Insulin resistance; β-cell dysfunction.

Figure 1

Functions of various immune cell types in pathogenesis of type 2 diabetes. IL: Interleukin; MCP-1: Monocyte chemoattractant protein-1; TNF-α: Tumor necrosis factor α.

Figure 2

Various hormone functions of insulin.

Figure 3

Target genes activated by NF-κB. TNF-α: Tumor necrosis factor-alpha; IFN-γ: Interferon-gamma; IL: Interleukin; TGF-β: Tumor growth factor-beta; MCP-1: Monocyte chemoattractant protein-1; MIP: Major intrinsic protein; TNFR: Tumor necrosis factor receptor; INFR: Interferon receptor; IL-R: Interleukin receptor; CD: Cluster of differentiation; ICAM: Intracellular cell adhesion molecule; VCAM: Vascular cell adhesion molecule; CCR: Chemokine CC receptor; TLR: Toll-like receptor; Lox: Lysyl oxidase; RAGE: Receptor advanced glycation end product; PAI: Plasminogen inhibitor activator; SAA: Serum amyloid; CRP: C-reactive protein; COX: Cyclo-oxygenase; iNOS: Inducible nitric oxide synthase; VEGF: Vascular endothelial growth factor; IGFBPs: Insulin-like growth factor binding protein; MnSOD: Manganese superoxide dismutase; RelA: Reticuloendotheliosis viral oncogene homolog A; NF-κB: Nuclear factor-kappa B; IKK: Inhibitor Kappa B kinase; IκBα: Inhibitor of NF-κB; TNFAIP3: TNF-α induced protein 3.

Figure 4

Mechanism of endoplasmic reticulum stress. ER: Endoplasmic-reticulum; ATF6: Activating transcription factor 6; PERK: Double-stranded RNA-activated protein kinase (PKR)-like ER kinase; IRE1: Inositol-requiring kinase 1; IL: Interleukin; MCP: Monocyte chemoattractant protein; TNF-α: Tumor necrosis factor α; JNK: c-Jun NH2-terminal kinase; NF-κB: Nuclear factor κB.

Figure 5

Activation of inflammasomes in type 2 diabetes (metabolic stress activates multiprotein complex, inflammasome in β-cells that induce caspase-1 to cleave pro-interleukin-1β (pro-IL-1β) into active IL-1β. β-cell-derived IL-1β promote the release of chemokines and recruitment of macrophages that are activated by human islet amyloid polypeptide, leading to deleterious concentrations of IL-1β. FFA: Free fatty acid; IL: Interleukin.