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

Table 1 Role of various inflammatory molecules in type 2 diabetes

Category	Molecule	Role
Pro-inflammatory cytokines and signaling molecules	TNF-α	Increased levels related to IR and T2D Reduces insulin sensitivity by influencing the phosphorylation state of the insulin receptor
	IL-6	Major pro-inflammatory cytokine that induces inflammation and IR leading to T2D
	CRP	Elevated serum CRP associated with the incidence of T2D
	IL-1	Associated with obesity and IR Affects insulin signaling directly through the induction of SOCS-3
	IL-8	Leads to IR via the inhibition of insulin-induced Akt phosphorylation in adipocytes
	IL-1β	Mediates auto-inflammatory process resulting in β-cell death
Transcription factors	NF-κB	Increase the expression of genes encoding cytokines, chemokines, transcription factors and various receptors involved in IR and pathogenesis of T2D
	JNK	Promotes IR through phosphorylation of serine residues in IRS-1
	IKKβ	Leads to IR through transcriptional activation of NF-κB
Adipokines	Leptin	High leptin levels, reflecting leptin resistance predict increased risk of T2D
	Adiponectin	Low levels of this protective adipokine correlate with T2D. Adiponectin is downregulated by TNF-α
	Resistin	Promotes IR and decreases insulin-stimulated glucose transporters in adipose tissue
	Adipsin	Role in maintaining β cell function Lower levels of adipsin found in T2D patient
	Visfatin	Visfatin binds to the insulin receptor at a site distinct from that of insulin and causes hypoglycaemia by reducing glucose release from liver cells and stimulating glucose utilization in adipocytes and myocytes
Chemokines	MCP-1	MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, IR and T2D
	IP-10/CXCL10	Downstream effector of pro-inflammatory cytokines involved in T2D-related complications
	CCR2	Imitates tissue inflammation and IR
Toll like receptor	TLR2 and TLR4	TLR2 and TLR4 play a critical role in the pathogenesis of IR and T2D
Adhesion molecules	E-slectin/P-slectin	Lead to leukocyte recruitment in local tissue and contributes to inflammation, IR and T2D
	ICAM-1/VCAM-1	Alters endothelial and sub-endothelial structure leading to reduced vascular permeability, reduced insulin delivery to peripheral insulin sensitive tissues and ultimately T2D
Nuclear receptors	PPARα, PPARγ, and PPARβ/δ	Mutations in PPAR genes associated with IR and T2D
	VDR	Regulates expression of insulin receptor preferentially by binding as a heterodimer with the RXR to VDREs in the promoter regions of insulin receptor gene

IR: Insulin resistance; CRP: C-reactive protein; T2D: Type 2 diabetes; SOCS-3: Suppressor of cytokine-3 signalling; NF-κB: Nuclear factor κB; JNK: c-Jun NH2-terminal kinase; IRS-1: Insulin receptor substrate; IKKβ: Inhibitor of nuclear factor κB kinase subunit β; MCP: Monocyte chemoattractant protein-1; IP-10: Interferon gamma-induced protein 10; CXCL10: Chemokine (C-X-C motif) ligand 10; CCR2: Chemokine (C-C) motif receptor 2; ICAM-1: Intracellular adhesion molecule 1; VCAM-1: Vascular cell adhesion molecule 1; PPAR: Peroxisome proliferator activated receptor; VDR: Vitamin D receptor; RXR: Retinoid X receptor; VDREs: Vitamin D response elements.