Convergence of innate immunity and insulin resistance as evidenced by increased nucleotide oligomerization domain (NOD) expression and signaling in monocytes from patients with type 2 diabetes

• Published in: Cytokine (Philadelphia, Pa.) Vol. 64; no. 2; pp. 564 - 570
• Main Authors: Shiny, Abhijit, Regin, Bhaskaran, Balachandar, Venketesan, Gokulakrishnan, Kuppan, Mohan, Viswanathan, Babu, Subash, Balasubramanyam, Muthuswamy
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2013
• Subjects: Adult; blood; CD11b Antigen; CD11b Antigen - metabolism; CD36 Antigens; CD36 Antigens - metabolism; correlation; Cytokines; Cytokines - blood; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - immunology; drug effects; gene expression; Gene Expression Regulation; Gene Expression Regulation - drug effects; genetics; Glucose; Glucose - pharmacology; glucose tolerance; glycemic control; Humans; Immunity, Innate; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunity, Innate - immunology; immunology; Inflammation; Inflammation Mediators; Inflammation Mediators - metabolism; Innate immunity; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - immunology; interleukin-6; intracellular signaling peptides and proteins; metabolism; Middle Aged; monocytes; Monocytes - drug effects; Monocytes - metabolism; Nod1 Signaling Adaptor Protein; Nod1 Signaling Adaptor Protein - genetics; Nod1 Signaling Adaptor Protein - metabolism; Nod2 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - metabolism; noninsulin-dependent diabetes mellitus; Nucleotide oligomerization domain (NOD); patients; pharmacology; proteins; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics; Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism; RNA, Messenger; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Subcellular Fractions; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; transcription (genetics); Transcription Factors; Transcription Factors - metabolism; Type 2 diabetes; Type 2 diabetes; T2DM; NOD; Nucleotide oligomerization domain (NOD); OR; RIPK2; Innate immunity; Inflammation; IL-6; PRR; NFκβ; TNF-α; PGN; IGT; MDP; Insulin resistance; HOMA; NGT; TLR; HbA1C; iEDAP; homeostasis assessment model; impaired glucose tolerance; odds ratio; interleukin-6; tumor necrosis factor – alpha; type 2 diabetes mellitus; receptor interacting protein kinase 2; muramyl dipeptide; toll like receptor; nuclear factor kappa beta; nucleotide binding oligomerization domain; peptidoglycan; normal glucose tolerance; glycated hemoglobin; γ-d-glutamyl-meso diaminopimelic acid; pattern recognition receptor
• DOI: 10.1016/j.cyto.2013.08.003
• ISSN: 1043-4666; 1096-0023

•Monocytes from diabetes patients exhibited increased NOD1 and NOD2 expression.•Proinflammatory markers (RIPK and NFκB) were also upregulated in diabetes patients.•Elevated levels of NODs correlated to poor glycemic control and insulin resistance.•High glucose activated NOD expression and augmented the actions of NOD-ligands. Despite the well known role of nucleotide oligomerization domain (NOD) receptor proteins in innate immunity, their association with diabetes is less explored. Here we report the transcriptional level of NODs and their downstream molecular signatures in CD14+ monocytes from subjects with different grades of glucose tolerance. NOD1 and NOD2 mRNA expression were significantly up-regulated in monocytes from patients with type 2 diabetes (T2DM) and positively correlated with HOMA-IR and poor glycemic control. Patients with T2DM also exhibited increased monocyte activation markers (CD11b and CD36) and proinflammatory signals downstream of NOD (RIPK2 and NFκB) along with the increased circulatory levels of TNF-α and IL-6. In vitro stimulation of monocytes with NOD specific ligands-i-EDAP and MDP significantly up regulated the mRNA expression of NOD1 and NOD2 respectively in T2DM. Our study exposes up regulation of NODs in monocytes as an important component of inflammation and insulin resistance in patients with T2DM.