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Inflammatory mediators and signalling cascades in pathophysiology of obesity induced insulin resistance

Saravanan Subramanian, PhD, Turna Mukherjee, Pradeep K Pallati, MD, Poonam Sharma, MD, Devendra Agrawal, PhD, Kalyana C Nandipati, MD. Creighton University School of Medicine

Introduction: Adipocyte induced pro-inflammatory cytokines and chemokines activates pathogenic inflammatory cells receptors and stimulates inflammatory signalling pathways that result in obesity induced insulin resistance. However, exact role of cell surface receptors and intracellular targets in inducing insulin resistance is unknown.

Methods and Procedures: We examined the mRNA expression by RT-PCR and protein expression by immunofluorescence for inflammatory mediators and receptors (TREM-1, TREM-2, DAP-12, HMGB-1, RAGE, TLRs) and total and phosphorylated intracellular signalling targets (p65 NFκB, IκB-α, JNK-1, PKCs and IRS-1) in omentum, subcutaneous and liver biopsy of obese diabetic (n=22) and non-diabetic subjects (n=24) and compared with non-obese non-diabetic controls (n=5).

Results: Obese diabetics showed significantly (P<0.05) increased expression levels of inflammatory cell receptors (TREM-1, DAP-12, HMGB-1, RAGE, TLR-4, TLR-2) and inflammatory signalling pathways (NFκB p65, p- NFκB p65, p-IκB-α, JNK-1, p-JNK-1, p-sIRS1, PKC-θ, δ and ε) in omentum, subcutaneous and liver biopsy tissues compared to obese non-diabetics. We also found a significant (P<0.05) decrease in TREM-2, IκB-α, IRS-1 and p-yIRS1 expression in obese diabetic subjects compared to obese non-diabetics (Table).

Conclusions: Obese diabetic patients had significantly increased levels of inflammatory receptors and inflammatory signalling cascades compared to obese non-diabetics and non-obese subjects. The cell surface targets like TREM-1 and TLRs can be a potential targets for developing therapeutic strategies to prevent insulin resistance.

Table. Expression of inflammatory cell receptors and inflammatory signalling pathways in obese non-diabetics (OND; N=24) and obese diabetics (OD; N=22) compared to non-obese subjects.

Target genes Omentum

Subcutaneous

Liver
OND n(%) OD n(%) R; P value OND n(%) OD (%) R; P value OND n(%) OD n(%) R; P value
TREM1 22; 91.7% 22; 100% NS 13; 54.2% 17; 77.3% NS 12; 50% 22; 100% R=0.569 P<0.0001
TLR4 23; 95.8% 22; 100% NS 13; 54.2% 17; 77.3% NS 7; 29.2% 22; 100% R=0.733; p<0.0001
NFkB p65 22; 91.7% 22; 100% NS 13; 54.2% 17; 77.3% NS 12; 50% 22; 100% R=0.569 P<0.0001
JNK 23; 95.8% 22; 100% NS 13; 54.2% 17; 77.3% NS 12; 50% 22; 100% R=0.569 P<0.0001

Presented at the SAGES 2017 Annual Meeting in Houston, TX.

Abstract ID: 79145

Program Number: P083

Presentation Session: Poster (Non CME)

Presentation Type: Poster

49

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