Can systemic inflammation impair insulin signaling and worsen insulin resistance?

Systemic inflammation is biologically capable of weakening insulin action through disruption of insulin-receptor substrate (IRS) signaling. This is particularly relevant in later life, when inflammatory markers and insulin resistance commonly coexist, although circulating inflammatory markers do not by themselves identify the responsible tissue or pathway.

Clinical and translational evidence

• In a community-based cohort of men around age 70, higher high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were independently associated with lower hyperinsulinemic–euglycemic-clamp insulin sensitivity, including among normal-weight men without diabetes or metabolic syndrome.
• Prospective MESA findings similarly linked elevated IL-6 and CRP with incident diabetes, though adiposity and pre-existing insulin resistance likely account for part of this relationship.
• Human mechanistic observations are directionally consistent: insulin-resistant individuals have shown greater JNK activation and IRS-1 Ser312 phosphorylation, alongside lower insulin-stimulated IRS-1 tyrosine phosphorylation.

Mechanistic basis

• TNF-α exposure in primary human skeletal-muscle cells increases inhibitory IRS-1 Ser312 phosphorylation and reduces insulin-stimulated Akt phosphorylation. IKKβ silencing restored Akt signaling and glucose metabolism, supporting inflammatory impairment of downstream insulin action.
• JNK can bind IRS-1 and phosphorylate inhibitory serine sites, reducing insulin-stimulated IRS-1 tyrosine phosphorylation. This limits PI3K/Akt signaling, a central pathway for insulin-responsive glucose metabolism.
• IKKβ/NF-κB signaling may amplify this process by sustaining inflammatory gene expression; however, the responsible kinase need not be identical to the one producing a specific IRS-1 phosphorylation site.

Clinical interpretation

• TNF-α infusion can impair insulin-stimulated glucose uptake in humans, but this does not prove that IRS-1 Ser312 phosphorylation accounts for the whole-body effect. Small TNF-α-blockade trials also did not improve insulin sensitivity despite reducing inflammatory markers.

Bottom line

• The claim is supported: inflammatory signaling can promote inhibitory IRS phosphorylation, impair insulin-receptor/IRS-to-Akt signaling, and thereby worsen insulin resistance. The pathway is strongly grounded mechanistically, while its precise causal contribution across tissues in humans remains less certain.