Role of the TLR signaling molecule TRIF in β-cell function and glucose homeostasis

Abstract

Type 2 diabetes is a metabolic and inflammatory disease characterized by deteriorating islet function and increased levels of inflammatory cytokines. The inflammatory milieu induced in type 2 diabetes exacerbates islet dysfunction and insulin resistance, and therapies that target inflammation can improve glycemic control in patients with type 2 diabetes. Inflammation in type 2 diabetes may be the result of the stimulation of Toll-like receptors (TLRs), one of the many mediators of inflammation. TLRs can be activated by both exogenous and endogenous ligands, and are responsible for activating NF-κB and interferon-inducible inflammatory gene expression. We examined the role of the TIR-domain containing adaptor-inducing interferon-β (TRIF or TICAM-1), a major signaling molecule for TLR3 and TLR4, in βa-cell function and glucose homeostasis by examining mice lacking TRIF (Trif-/-), TLR3 (Tlr3-/-) or TLR4 (Tlr4-/-).Male, 10-week old Trif-/- mice exhibit a moderate but significant increase in fasting blood glucose compared to C57BL/6 controls (12.0±0.9 vs. 9.7±0.4 mM; p