Meredith J. H. Hutton, Galina Soukhatcheva, James D. Johnson and C. Bruce Verchere

Meredith J. H. Hutton

Departments of Pathology & Laboratory Medicine; University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada

Galina Soukhatcheva

Departments of Pathology & Laboratory Medicine; University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada

James D. Johnson

Cellular & Physiological Sciences, and Surgery; University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada

C. Bruce Verchere

Departments of Pathology & Laboratory Medicine; University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada

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<0.05) as well as impaired glucose tolerance revealed by IPGTT (AUC: 2850±236 vs. 2050±108; p<0.005) whereas Tlr3^-/- and Tlr4^-/- mice have normal glucose tolerance. Interestingly, Trif^-/- mice have normal insulin sensitivity yet have increased plasma insulin levels (180±22 vs. 89±24 pM; p<0.05). Islets isolated from Trif-/- mice have impaired glucose-stimulated insulin secretion, with a diminished first-phase insulin response to glucose. Immunohistological analysis revealed that age-matched Trif-/- and control mice have normal islet morphology, although Trif^-/- mice have increased β-cell mass (3.5±0.9 vs. 1.7±0.2 mg; p<0.05). In summary, mice lacking TRIF have hyperglycemia associated with β-cell dysfunction that may be partly compensated for by increased β-cell mass. These studies suggest a role for TLR signaling in glucose homeostasis, and raise the possibility that TRIF signaling is required for normal β-cell function.