title: 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 NFκB 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 b-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 b-cell mass (3.5 ± 0.9 vs. 1.7 ± 0.2 mg; p < 0.05). In summary, mice lacking TRIF have hyperglycemia associated with b-cell dysfunction that may be partly compensated for by increased b-cell mass. These studies suggest a role for TLR signaling in glucose homeostasis, and raise the possibility that TRIF signaling is required for normal b-cell function.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, Canada.
authors.forename: Meredith J H
authors.initials: MJ
authors.lastname: Hutton
authors.forename: Galina
authors.initials: G
authors.lastname: Soukhatcheva
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics; D010179:Pancreas / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D005947:Glucose; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse