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

Islets. Mar-Apr 2010;2(2):104-11. doi: 10.4161/isl.2.2.11209.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Adaptor Proteins, Vesicular Transport / physiology*
  • Animals
  • Glucose / metabolism*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size / genetics
  • Pancreas / anatomy & histology
  • Pancreas / cytology
  • Pancreas / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism
  • Toll-Like Receptors / physiology


  • Adaptor Proteins, Vesicular Transport
  • TICAM-1 protein, mouse
  • Toll-Like Receptors
  • Glucose