Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion

Diabetes. 2015 Oct;64(10):3425-38. doi: 10.2337/db14-0838. Epub 2015 Apr 27.


Toll-like receptors (TLRs) have been implicated in the pathogenesis of type 2 diabetes. We examined the function of TLR3 in glucose metabolism and type 2 diabetes-related phenotypes in animals and humans. TLR3 is highly expressed in the pancreas, suggesting that it can influence metabolism. Using a diet-induced obesity model, we show that TLR3-deficient mice had enhanced glycemic control, facilitated by elevated insulin secretion. Despite having high insulin levels, Tlr3(-/-) mice did not experience disturbances in whole-body insulin sensitivity, suggesting that they have a robust metabolic system that manages increased insulin secretion. Increase in insulin secretion was associated with upregulation of islet glucose phosphorylation as well as exocytotic protein VAMP-2 in Tlr3(-/-) islets. TLR3 deficiency also modified the plasma lipid profile, decreasing VLDL levels due to decreased triglyceride biosynthesis. Moreover, a meta-analysis of two healthy human populations showed that a missense single nucleotide polymorphism in TLR3 (encoding L412F) was linked to elevated insulin levels, consistent with our experimental findings. In conclusion, our results increase the understanding of the function of innate receptors in metabolic disorders and implicate TLR3 as a key control system in metabolic regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Area Under Curve
  • Blood Glucose / metabolism
  • Cholesterol, VLDL / blood
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Glucose / metabolism*
  • Glucose / pharmacokinetics
  • Glucose Tolerance Test
  • Homeostasis
  • Humans
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Polymorphism, Genetic
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism*


  • Blood Glucose
  • Cholesterol, VLDL
  • Dietary Fats
  • Insulin
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Glucose