TLR4 triggered complex inflammation in human pancreatic islets

Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):86-97. doi: 10.1016/j.bbadis.2018.09.030. Epub 2018 Oct 1.


Type 2 Diabetes (T2D) is strongly associated with obesity and inflammation. Toll-like receptor-4 (TLR-4) is the major pro-inflammatory pathway with its ligands and downstream products increased systemically in T2D and in at-risk individuals. Detailed mechanisms of the complex proinflammatory response in pancreatic islets remain unknown. In isolated human islets LPS induced IL-1β, IL-6, IL-8 and TNF production in a TLR4-dependent manner and severely impaired β-cell survival and function. IL-6 antagonism improved β-cell function. IL-8, which was identified specifically in α-cells, initiated monocyte migration, a process fully blocked by IL-8 neutralization. The TLR4 response was potentiated in obese donors; with higher IL-1β, IL-6 and IL-8 expression than in non-obese donors. TLR4 activation leads to a complex multi-cellular inflammatory response in human islets, which involves β-cell failure, cytokine production and macrophage recruitment to islets. In obesity, the amplified TLR4 response may potentiate β-cell damage and accelerate diabetes progression.

Keywords: Apoptosis; Chemokine; Cytokine; Inflammation; Insulin; Obesity; TLR4; Type 2 diabetes; α-Cells; β-Cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Movement
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Progression
  • Gene Expression Regulation
  • Humans
  • Inflammation / metabolism*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Islets of Langerhans / metabolism*
  • Macrophages / metabolism
  • Obesity / complications
  • Obesity / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Chemokines
  • Cytokines
  • Insulin
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha