Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male mice

Endocrinology. 2013 Sep;154(9):3077-88. doi: 10.1210/en.2012-2138. Epub 2013 Jul 8.


Elevated levels of circulating proinflammatory cytokines are associated with obesity and increased risk of type 2 diabetes, but the mechanism is unknown. We tested whether proinflammatory cytokines IL-1B+IL-6 at low picogram per milliliter concentrations (consistent with serum levels) could directly trigger pancreatic islet dysfunction. Overnight exposure to IL-1B+IL-6 in islets isolated from normal mice and humans disrupted glucose-stimulated intracellular calcium responses; cytokine-induced effects were more severe among islets from prediabetic db/db mice that otherwise showed no signs of dysfunction. IL-1B+IL-6 exposure reduced endoplasmic reticulum (ER) calcium storage, activated ER stress responses (Nos2, Bip, Atf4, and Ddit3 [CHOP]), impaired glucose-stimulated insulin secretion, and increased cell death only in islets from prediabetic db/db mice. Furthermore, we found increased serum levels of IL-1B and IL-6 in diabetes-prone mice at an age before hyperglycemia was exhibited, suggesting that low-grade systemic inflammation develops early in the disease process. In addition, we implanted normal outbred and inbred mice with subcutaneous osmotic mini-pumps containing IL-1B+IL-6 to mimic the serum increases found in prediabetic db/db mice. Both IL-1B and IL-6 were elevated in serum from cytokine-pump mice, but glucose tolerance and blood glucose levels did not differ from controls. However, when compared with controls, isolated islets from cytokine-pump mice showed deficiencies in calcium handling and insulin secretion that were similar to observations with islets exposed to cytokines in vitro. These findings provide proof of principle that low-grade systemic inflammation is present early in the development of type 2 diabetes and can trigger ER stress-mediated islet dysfunction that can lead to islet failure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Outbred Strains
  • Apoptosis / drug effects
  • Calcium Signaling / drug effects
  • Drug Implants
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress* / drug effects
  • Glucose / metabolism
  • Humans
  • Infusions, Subcutaneous
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Interleukin-1beta / administration & dosage
  • Interleukin-1beta / adverse effects
  • Interleukin-1beta / blood*
  • Interleukin-6 / administration & dosage
  • Interleukin-6 / adverse effects
  • Interleukin-6 / blood*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • Prediabetic State / blood*
  • Prediabetic State / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Specific Pathogen-Free Organisms
  • Tissue Culture Techniques


  • Drug Implants
  • Insulin
  • Interleukin-1beta
  • Interleukin-6
  • Recombinant Proteins
  • Glucose