Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release

J Clin Invest. 1999 Jul;104(1):67-72. doi: 10.1172/JCI6438.


Infiltration of immunocytes into pancreatic islets precedes loss of beta cells in type 1 diabetes. It is conceivable that local release of cytokines affects the function of beta cells before their apoptosis. This study examines whether the elevated proinsulin levels that have been described in prediabetes can result from exposure of beta cells to cytokines. Human beta-cell preparations were cultured for 48 or 72 hours with or without IL-1beta, TNF-alpha, or IFN-gamma, alone or in combination. None of these conditions were cytotoxic, nor did they reduce insulin biosynthetic activity. Single cytokines did not alter medium or cellular content in insulin or proinsulin. Cytokine combinations, in particular IL-1beta plus IFN-gamma, disproportionately elevated medium proinsulin levels. This effect expresses an altered functional state of the beta cells characterized by preserved proinsulin synthesis, a slower hormone conversion, and an increased ratio of cellular proinsulin over insulin content. The delay in proinsulin conversion can be attributed to lower expression of PC1 and PC2 convertases. It is concluded that disproportionately elevated proinsulin levels in pre-type 1 diabetic patients might result from exposure of their beta cells to cytokines released from infiltrating immunocytes. This hormonal alteration expresses an altered functional state of the beta cells that can occur independently of beta-cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Apoptosis
  • Biomarkers
  • Cells, Cultured
  • Culture Media, Conditioned / chemistry
  • Cytokines / pharmacology*
  • Cytokines / toxicity
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Drug Synergism
  • Humans
  • Hyperinsulinism / chemically induced*
  • Insulin / metabolism
  • Insulin Secretion
  • Interferon-gamma / pharmacology
  • Interferon-gamma / toxicity
  • Interleukin-1 / pharmacology
  • Interleukin-1 / toxicity
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Middle Aged
  • Prediabetic State / diagnosis*
  • Prediabetic State / physiopathology
  • Pro-Opiomelanocortin / metabolism
  • Proinsulin / biosynthesis
  • Proinsulin / genetics
  • Proinsulin / metabolism*
  • Proprotein Convertase 2
  • Reverse Transcriptase Polymerase Chain Reaction
  • Secretory Rate / drug effects
  • Subtilisins / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / toxicity


  • Biomarkers
  • Culture Media, Conditioned
  • Cytokines
  • Insulin
  • Interleukin-1
  • Tumor Necrosis Factor-alpha
  • Pro-Opiomelanocortin
  • Interferon-gamma
  • Proinsulin
  • Subtilisins
  • Proprotein Convertase 2