Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1

Diabetologia. 2004 Feb;47(2):249-58. doi: 10.1007/s00125-003-1293-3. Epub 2004 Jan 13.

Abstract

Aims/hypothesis: Pancreatic beta-cell apoptosis is a common feature of Type 1 and Type 2 diabetes and leptin exerts an anti-apoptotic function in these cells. The beta-cell line INS-1 was used to test the hypothesis that the adipocyte hormone adiponectin might mediate an anti-apoptotic effect comparable to leptin.

Methods: Apoptosis was induced by culturing cells with a cytokine combination (interleukin-1beta/interferon-gamma) or palmitic acid in absence or presence of leptin or the globular domain of adiponectin (gAcrp30), respectively.

Results: INS-1 cells had a prominent sensitivity towards cytokine- and fatty acid-induced apoptosis, resulting in about three- and six-fold increases in caspase 3 activation and DNA fragmentation, respectively. gAcrp30 strongly (50-60%) inhibited palmitic acid-induced apoptosis, with a weaker effect against cytokine-induced apoptosis (35%). The same result was observed for leptin with both adipokines being non-additive. Reduction of apoptosis by an inhibitor of IkappaB-kinase (IKK) indicated the involvement of the nuclear factor (NF)-kappaB pathway in both cytokine- and fatty acid-induced apoptosis, however, leptin and gAcrp30 were unable to block NF-kappaB activation. Cytokine- and fatty-acid-induced suppression of glucose/forskolin-stimulated insulin secretion was completely prevented through the action of gAcrp30, whereas leptin was only effective against lipotoxicity-mediated beta-cell dysfunction.

Conclusion/interpretation: Our data show that gAcrp30 partially rescues beta cells from cytokine- and fatty-acid-induced apoptosis and completely restores autoimmune- and lipotoxicity-induced dysfunction of insulin-producing cells. We suggest that gAcrp30 exerts its anti-apoptotic function without modulating NF-kappaB activation. This novel beta cell protective function of gAcrp30 might serve to counteract autoimmune- and lipotoxicity-induced beta-cell destruction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin
  • Animals
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Colforsin / pharmacology
  • Cytokines / pharmacology*
  • DNA Fragmentation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Acids / pharmacology*
  • Glucose / pharmacology
  • I-kappa B Kinase
  • Insulin / metabolism
  • Insulin Secretion
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Leptin / pharmacology
  • Microscopy, Fluorescence
  • NF-kappa B / metabolism
  • NF-kappa B / physiology
  • Palmitic Acid / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Rats

Substances

  • Adiponectin
  • Cytokines
  • Fatty Acids
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1
  • Leptin
  • NF-kappa B
  • Colforsin
  • Palmitic Acid
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Glucose