title: Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation.
abstract: BACKGROUND
  The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined.
  
  
  RESULTS
  Increasing glucose (5-25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β.
  
  
  CONCLUSIONS
  Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tanabe
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Syed D
authors.initials: SD
authors.lastname: Hasan
authors.forename: Sara C
authors.initials: SC
authors.lastname: Martinez
authors.forename: Corentin
authors.initials: C
authors.lastname: Cras-Méneur
authors.forename: Cris M
authors.initials: CM
authors.lastname: Welling
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tanizawa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: Erik
authors.initials: E
authors.lastname: Zmuda
authors.forename: Tsonwin
authors.initials: T
authors.lastname: Hai
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D019308:Palmitic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D005947:Glucose