Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation

Katsuya Tanabe, Yang Liu, Syed D. Hasan, Sara C. Martinez, Corentin Cras-Méneur, Cris M. Welling, Ernesto Bernal Mizrachi, Yukio Tanizawa, Christopher J. Rhodes, Erik Zmuda, Tsonwin Hai, Nada A. Abumrad, M. Alan Permutt

Research output: Contribution to journalArticle

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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. Principal Findings: 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/Significance: 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.

Original languageEnglish (US)
Article numbere18146
JournalPLoS One
Volume6
Issue number4
DOIs
StatePublished - 2011
Externally publishedYes

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Glycogen Synthase Kinase 3
JNK Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
B-lymphocytes
B-Lymphocytes
Fatty Acids
apoptosis
Chemical activation
Cells
Apoptosis
fatty acids
Glucose
glucose
Endoplasmic Reticulum Stress
Islets of Langerhans
Nonesterified Fatty Acids
endoplasmic reticulum
free fatty acids
Palmitates
palmitates

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tanabe, K., Liu, Y., Hasan, S. D., Martinez, S. C., Cras-Méneur, C., Welling, C. M., ... Permutt, M. A. (2011). Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. PLoS One, 6(4), [e18146]. https://doi.org/10.1371/journal.pone.0018146

Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. / Tanabe, Katsuya; Liu, Yang; Hasan, Syed D.; Martinez, Sara C.; Cras-Méneur, Corentin; Welling, Cris M.; Bernal Mizrachi, Ernesto; Tanizawa, Yukio; Rhodes, Christopher J.; Zmuda, Erik; Hai, Tsonwin; Abumrad, Nada A.; Permutt, M. Alan.

In: PLoS One, Vol. 6, No. 4, e18146, 2011.

Research output: Contribution to journalArticle

Tanabe, K, Liu, Y, Hasan, SD, Martinez, SC, Cras-Méneur, C, Welling, CM, Bernal Mizrachi, E, Tanizawa, Y, Rhodes, CJ, Zmuda, E, Hai, T, Abumrad, NA & Permutt, MA 2011, 'Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation', PLoS One, vol. 6, no. 4, e18146. https://doi.org/10.1371/journal.pone.0018146
Tanabe, Katsuya ; Liu, Yang ; Hasan, Syed D. ; Martinez, Sara C. ; Cras-Méneur, Corentin ; Welling, Cris M. ; Bernal Mizrachi, Ernesto ; Tanizawa, Yukio ; Rhodes, Christopher J. ; Zmuda, Erik ; Hai, Tsonwin ; Abumrad, Nada A. ; Permutt, M. Alan. / Glucose and fatty acids synergize to promote B-cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. In: PLoS One. 2011 ; Vol. 6, No. 4.
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