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17 EXPRESSION OF SOCS PROTEINS PROTECTS PANCREATIC BETA CELLS FROM GLUCOSE AND INTERLEUKIN-1β-INDUCED APOPTOSIS.
  1. R. Kosik1,
  2. N. Sauter1,
  3. F. Schulthess1,
  4. K. Maedler1
  1. 1David Geffen School of Medicine at UCLA, Los Angeles, CA.

Abstract

Type 2 diabetes is characterized by beta-cell apoptosis and impaired insulin secretion. Chronic exposure of islets to high glucose accelerates this process, so-called glucotoxicity. This involves proinflammatory cytokines, specifically interleukin-1β. SOCS (suppressors of cytokine signaling) genes control cytokine action. We hypothesize that SOCS genes protect beta cells from apoptosis. Human islets were transfected with GFP, cis, SOCS-1, SOCS-2, and SOCS-3 adenoviruses. After culture at 5.5 mM (control), 11.1 or 33.3 mM glucose with or without IL-1β, apoptosis was measured by the TUNEL assay, SOCS-3 expression by Western blot analysis, and gene expression by quantitative RT-PCR. Western blot analysis revealed a 20-fold induction of SOCS-3 expression by 2 ng/mL IL-1β and 15-fold by 33.3 mM glucose. In parallel, exposure of islets to 2 ng/mL IL-1β or 33.3 mM glucose induced a 3.3-fold or 2.95-fold increase in beta-cell apoptosis, respectively (p < .001). Islets transfected with cis, SOCS-1, or SOCS-3 but not SOCS-2 were protected. PDX-1 mRNA, an important beta-cell transcription factor, and insulin mRNA were 1.7- and 3.4-fold and 1.8- and 2.1-fold decreased by 11.1 and 33.3 mM glucose, respectively (p < .001). Again, cis, SOCS-1, or SOCS-3 but not SOCS-2 overexpression was protective against this decrease. Caspase 1, which converts IL-1β into its active form, was 2.92- and 3.06-fold increased by 11.1 and 33.3 mM glucose, respectively, in nontransfected but not in transfected islets. Our data show that SOCS expression in the beta cell protects the cell from apoptosis and is a strategy to conserve a sufficient beta-cell mass in islet transplantation and diabetes.

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