Lack of TXNIP protects against mitochondria-mediated apoptosis, but not against fatty acid-induced, ER-stress-mediated beta cell death

  1. Junqin Chen1,
  2. Ghislaine Fontes2,
  3. Geetu Saxena1,
  4. Vincent Poitout2 and
  5. Anath Shalev (as7{at}
  1. 1Department of Medicine, University of Wisconsin and William F. Middleton Veterans Administration Hospital, Madison, WI 53792, USA and
  2. 2Montreal Diabetes Research Center, CRCHUM,, and Department of Medicine, University of Montreal, QC, Canada


    Objective: We have previously shown that lack of thioredoxin-interacting protein (TXNIP) protects against diabetes and glucotoxicity-induced beta-cell apoptosis. Since the role of TXNIP in lipotoxicity is unknown, the goal of the present study was to determine whether TXNIP expression is regulated by fatty acids and whether TXNIP-deficiency also protects beta-cells against lipoapoptosis.

    Resarch design and methods: To determine the effects of fatty acids on beta-cell TXNIP expression, INS-1 beta-cell and isolated islets were incubated with/without palmitate and rats underwent cyclic infusions of glucose and/or intralipid prior to islet isolation and analysis by quantitative real-time RT-PCR and immunoblotting. Using primary wild-type and TXNIP-deficient islets, we then assessed the effects of palmitate on apoptosis (TUNEL), mitochondrial death pathway (cytochrome C release) and endoplasmic reticulum (ER) stress (BiP, CHOP). Effects of TXNIP-deficiency were also tested in the context of staurosporine (mitochondrial damage) or thapsigargin (ER-stress).

    Results: Glucose elicited a dramatic increase in islet TXNIP expression both in vitro and in vivo, whereas fatty acids had no such effect and, when combined with glucose, even abolished the glucose effect. We also found that TXNIP-deficiency does not effectively protect against palmitate or thapsigargin-induced beta-cell apoptosis, but specifically prevents staurosporine or glucose-induced toxicity.

    Conclusions: Our results demonstrate that unlike glucose, fatty acids do not induce beta-cell expression of pro-apoptotic TXNIP. They further reveal that TXNIP deficiency specifically inhibits the mitochondrial death pathway underlying beta-cell glucotoxicity, whereas it has very little protective effects against ER-stress-mediated lipoapoptosis.


      • Received June 29, 2009.
      • Accepted October 22, 2009.