title: Involvement of SIRT1 in Zn2+, Streptozotocin, Non-Obese Diabetic, and Cytokine-Mediated Toxicities of β-cells.
abstract: Zn2+toxicity is implicated in pancreatic β-cell death that occurs secondarily to: streptozotocin exposurein vitro; and both autoimmune attack or streptozotocinin vivomodels of T1DM. This is demonstrated by reduced β-cell death or diabetic incidence in vitro or in NOD mice after treatment with Zn2+preferring chelators, pyruvate, nicotinamide, a reduced zinc diet, sirtuin inhibitors, or zinc transporter knockout. These therapeutics are also demonstrated to be efficacious against Zn2+neurotoxicity.
  
  
  
  To determine if the sirtuin pathway is involved in Zn2+-, streptozotocin-, or cytokine-mediated β-cell death in vitro, and streptozotocin-, or NOD induced T1DMin vivo.
  
  
  
  Sensitivity of MIN6 cells expressing empty vector, sirtuin protein-1 (SIRT1) or its siRNA, to Zn2+, streptozotocin, or cytokines, and effects on NAD+levels were determined. Covariance of manipulating SIRT1 levels with diabetic incidence was tested in vivo.
  
  
  
  1) sirtuin pathway inhibition or SIRT1 knockdown attenuated Zn2+-, STZ-, and cytokine-mediated toxicity and NAD+loss in β-cells, 2) SIRT1 overexpression potentiated these toxicities, 3) young SIRT1 β-cell transgenic mice have improved glucose tolerance under basal conditions, but upon aging showed increased sensitivity to streptozotocin compared to SIRT1 +/- mice, and 4) SIRT1 +/- mice in an NOD background or exposed to streptozotocin trended toward reduced diabetic incidence and mortality compared to wildtype.
  
  
  
  These results have implicated SIRT1-mediated NAD+loss in Zn2+, STZ, or cytokine toxicities of MIN6, and in NOD or streptozotocin T1DM animal models. Modulation of β-cell Zn2+ and NAD+levels, and the sirtuin pathway could be novel therapeutic targets for T1DM.
authors.affiliation: Louisiana State University Health Sciences Center, LA, USA.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
keywords: MIN6; NAD+; SIRT1 knockout; Sirtuins
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