alexa Involvement of SIRT1 in Zn2+, Streptozotocin, Non-Obese Diabetic, and Cytokine-Mediated Toxicities of and#946;-cells | OMICS International | Abstract
ISSN: 2155-6156

Journal of Diabetes & Metabolism
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Research Article

Involvement of SIRT1 in Zn2+, Streptozotocin, Non-Obese Diabetic, and Cytokine-Mediated Toxicities of β-cells

Christian T. Sheline*

Louisiana State University Health Sciences Center, LA, USA

*Corresponding Author:
Christian T. Sheline
Department of Ophthalmology and The Neuroscience Center of Excellence
Louisiana State University Health Sciences Center
2020 Gravier St., Suite D, New Orleans
LA 70112, USA
Tel: (504) 599-0880
Fax: (504) 599-0891
E-mail: [email protected]

Received date: March 20, 2011; Accepted date: May 28, 2012; Published date: May 31, 2012

Citation: Sheline CT (2012) Involvement of SIRT1 in Zn2+, Streptozotocin, Non- Obese Diabetic, and Cytokine-Mediated Toxicities of β-cells. J Diabetes Metab 3:193.doi:10.4172/2155-6156.1000193

Copyright: © 2012 Sheline CT. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Zn2+ toxicity is implicated in pancreatic β-cell death that occurs secondarily to: streptozotocin exposure in vitro; and both autoimmune attack or streptozotocin in vivo models 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.

Aims: To determine if the sirtuin pathway is involved in Zn2+-, streptozotocin-, or cytokine- mediated β-cell death in vitro, and streptozotocin-, or NOD induced T1DM in vivo.

Methods: 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.

Results: 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.

Conclusions: 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.

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