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

UNLABELLED

Zn toxicity is implicated in pancreatic β-cell death that occurs secondarily to: streptozotocin exposure ; and both autoimmune attack or streptozotocin models of T1DM. This is demonstrated by reduced β-cell death or diabetic incidence in vitro or in NOD mice after treatment with Zn preferring chelators, pyruvate, nicotinamide, a reduced zinc diet, sirtuin inhibitors, or zinc transporter knockout. These therapeutics are also demonstrated to be efficacious against Zn neurotoxicity.

AIMS

To determine if the sirtuin pathway is involved in Zn-, streptozotocin-, or cytokine-mediated β-cell death in vitro, and streptozotocin-, or NOD induced T1DM

METHODS

Sensitivity of MIN6 cells expressing empty vector, sirtuin protein-1 (SIRT1) or its siRNA, to Zn, 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 Zn-, 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 Zn, 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.