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.
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.
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.