Abstract
Zn(2+) 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 Zn(2+) preferring chelators, pyruvate, nicotinamide, a reduced zinc diet, sirtuin inhibitors, or zinc transporter knockout. These therapeutics are also demonstrated to be efficacious against Zn(2+) neurotoxicity. AIMS: To determine if the sirtuin pathway is involved in Zn(2+)-, 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 Zn(2+), 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(2+)-, 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(2+), 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.