Zn2+ toxicity is implicated in pancreatic -cell death that occurs secondarily to: streptozotocin exposure in vitro;\r\nand both autoimmune attack or streptozotocin in vivo models of T1DM. This is demonstrated by reduced -cell death\r\nor diabetic incidence in vitro or in NOD mice after treatment with Zn2+ preferring chelators, pyruvate, nicotinamide,\r\na reduced zinc diet, sirtuin inhibitors, or zinc transporter knockout. These therapeutics are also demonstrated to be\r\n \r\n \r\n \r\n2+ neurotoxicity.\r\nAims: To determine if the sirtuin pathway is involved in Zn2+-, streptozotocin-, or cytokine- mediated -cell death\r\nin vitro, and streptozotocin-, or NOD induced T1DM in vivo.\r\nMethods: Sensitivity of MIN6 cells expressing empty vector, sirtuin protein-1 (SIRT1) or its siRNA, to Zn2+,\r\nstreptozotocin, or cytokines, and effects on NAD+ levels were determined. Covariance of manipulating SIRT1 levels\r\nwith diabetic incidence was tested in vivo.\r\nResults: 1) sirtuin pathway inhibition or SIRT1 knockdown attenuated Zn2+-, STZ-, and cytokine-mediated\r\ntoxicity and NAD+ loss in -cells, 2) SIRT1 overexpression potentiated these toxicities, 3) young SIRT1 -cell\r\ntransgenic mice have improved glucose tolerance under basal conditions, but upon aging showed increased\r\nsensitivity to streptozotocin compared to SIRT1 +/- mice, and 4) SIRT1 +/- mice in an NOD background or exposed\r\nto streptozotocin trended toward reduced diabetic incidence and mortality compared to wildtype.\r\nConclusions: These results have implicated SIRT1-mediated NAD+ loss in Zn2+, STZ, or cytokine toxicities of\r\nMIN6, and in NOD or streptozotocin T1DM animal models. Modulation of -cell Zn2+ and NAD+ levels, and the sirtuin\r\npathway could be novel therapeutic targets for T1DM.
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