Clioquinol attenuates zinc-dependent beta-cell death and the onset of insulitis and hyperglycemia associated with experimental type I diabetes in mice.
Zinc in the pancreas is co-released with insulin from beta-cells reaching concentrations similar to those found in the vicinity of glutamatergic synapses. In the brain, the role of zinc in excitotoxic brain damage is well established. In contrast, its role in islet destruction during diabetes is poorly understood. We have studied the efficacy of zinc homeostatic proteins and an intracellular zinc chelator, clioquinol, in conferring resistance against zinc toxicity in pancreatic islets. We further assessed the ability of clioquinol to protect the islets in an experimental model of type I diabetes. Our results indicate that endogenous mechanisms for lowering [Zn]i are deficient in the insulinoma cell line, MIN6, and that permeation of Zn2+ triggered cell death. Application of the low affinity, intracellular zinc chelator, clioquinol, reduced Zn2+-induced cell death by 80%. In addition, chelation of zinc ions by clioquinol in vivo prevented onset of multiple low dose streptozotocin-induced diabetes, and reduced the insulitis and hyperglycemia associated with this model. Furthermore, the glucose tolerance test (GTT) score of multiple low dose streptozotocin (MLD-STZ) mice pretreated with clioquinol was, statistically indistinguishable from that of untreated, control mice. Taken together, our results point to the potential utility of in vivo zinc chelation as a therapeutic strategy for treatment of idiopathic type I diabetes.
Priel
Tsvia
T
Department of Physiology and Zlotowski Center for Neurosciences, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Aricha-Tamir
Barak
B
Sekler
Israel
I
D000818:Animals; D027682:Cation Transport Proteins / Q000032:analysis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000627:therapeutic use*; D007464:Clioquinol / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D006943:Hyperglycemia / Q000188:drug therapy*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012964:Sodium / Q000378:metabolism; D013311:Streptozocin; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*
D027682:Cation Transport Proteins; D002614:Chelating Agents; C485803:Slc30a1 protein, mouse; D013311:Streptozocin; D007464:Clioquinol; D012964:Sodium; D015032:Zinc