The role of metallothionein-3 in streptozotocin-induced beta-islet cell death and diabetes in mice

Abstract

Metallothionein-3 (Mt3), a zinc (Zn)-regulatory protein mainly expressed in the central nervous system, may contribute to oxidative cell death. In the present study, we examined the possible role of Mt3 in streptozotocin (STZ)-induced islet cell death and consequent hyperglycemia. Quantitative real-time polymerase chain reaction (RT-PCR) confirmed that islet cells expressed Mt3 mRNA. In all cases, wild-type (WT) mice injected with STZ exhibited hyperglycemia 7-21 days later. In stark contrast, all Mt3-null mice remained normoglycemic following STZ injection. STZ treatment increased free Zn levels in islet cells and induced their death in WT mice, but failed to do so in Mt3-null mice. Consistent with this, cultured Mt3-null islet cells exhibited striking resistance to STZ toxicity. Notably, PDE3a (phosphodiesterase 3A) was downregulated in islets of Mt3-null mice compared to those of WT mice, and was not induced by STZ treatment. Moreover, the PDE3 inhibitor cilostazol reduced islet cell death, likely by increasing cAMP levels, further supporting a role for PDE3 in STZ-induced islet cell death. Collectively, these results demonstrate that Mt3 may act through PDE3a to play a key role in Zn dyshomeostasis and cell death in STZ-treated islets.

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

“…Another G-protein coupled receptors GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R) increase the level of cAMP in β-cells upon binding gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), two primary incretin hormones, to exert their insulinotropic, anti-apoptotic, and proliferative effects 30 – 38 . Several of PDEs including PDE3B 39 and PDE3A 40 are highly expressed in β-cells. Inhibition of PDE3 with cilostamide reduced streptozotocin (STZ)-induced islet cell death in mice 40 and augmented β-cell proliferation and regeneration in rat islets and zebrafish 7 , 10 .…”

“…Several of PDEs including PDE3B 39 and PDE3A 40 are highly expressed in β-cells. Inhibition of PDE3 with cilostamide reduced streptozotocin (STZ)-induced islet cell death in mice 40 and augmented β-cell proliferation and regeneration in rat islets and zebrafish 7 , 10 . Intriguingly, cAMP-inducing β-adrenergic receptor (βAR) agonists have been shown to increase the mechanistic target of rapamycin (mTOR)-containing complex mTORC1 activity and Uncoupling protein-1 ( Ucp1 ) expression that critically contribute to white adipose browning 41 , 42 .…”

PM2.5-induced airway inflammation and hyperresponsiveness in NC/Nga mice

“…Although many studies demonstrated antioxidative and cytoprotective effects of Mt3, several groups have shown the evidences that Mt3 contributes to neuronal and astrocytic cell death in acute injury of CNS. By Mt3 null mice, it has been proposed that Mt3 acts as a source of toxic Zn accumulation in brain cells (Byun et al, ). In the present study, high expression of Mt3 in the lung of PM2.5‐exposed mice may support toxic Zn accumulation although expressing cells of Mt3 in the lung was not clear.…”

Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases

“…Specifically, MT3 mRNA is highly expressed in pancreatic islets [ 73 ], in high association with Zn dyshomeostasis. According to a previous report by Byun et al [ 77 ], MT3 also regulates phosphodiesterase 3a (PDE3a), an enzyme that regulates levels of cAMP and cGMP in diabetes. MT3-null mice were less sensitive to STZ- and sodium nitroprusside (SNP)-induced toxicity due to reduced Zn release associated with oxidative toxicity and decreased PDE3a expression or activity [ 77 ].…”