Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.

中文翻译：

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微剂量锂可预防链脲佐菌素诱发的糖尿病性胰岛破坏和肾功能损害。

精神科使用锂与降糖作用有关，但对1型糖尿病（T1D）的作用尚不清楚。在链脲佐菌素（STZ）诱导的T1D小鼠模型中，微剂量锂疗法可改善高血糖症，减轻体重减轻并预防糖尿病性肾损伤的早期迹象。这种有益的作用与保存胰岛的组织学和胰岛素的β细胞产生以及减轻胰岛的氧化损伤有关。从机理上讲，胰岛细胞中的锂诱导了糖原合酶激酶3β（GSK3β）的抑制性磷酸化，糖原合酶激酶3β是锂的主要分子靶标，最近被证实与Nrf2活性的非常规调节有关。反过来，Nrf2抗氧化反应在胰岛中得到增强，Nrf2的核易位和其目标抗氧化剂酶血红素加氧酶1（HO-1）的表达增强为标志。相反地​​，与Trigonelline共同治疗，选择性阻断Nrf2，抵消了锂在胰岛中增强的Nrf2抗氧化反应，减弱了锂对胰岛和β细胞的保护作用，并取消了STZ损伤小鼠中锂的降血糖活性。总的来说，我们的研究结果表明，微剂量锂通过靶向GSK3β调节的Nrf2抗氧化反应，对胰岛β细胞具有保护作用，从而改善T1D及其相关的肾脏损害。削弱了锂对胰岛和β细胞的保护作用，并取消了锂对STZ损伤小鼠的降血糖活性。总的来说，我们的研究结果表明，微剂量锂通过靶向GSK3β调节的Nrf2抗氧化反应，对胰岛β细胞具有保护作用，从而改善T1D及其相关的肾脏损害。削弱了锂对胰岛和β细胞的保护作用，并取消了锂对STZ损伤小鼠的降血糖活性。总的来说，我们的研究结果表明，微剂量锂通过靶向GSK3β调节的Nrf2抗氧化反应，对胰岛β细胞具有保护作用，从而改善T1D及其相关的肾脏损害。