Microdose Lithium Protects against Pancreatic Islet Destruction and Renal Impairment in Streptozotocin-Elicited Diabetes

Abstract

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.

Antioxidants Isolated from Elaeagnus umbellata (Thunb.) Protect against Bacterial Infections and Diabetes in Streptozotocin-Induced Diabetic Rat Model

“…The borderline of pancreas endocrine and exocrine portion was unclear. According to the reported literature [ 50 ], a decrease in islets β-cells number and size was also observed. Normal histopathological pattern of pancreas was observed for glibenclamide (50 g/kg/overly) and morin (15, 30, 50 mg/kg; p.o.)…”

Exploring the Effects of Greek Yogurt Supplementation and Exercise Training on Serum Lithium and Its Relationship With Musculoskeletal Outcomes in Men

“…Lithium (Li) is a monovalent cation commonly prescribed for bipolar disorder; however, psychiatric use of Li requires a dose high enough (~0.8 mM serum Li) to penetrate the blood brain barrier and to exert benefits on mental health ( 1 ). Unfortunately, these high doses of Li have been associated with adverse effects to peripheral organs such as the kidney, thyroid, and gastrointestinal tract ( 2 – 5 ).…”

Isoform-Specific Role of GSK-3 in High Fat Diet Induced Obesity and Glucose Intolerance

“…Moreover, lithium showed a hypoglycemic effect in diabetes patients. Consistently, lithium has reduced blood glucose levels in mouse models of diabetes [51,52]. Furthermore, increased body weight gain is a well-known side effect of lithium therapy [53][54][55].…”