Abstract
Background:
Insulin resistance is a recognized risk factor for significant health issues, including type 2 diabetes mellitus (T2DM), cardiovascular disease, and ischemic stroke. Dexa can directly impede insulin-mediated glucose absorption in hepatic cells, leading to hyperglycemia. The serine/threonine kinase AKT (protein kinase B) has been recognized as a vital regulator of insulin action over the past two decades, substantiated by considerable evidence. Lithium (Li) enhances glucose homeostasis by promoting glycogen synthesis and glucose uptake

Aim:
This study investigated the effect of lithium on glucose homeostasis using dexamethasone as a positive control for diabetes induction in an experimental trial. The role of AKT was also examined in conjunction with Li.

Methods:
The experimental rats were divided into 8 groups each containing 10-rats/groups. Group 1 was assigned as the control. Group 2 rats received Dexa. Group 3 rats received an Akt inhibitor. Group 4: rats that received Li. Group 5 rats received a combination of Dexa and Li. Group 6 rats received a combination of Dexa and AKTi. Rats in Group 7 received a combination of Li and AKTi, while Group 8: rats received a combination of Dexa, AKTi, and Li. Various experiments were conducted to investigate the effects of the different treatments on the survival rates, body weight, glycogen content, and hepatic levels of phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 3,4,5-bisphosphate (PIP3), phosphorylated protein kinase B (p-Ser-473AKT), and phosphorylated glycogen synthase kinase 3β (p-Ser9 GSK3β) were measured using enzyme-linked immunosorbent assay (ELISA).

Results:
Liver glycogen content was significantly reduced upon dexamethasone, AKTi, or their combination administration compared with the control. Interestingly, Li administration alone caused a significant increase in the glycogen content. Co-exposure of rats to Li + Dexa, Li + AKTi, or Li + Dexa + AKTi caused a restoration of the glycogen content to levels comparable with the control. Phosphatidyl inositol 4,5 bisphosphate (PIP2) and phosphatidyl inositol 1, 4,5 bisphosphate (PIP3) contents in the experimental groups showed the same trend. The activity and the expression of P-β- Arrestin II in the experimental groups were similar.

Conclusion:
This study revealed that Li provides protective effects against Dexa-induced disruptions in glucose homeostasis through AKT-dependent mechanisms. Specifically, through the activation of β-arrestin-2 and the inhibition of PIP2 and PIP3.

Key words: Glucose homeostasis; Dexamethasone; AKT inhibitor; Lithium.