1512-P: The Novel Roles of Intracellular Calcium and Phosphoinositides in Insulin Signaling and Metabolic Disease

Insulin resistance is closely associated with elevated intracellular Ca²⁺ concentration under ectopic lipid accumulation and hyperglycemia-induced intracellular stress conditions. We recently identified that obesity impairs intracellular Ca²⁺ homeostasis, which prevents membrane localization of PH domain-containing proteins such as AKT, PLCδ, and IRS through the formation of Ca²⁺-phosphoinositides (PIPs), resulting in dysregulation of glucose homeostasis and insulin resistance. It is unclear, however, whether insulin sensitivity can be improved by targeting intracellular Ca²⁺ overload. Therefore, we screened nine angiotensin-II-receptor blockers (ARBs), a class of antihypertensive agents, for beneficial effects on palmitic acid (PA)-induced insulin resistance in human HepG2 cells. Two of the ARBs attenuated PA-induced intracellular Ca²⁺ overload by inhibiting dysregulated store-operated channel (SOC)-mediated Ca²⁺ entry into cells, which ameliorated insulin resistance by promoting insulin-stimulated membrane localization of AKT and by increasing the phosphorylation of AKT and its downstream substrates in PA-treated HepG2 cells. Furthermore, certain ARBs ameliorated obesity-induced insulin resistance, hepatic steatosis, and tissue inflammation in mice fed a high-fat diet. Meanwhile, certain ARBs normalized intracellular Ca²⁺ homeostasis by regulating obesity-associated SOC-mediated Ca²⁺ entry, which rescued impaired insulin signaling in liver and muscle tissues by promoting postprandial membrane localization of AKT and IRS2. These findings underscore the contribution of dysregulated intracellular Ca²⁺ homeostasis to the pathophysiology of insulin resistance and suggest a therapeutic strategy to use specific ARBs to ameliorate insulin resistance.