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. Disclosure J.Lee: None. Y.Jung: None. S.Im: None. D.Lee: None. H.Lee: None. I.Hong: None. O.Kim: None. B.Oh: None. Funding Korean Ministry of Health & Welfare (HI14C1135 to B-C.O.); Basic Science Research Program (2021R1I1A1A01051429 to O-H.K.); Mid-Career Researcher Program (2019R1A2C2008130, 2022R1A2C2092700 to B-C.O.); National Research Foundation of Korea (2021R1A5A203033)