Long-Term Administration of Antioxidant N-Acetyl-L-Cysteine Impacts Beta Cell Oxidative Stress, Insulin Secretion, and Intracellular Signaling Pathways in Aging Mice

Research into the effects of long-term antioxidant supplementation on the islet microenvironment is limited. This study examined whether long-term N-acetyl-L-cysteine (NAC) supplementation can prevent changes in metabolic outcomes, beta cell function, and pancreatic stellate cell (PaSC) activation in aging mice. Male C57BL/6N mice at 18 weeks were administered 50 mM NAC through their daily drinking water and treated for up to 60 weeks. Aging NAC mice displayed lower body weights and improved glucose tolerance but reduced insulin secretion and insulin signaling compared to control (ND) mice. When some 40-week-old ND and NAC mice were subjected to 8 weeks of a high-fat diet (HFD)-stress challenge, results showed that NAC reduced HFD-induced beta cell oxidative stress and preserved nuclear PDX-1 expression. The findings from this study suggest that while NAC can be beneficial for diet-induced stress during aging, the effects of long-term NAC on the islets of physiologically aging mice are more ambiguous. Further exploration is required to determine the effects of NAC-mediated lowering of beta cell oxidative stress on insulin secretion and signaling pathways. This study highlights the importance of investigating oxidative stress balance in aging islets under normal diet conditions to determine if antioxidative therapies can be utilized without interfering with essential physiological processes.