280-OR: Manganese Regulates Hepatic Insulin Sensitivity and Glucose Tolerance

Introduction & Objective: Metals are known to be necessary for cellular processes such as signal transduction and in protein conformation, though the characterization of which proteins bind metals is incomplete. Manganese (Mn) is known to be required for life but is one of the least understood metals. We aim to: (i) determine the mechanisms that regulate Mn and (ii) the molecular targets of Mn.

Methods: We used a mouse model of Mn excess that depletes the Mn efflux transporter, Slc30a10, from the liver and intestine (Slc30a10^Tbg,Vil). We conducted metabolic studies on mice kept on a standard chow diet or fed a high-fat diet for eight weeks. We used primary hepatocytes treated with Mn ex vivo to perform glucose production assays and assess the phosphorylation cascade in the insulin signaling pathway.

Results: We found that Slc30a10^Tbg,Vil mice have a significant improvement in glucose tolerance on a standard chow diet and are protected from impaired glucose tolerance when put on a high-fat diet. We treated hepatocytes with Mn ex vivo and found a significant reduction in glucose production. These data were associated with increased phosphorylation of Akt targets without increased phosphorylation of Akt itself. Using knockout and inhibitor approaches, we found that Mn acts downstream of both insulin receptor and PI3 kinase, suggesting that Mn acts directly on Akt. Fasting and refeeding studies on wildtype mice found Slc30a10 is low during fasting and increases rapidly after refeeding.

Conclusions: These data suggest Mn acts directly on Akt to sensitize hepatocytes to insulin. Further, our finding that Slc30a10 is regulated nutritionally suggests the possibility that controlled access to Mn may be a physiological mechanism to regulate Akt activity. These results highlight a novel role of Mn in the insulin signaling pathway and shed light on how Mn homeostasis is regulated in the liver.