鐵質誘發巨噬細胞活化與遷移對胰島素耐受性的影響

Human population studies showed increased body iron (Fe) stores and heme Fe intake are associated with type 2 diabetes. Clinical study indicates diabetic patients have higher risk for anemia (23%) but patients received Fe therapy may increase risk of hepatic Fe overload. The mechanisms underlie Fe trafficking, chronic inflammation and glucose homeostasis is still unclear. Macrophages (MΦ) are responsible for heme Fe recycling but MΦ-mediated inflammation also play key role in type 2 diabetes. As the first step in solving this problem, we aim to investigate effects of Fe enriched diet on P-Selectin Glycoprotein Ligand (PSGL1)-mediated MΦ migration and glucose homeostas i s . Two animal models wi l l be used in this s tudy: (1) streptozotocin-induced type 2 diabetic rats receive Fe enriched diet. This model will provide the molecular insight into the mechanism by which Fe regulate insulin signaling pathways. (2) adoptive transfer monocyte (PSGL1-/- and Wt) to type 2 diabetic mouse fed with Fe/normal diet. This model will help to clarify the role of PSGL1 on Fe-mediated macrophage migration and repopulation in diabetic mouse. Our preliminary results showed diabetic rats received Fe supplementations had pancreatic islet hypertrophy, insulin resistance and splenic Fe overload compared with diabetic rats received normal diet. In vitro study showed Fe molecules triggered MΦ activation and migration. Pre-treatment of PSGL1 antibody inhibited apoferritin-mediated MΦ migration. Based on these promising results, we propose the following specific aims: (1) to investigate effects of Fe enriched diet on insulin signaling pathway; (2) to dissect mechanisms involved in Fe efflux and Fe trafficking; (3) to evaluate the role of PSGL1 on Φ-mediated inflammation and insulin resistance. Successful diabetes management is to keep blood glucose levels normal and to avoid the diabetes complication. This study will provide the molecular insight into the molecular mechanism by which Fe promotes diabetes complication and how to treat diabetic patients with anemia of inflammation.