Selenoprotein P (SeP) functions as a selenium (Se)-supply protein. SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. Thus, the suppression of Se-supply activity of SeP might improve glucose metabolism. Here, we develop an anti-human SeP monoclonal antibody AE2 as with neutralizing activity against SeP. Administration of AE2 to mice significantly improves glucose intolerance and insulin resistance that are induced by human SeP administration. Furthermore, excess SeP administration significantly decreases pancreas insulin levels and high glucose-induced insulin secretion, which are improved by AE2 administration. Epitope mapping reveals that AE2 recognizes a region of human SeP adjacent to the first histidine-rich region (FHR). A polyclonal antibody against the mouse SeP FHR improves glucose intolerance and insulin secretion in a mouse model of diabetes. This report describes a novel molecular strategy for the development of type 2 diabetes therapeutics targeting SeP.

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Essential trace elements play pivotal roles in numerous structural and catalytic functions of proteins. Adequate intake of essential trace elements from the daily diet is indispensable to the maintenance of health, and their deficiency leads to a variety of conditions. However, excessive amounts of these trace elements may be highly toxic, and in some cases, may cause damage by the production of harmful reactive oxygen species. Homeostatic dysregulation of their metabolism increases the risk of developing diseases. Specific transport proteins that facilitate influx or efflux of trace elements play key roles in maintaining the homeostasis. Recent elucidation of their crucial functions significantly facilitated our understanding of the molecular mechanisms of iron (Fe), copper (Cu), and zinc (Zn) absorption in the small intestine. This paper summarizes their absorption mechanisms, with a focus on indispensable functions of the molecules involved in it, and briefly discusses the mechanisms of homeostatic control of each element at the cellular and systemic levels.

Manganese homeostasis involves coordinated regulation of specific proteins involved in manganese influx and efflux. However, the proteins that are involved in detoxification/efflux have not been completely resolved nor has the basis by which they select their metal substrate. Here, we compared six proteins, which were reported to be involved in manganese detoxification/efflux, by evaluating their ability to reduce manganese toxicity in chicken DT40 cells, finding that human ZnT10 (hZnT10) was the most significant contributor. A domain swapping and substitution analysis between hZnT10 and the zincspecific transporter hZnT1 showed that residue Asn 43 , which corresponds to the His residue constituting the potential intramembranous zinc coordination site in other ZnT transporters, is necessary to impart hZnT10's unique manganese mobilization activity; residues Cys 52 and Leu 242 in transmembrane domains II and V play a subtler role in controlling the metal specificity of hZnT10. Interestingly, the His 3 Asn reversion mutant in hZnT1 conferred manganese transport activity and loss of zinc transport activity. These results provide important information about manganese detoxification/efflux mechanisms in vertebrate cells as well as the molecular characterization of hZnT10 as a manganese transporter.

Our results indicate that many SLC30A2/ZnT2 mutations cause or potentially cause TNZD. Genetic information concerning TNZD pathogenesis is limited, and our results suggest that the TNZD frequency may be higher than previously thought.