Manganese (Mn) deficiency results in diabetic-like glucose intolerance. Data from our laboratory has shown that (1) insulin secretion is 7-fold lower in Mn- rats; the result of decreased synthesis and increased degradation of the hormone, (2) the decreased insulinogenesis in Mn- pancreata is the result of lower insulin mRNA levels, probably the result of impaired insulin transcription, and (3) that insulin-stimulated glucose transport is decreased 50% in Mn- rats, due to fewer carriers available to mediate glucose flux. The objective of this research is to gain insight into the cellular and molecular mechanisms by which Mn nutriture affects insulin gene expression and peripheral insulin action in the adipose cell. We will use in situ hybridization and standard RNA isolation/blotting methodologies to further define the effects of Mn deficiency on insulin mRNA levels under different glycemic conditions, both in vivo and in isolated islets. The specificity of these effects will be determined by measuring message levels of other islet proteins. Insulin transcription rates will be determined both in isolated islets and nuclei, and we will use DNA footprinting techniques to examine the possibility that Mn deficiency might alter the expression of DNA binding proteins important for insulin transcription. The effect of Mn on the """"""""glucose sensing"""""""" ability of the beta-cell will be examined by measuring the activity, protein and mRNA levels of glucokinase and the #-cell glucose transporter (GLUT2). The effect of Mn deficiency on adipose cell glucose transporter gene expression will also be examined. The proposed studies will examine which glucose transporter is affected by Mn deficiency; the """"""""hepG2 /erythrocyte"""""""" (GLUT1) or """"""""insulin-sensitive"""""""" (GLUT4) transporter both at the level of protein and message. Again, the specificity of these effects will be determined by examining the effect of Mn deficiency on the expression of other adipose cell proteins. Glucose transporter transcription rates will be measured in isolated nuclei, and the involvement of DNA binding proteins will be examined using DNA footprinting techniques. These studies will provide insight into how Mn nutriture affects cellular processes of glucose homeostasis, which may ultimately be important in understanding the pathogenesis and potential treatments of diabetes and other disease states involving alterations in Mn metabolism.
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