To investigate whether selenium (Sel) treatment would impact on the onset of diabetes,we examined serum biochemical components including glucose and insulin,endoplasmic reticulum (ER) stress and insulin signalling proteins, hepatic C/EBP-homologous protein (CHOP) expression and DNA fragmentation in diabetic and non- diabetic conditions of non-obese diabetic (NOD) mice. We conclude that (i) Sel treatment induced insulin-like effects in lowering serum glucose level in Sel-treated NOD mice, (ii) Sel-treated mice had significantly decreased serum biochemical components associated with liver damage and lipid metabolism, (iii) Sel treatment led to the activation of the ER stress signal through the phosphorylation of JNK and eIF2 protein and insulin signal mechanisms through the phosphorylation of Akt and PI3 kinase, and (iv) Sel-treated mice were significantly relieved apoptosis of liver tissues indicated by DNA fragmentation assay in the diabetic NOD group. These results suggest that Sel compounds not only serve as insulin-like molecules for the downregulation of glucose level and the incidence of liver damage, but may also have the potential for the development of new drugs for the relief of diabetes by activating the ER stress and insulin signalling pathways.

Abstract.To characterize the changes in global gene expression in the livers of H1/siRNA insulin -CMV/hIDE transgenic (Tg) mice in response to the reduced bioavailability of insulin, total RNA extracted from the livers of 20-weekold Tg and non-Tg mice was converted to cDNA, labeled with biotin and hybridized to oligonucleotide microarrays. The microarray results were confirmed by a real-time reverse transcription-polymerase chain reaction. Two hundred and fifty-one and 73 genes were up-and down-regulated, respectively by insulin in H1/siRNA insulin -CMV/hIDE Tg mice compared to the controls. Genes encoding for physiological processes, extracellular defense response and response to biotic stimuli were significantly over-represented in the up-regulated group. Among the down-regulated transcripts, those encoding for extracellular matrix proteins were dramatically over-represented, followed by those related to monooxygenase and oxidoreductase activities. The major genes in the up-regulated categories included Egr1, Saa2, Atf3, DNAJB1 and cCL2, whereas those in the downregulated categories were Cyp17a1, Adn, Gadd45g, Eno3 and Moxd1. These results indicate that the microarray analysis identifies several gene functional groups and individual genes that respond to a sustained reduction in the insulin levels in the livers of Tg mice. These results also suggest that microarray testing is a useful tool for the better understanding of insulin-regulated diabetes-related diseases.

Abstract. Abnormalities in the ret proto-oncogene are found in several disorders such as multiple endocrine neoplasia (MEN) 2, sporadic medullary thyroid cancer, congenital megacolon and papillary thyroid cancer. In MEN 2A or 2B, early genetic diagnosis before the development of clinical tumors is crucial for the cure of the disease. We studied mutations of ret proto-oncogene in 3 Korean families with MEN 2A and searched for new restriction sites that could be used for genetic diagnosis. By direct sequencing of exon 10 and 11 harboring 'hot' spots, heterozygous point mutation was detected at positions translating cysteine codon in all 3 families. In 2 families, mutations at codon 634 in exon 11 were found (from TGC to CGC or TAC), yielding a new CfoI or Rsal restriction site. In one family, a mutation was located at codon 618 in exon 10 (from TGC to CGC), generating a new CfoI restriction site. These new restriction sites were used in detecting 2 undiagnosed family members without clinical symptoms or signs. In one of them, thyroidectomy was performed to disclose a small medullary thyroid cancer. These results indicate that Korean MEN 2A patients have germ-line mutations in the ret protooncogene at the cysteine residues like patients of other races, and the strategy employing direct sequencing to find mutations at 'hot spot' and search for ensuing new restriction sites could be a useful approach for the molecular diagnosis of genetic diseases accompanied by mutations in restricted areas of disease genes such as MEN 2.

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