Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1.

Monogenic forms of diabetes can result from mutations in genes encoding transcription factors. Mutations in the homeodomain transcription factor IDX-1, a critical regulator of pancreas development and insulin gene transcription, confer a strong predisposition to the development of diabetes mellitus in humans. To investigate the role of IDX-1 expression in the pathogenesis of diabetes, we developed a model for the inducible impairment of IDX-1 expression in pancreatic beta cells in vivo by engineering an antisense ribozyme specific for mouse IDX-1 mRNA under control of the reverse tetracycline transactivator (rtTA). Doxycycline-induced impairment of IDX-1 expression reduced activation of the Insulin promoter but activated the Idx-1 promoter, suggesting that pancreatic beta cells regulate IDX-1 transcription to maintain IDX-1 levels within a narrow range. In transgenic mice that express both rtTA and the antisense ribozyme construct, impaired IDX-1 expression elevated glycated hemoglobin levels, diminished glucose tolerance, and decreased insulin/glucose ratios. Metabolic phenotypes induced by IDX-1 deficiency were observed predominantly in male mice over 18 months of age, suggesting that cellular mechanisms to protect IDX-1 levels in pancreatic beta cells decline with aging. We propose that even in the absence of Idx-1 gene mutations, pathophysiological processes that decrease IDX-1 levels are likely to impair glucose tolerance. Therapeutic strategies to attain normal glucose homeostasis by restoring normal IDX-1 levels may be of particular importance for older individuals with diabetes mellitus.

Lymphocyte subpopulations in lymphoid organs of rats after acute resistance exercise.

PURPOSE: The ability of aerobic exercise to change lymphocyte subpopulation distributions is well documented; much less is known about resistance exercise. The purpose of this experiment was to determine the effects of an acute bout of resistance exercise on lymphocyte subpopulations in primary and secondary lymphoid compartments. METHODS: Male rats were operantly conditioned to climb a ladder while carrying weights that were progressively increased to equal body weight. During the acute session, rats performed repetitive climbs until exhaustion. Thymus, spleen, blood, and axial and inguinal lymph nodes were removed; leukocytes were isolated and incubated with monoclonal antibodies against differentiation markers, activation antigens, and adhesion molecules. RESULTS: Exercised versus control rats had greater numbers of leukocytes in the thymus, axial, and inguinal nodes but not in the blood or spleen. The percentage of CD4+ cells increased after exercise in the thymus, spleen, and blood. The percentages of cells expressing the integrin LFA-1beta were elevated in all the tissues except inguinal lymph nodes. In addition, more leukocytes from exercised than nonexercised rats expressed detectable numbers of activation markers, IL-2 receptor-alpha and MHC class II molecules; however, as indicated by proliferating cell nuclear antigen analysis, the cells were not actively dividing at the time of assay. CONCLUSIONS: Based on these and published data, it appears that a single bout of resistance exercise can affect lymphoid cell subpopulations probably by inducing changes in leukocyte trafficking.

Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene.

Targeted disruption of the mouse Ftz-F1 gene, which encodes the orphan nuclear receptors steroidogenic factor 1 (SF-1) and embryonal long terminal repeat-binding protein (ELP), established that this gene is essential for development of the primary steroidogenic tissues and for male sexual differentiation. Associated with these dramatic developmental abnormalities, all Ftz-F1-disrupted mice died in the immediate postnatal period and had very low glucocorticoid levels. In this report, we show that treatment with corticosteroids markedly prolonged survival of the Ftz-F1-disrupted mice, proving that steroid hormone deficiency causes their death. We also generated SF-1-specific knockout mice with a targeting construct that specifically disrupted the SF-1 coding sequence without impairing the ELP protein. The phenotype of the SF-1-specific knockout mice was indistinguishable from that observed in Ftz-F1-disrupted mice that lack both SF-1 and ELP. Taken together, these results indicate that SF-1 is the Ftz-F1-encoded protein that is required for multiple aspects of endocrine development and for postnatal survival.