Metabolic consequences of securin disruption

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DESCRIPTION (provided by applicant): Cell cycle-dependent securin proteins regulate sister chromatid separation by inhibiting separin function. We isolated and have characterized pituitary tumor transforming gene (PTTG) from rat pituitary tumor cells, and PTTG is functionally homologous to yeast securin. PTTG is overexpressed in several tumor types, and also in some normal replicating tissues (including testis, lympocytes). When the PTTG gene was deleted, resultant knockout mice were viable, fertile and exhibited splenic and testicular hypoplasia and thrombocytopenia. Surprisingly, after 6 months, male PTTG -/- mice do not gain weight, develop profound hyperglycemia, hypo-insulinemia, and hypo-leptinemia with intact insulin sensitivity. In preliminary experiments, pancreatic beta cells appear hypoplastic with diminished islet insulin immunoreactivity, and no evidence for autoimmune islet involvement. This proposal aims to study the role of mammalian securin in pancreatic beta cell function by assessing insulin transcription, secretion and action, regulation of adipocyte hormones and assessment of pancreatic beta cell development and replication, and pancreatic regeneration. As securin-deficient diabetes is restricted to male mice, intact or gonadectomized PTTG -/- animals will be treated with sex steroids, and their impact on glycemia and pancreatic function assessed. These studies highlight the role of a cell cycle-regulating protein in pancreatic beta cell development and function. In the context of this unique genetic background, these experiments identify securin as a critical factor for pancreatic cell function and provide insights into a novel monogenic cause of diabetes.