IGFBP-3 IN APOPTOSIS OF B CELLS AND TYPE I DIABETES

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The greatest endocrinological disease facing children is type I diabetes mellitus (T1DM), caused by autoimmune beta cell death and attendant insulin deficiency. It has been shown that cytokine-mediated apoptosis (programmed cell death) of beta cells in vivo leads to T1DM in the non-obese diabetic (NOD) mouse. The insulin-like growth factor (IGF) axis is crucial to the processes of cell growth and death. Studies in vitro have confirmed that IGF binding protein-3 (IGFBP-3) induces apoptosis in prostatic and breast cells by both IGF-dependent and IGF-independent pathways. In vitro studies of beta cell lines which do not usually secrete IGFBP-3 have shown that apoptosis-inducing cytokines induce IGF binding protein-3 (IGFBP-3) production. Our central hypothesis is that IGFBP-3 is an important mediator of beta cell apoptosis (death) and therefore the pathogenesis of T1DM. To test this hypothesis we will characterize the IGF-IGFBP axis in pancreatic islets of the NOD mouse. We expect islet over-secretion of IGFBP-3 to precede islet apoptosis in NOD mice. We will also construct a transgenic mouse using the rat insulin promoter, which is expressed exclusively in beta cells, to drive overproduction of islet IGFBP-3. We expect this novel transgenic mouse to develop beta cell apoptosis and T1DM. Finally, we will crossbreed NOD mice with IGFBP-3 knockout mice (which are not diabetic). We expect to see a direct relationship between islet IGFBP-3 secretion and T1DM in the progeny. Studying the relationships between the IGF-IGFBP axis and beta cell function will uncover important mechanisms which cause diabetes and can lead to novel treatments which alleviate or prevent diabetes and its complications.