A major thrust of our research is understanding what controls beta cell mass of the pancreas. With age and type 2 diabetes, there is a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased beta cell neogenesis. We have been investigating the properties of GLP-1, a gut hormone, as they relate to insulin release. We found that it upregulates insulin biosynthesis, increases translocation of pdx-1, a transcription factor necessary for maintenance of the beta cell phenotype, and it increases glucokinase protein levels (the essential glucose sensor in beta cells). We also found that it increases beta cell mass in islets of Langerhans. Other investigators demonstrated antiopototic effects of GLP-1 in beta cell lines and whole islets. GLP-1 is a serious candidate to treat type 2 diabetes in the elderly because its insulin-releasing mechanism of action is dependent on the presence of glucose being transported into beta cells. Therefore, hypoglycemia does not develop. A major component of our basic research is investigating how GLP-1 is both antiapoptotic and proneogenic to beta cells of the pancreas. We recently uncovered evidence for the Notch pathway in adult beta cells and its regulation by GLP-1. GLP-1 increases notch translocation to the nucleus of beta cells with a subsequent upregulation of IRS-2, and beta cell growth and differentiation. This does not occur in GLP-1 receptor knockout animals, demonstrating the specificity of the effects of GLP-1.
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