Aging And The Pancreas

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A major component of our research in the Diabetes Section is to understand what controls beta cell function and mass in the pancreas. With age and type 2 diabetes failure of beta cells to respond to rising blood glucose levels (beta cell dysfunction) becomes evident and there appears to be a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased neogenesis. We have been studying the mechanisms of action of GLP-1, a gut hormone, as they relate to insulin release. We found that not only is GLP-1 a potent insulinotropic agent, it upregulates insulin biosynthesis, increases translocation of pdx-1, a transcription factor necessary for maintenance of the beta cell phenotype, to the nucleus and it increases glucokinase protein levels (the essential glucose sensor in beta cells). We also found that it increases beta cell mass in rodents by increasing beta cell proliferation in islets of Langerhans. Other investigators demonstrated antiapoptotic effects of GLP-1 in beta cell lines and whole islets. A GLP-1 receptor agonist, exendin-4, is now available for treating type 2 diabetes. A component of our basic work is investigating how GLP-1 increases beta cell turnover. Of relevance to aging, we have found that the ability of GLP-1 receptor agonists to increase beta cell turnover is reduced in islets from old rodents: however, continuous, unremitting treatment of the animals with GLP-1 receptor agonists can overcome this. In addition to defective beta cell function and proliferation, we have found that alpha cells are increased. This led us to speculate that proper beta cell function is needed to control alpha cell function and numbers. Additionally, free fatty levels are increased in aging and type 2 diabetes. We are hypothesizing a unifying mechanism covering beta cell dysfunction, alpha cell hyperactivity, insulin resistance and increased cytokine levels. Eventually, we hope to outline novel therapeutic targets within this concept.