According to the American Association of Diabetes, 20.8 million children and adults in the United States, or 7% of the population, suffer from diabetes. In addition to those already having diabetes, 54 million Americans have pre-diabetes. Diabetes results from the disruption in either production or utilization of insulin, a hormone that is needed to convert food into energy needed for daily life. Insulin is produced in the pancreas by specific endocrine cells, known as β-cells. Overt diabetes occurs when the β-cells are unable to secrete a sufficient amount of insulin to maintain normal levels of sugars in the blood. Reduced insulin levels may be due to pure β-cell loss (as in type I diabetes), pure β-cell dysfunction (as with some monogenic disorders affecting the β-cells), or to a mixed picture with both β-cell secretory dysfunction and β-cell loss, as in classic type II diabetes. Although the data are quite limited, there is evidence that β-cell regeneration can occur early in both type I and type II diabetes, but this early regenerative response is lost over time. Understanding the biology of β-cell regeneration has a high potential to provide new approaches to therapeutic intervention in diabetes.
In this proposal we aim to test the hypothesis that there is a subset of cells within the non-endocrine pancreatic cell population that serve as stem/progenitor cells, which under certain conditions are capable of endocrine differentiation to supply lost β-cells. Answering this question will have tremendous importance for developing treatment strategies for diabetes. We will address this by developing two sets of tools that will be useful not only for answering this particular question, but can be applied for further research on pancreatic cells.
To this end, we propose to develop two specific tools. First tool will include a set of biomarkers that will uniquely identify the stem/progenitor cells within the non-endocrine pancreatic cell population. Significantly, instead of a highly labor intensive analysis process involving a high degree of subjectivity, we will develop a second tool, an automatic software package, that will be capable of precise and detailed analysis of the pancreatic tissue sections to assess the presence of β-cells differentiated from the stem/progenitor precursors and robustness of the differentiation.
Conclusion. Identifying the cells within that have the potential to exhibit endocrine differentiation is of enormous significance in defining the nature of those progenitors in the adult pancreas. In the long term, this will lead to a large increase in the supply of β-cells available for transplantation for diabetic patients and should also guide efforts to induce β-cell neogenesis in vivo.
Diabetes is a very significant health problem in California. Some of the ethnic groups known to be high risk for diabetes, such as Hispanic Americans, Native Americans and Asian Americans, comprise a very significant segment of our population. Research aimed at understanding the biology of β-cells and their progenitors in the adult pancreas is of tremendous importance for increasing the supply of β-cells available for transplantation for diabetic patients, as well as for developing novel treatment strategies.