Type 2 diabetes is a leading cause of death in the US and its incidence is rapidly rising. This disease is associated with insulin resistance (ineffective use of insulin) and impaired insulin secretion from pancreatic beta cells. These cells are found in small clusters of approximately 2000 cells known as islets of Langerhans. In most forms of type 2 diabetes, the defects leading to impaired insulin secretion are unknown. A greater understanding of insulin secretion would be invaluable in identifying possible defects associated with diabetes. It is known that metabolism of glucose generates a variety of second messengers (small intracellular molecules) including ATP and Ca2+ that ultimately evoke secretion; however, the current model cannot explain observations such as oscillations in secretion and possible links between insulin resistance and insulin secretion. In this work, we propose to develop novel analytical tools for studying insulin secretion at the level of single cells and single islets. These tools include: 1) a microfabricated workstation that incorporates sensors and a high-speed capillary electrophoresis system for simultaneous monitoring of metabolic changes, second messenger level, and insulin secretion with high temporal resolution; 2) novel chromatographic assays for second messengers; and 3) a technique for imaging secretion around a cell. These novel analytical instruments and methods will play an important role in determining the normal molecular mechanisms of insulin secretion and possible defects associated with diabetes. In this work, these tools will be used to study the oscillatory behavior of isle and the role of insulin in controlling insulin secretion through a feedback loop. These issues are both at the forefront of beta-cell research as loss of oscillations are a key event in onset of diabetes and insulin feedback through insulin receptors on the beta cell is a possible link between impaired insulin secretion and insulin resistance.
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