Failure of pancreatic beta cells to increase insulin secretion in the face of insulin resistance is a major determinant of type 2 diabetes. The goal of this proposal is to test an innovative intracellular mechanism regulating insulin secretion involving a mitochondrial regulatory protein called cytochrome c. Although calcium is an essential signal for insulin secretion, stimulation requires additional metabolic co-factors generated by nutrient metabolism independent of mitochondrial generation of energy.
Cytochrome c can exist in two states, and our data has lead us to propose that one form of cytochrome c is a critical signal that can cause beta cells to secrete insulin, independent of its role in generating ATP. Further, we have found that movement of cytochrome c from one region of the cell to another is exquisitely sensitive to the levels of glucose and related to rates of insulin secretion.
In this proposed study we will test whether the movement of cytochrome c is necessary and sufficient to stimulate insulin secretion in the face of elevated calcium signaling. This will be done by two approaches designed to alter cytosolic cytochrome c levels: direct insertion of cytochrome c into the cytosol and inactivation of the proteins that control the rate of cytochrome c movement. A definitive demonstration of a signaling role for cytochrome c movement in the secretion of insulin would lay the foundation for future studies on whether this mechanism could play a role in the development of diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Lack of insulin secretion by the pancreatic islet is the underlying defect leading to diabetes. My research is focused on identifying the molecular mechanisms used by the islets to control the amount of insulin released into the blood. The research being conducted will support the development of new therapies aimed at increasing the secretion of insulin in patients with Type 2 diabetes. It is likely that correcting the inadequate amount of insulin secreted will prevent the complications that arise after many years with the disease.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The most likely way to enhance insulin secretion by the beta cell is to stimulate the naturally occurring mechanisms that the body uses to increase insulin secretion. We have identified a molecule that may serve as a control point in the regulation of insulin secretion. If this is the case, then drugs will be developed to target this control point in order to stimulate insulin secretion.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I was diagnosed with diabetes in 1983, and began doing diabetes research in 1986. Thankfully my kids have not been afflicted with this disease, but I want to do what I can so I can remain healthy and see them grow up. Research is the only hope for understanding the causes of diabetes and further development of treatments to prevent or cure the disease.
I have been working on identification of critical signals that mediate insulin secretion when glucose is elevated. Insulin is essential for survival but too much can lead to hypoglycemia. Stimulation of insulin secretion by glucose is mediated by multiple signals inside the beta cells in order to safeguard against accidental stimulation. Calcium is one of these signals. We now have evidence that translocation of a protein located in the mitochondria of beta cells, cytochrome c, generates unique signals that are also essential for glucose to stimulate insulin secretion.
The hypothesis that cytochrome c plays an essential signaling role is novel and innovative, and funds are needed to fully verify this hypothesis, and importantly to elucidate how this protein interacts with cellular processes that secrete insulin. Small grants such as those provided by the ADA for new areas of research are critical to jumpstart new projects and to follow new leads. Progress here would impact efforts to understand why beta secretory functions fails in diabetes and to develop drugs to prevent this failure.
In what direction do you see the future of diabetes research going?
Additional drugs will be developed that stimulate insulin secretion only in the presence of elevated glucose. Tighter control of glucose will thus be achievable without the dangerous risk of hypoglycemia. In addition, drugs that prevent the loss of beta cell mass that occurs in long standing diabetes are also needed. Accomplishing this may depend on understanding the relation between production of energy by the beta cell and the ability of the beta cell to grow as well as function.