Mitochondrial Dynamics in a Zebrafish Model of Diabetes

Diabetes is a disease of increased sugar (glucose) in the blood that leads over time to serious health problems. Insulin, which is produced by beta cells in the pancreas, stimulates cells to take up glucose. In diabetes, there is decreased insulin and the insulin that is produced does not work properly. Within cells, mitochondria are critical for turning glucose into energy. In beta cells, mitochondria play a second important role in controlling the release of insulin. Mitochondria are complex structures that can assume highly variable shapes. Recent research suggests that changes in mitochondria shape affects their ability to produce energy and control insulin secretion. This in turn influences the health of beta cells. Through the proposed research, we hope to learn more about what goes wrong in mitochondria in diabetes, and how that makes beta cells less able to do their job and leads to beta cell loss. This work will provide support for the hypothesis that beta cells can be protected, and therefore diabetes treated, by influencing mitochondria. For this project, we use the model organism zebrafish, which has a pancreas that is similar to man. Furthermore, we will use zebrafish that have a condition similar to human diabetes. Zebrafish are especially useful for such studies because they are small, easy to grow, and transparent at early stages, meaning we can look at mitochondria within the pancreas of the living animal with high detail. We will determine the shapes of mitochondria in healthy beta cells as compared to in beta cells in animals with diabetes. Using high resolution microscopes, we will look at how mitochondria change their shape and under what conditions this occurs. In particular, we predict that, under the influence of excess feeding, mitochondria change shape and this is related to worsening diabetes. We will further use the zebrafish, both healthy normal fish and fish with diabetes, to develop methods to look at how glucose enters cells under the influence of insulin. We hope to learn more about how this process is controlled, how it goes wrong in diabetes, and to identify new approaches to lower blood glucose in diabetes.

Diabetes is a disease of increased sugar (glucose) in the blood that leads over time to serious health problems. Insulin, which is produced by beta cells in the pancreas, stimulates cells to take up glucose. In diabetes, there is decreased insulin and the insulin that is produced does not work properly. In this project we examined cell components called mitochondria, which are critical for turning glucose into energy, and which help control insulin release in beta cells. Mitochondria are complex structures that can assume highly variable shapes, and recent research suggests that changes in mitochondria shape affects their ability to produce energy. This in turn influences cell health, which can impact organ formation during development and organ function in mature animals. To study mitochondria in the pancreas, we used the model organism zebrafish, which has a pancreas that is similar to man, and importantly transparent at early stages. This allowed us to look at mitochondria within the pancreas of the living animal with high detail. We detected complex and changing mitochondrial shapes during development of the pancreatic islet, and we developed new methods to examine and characterize these shapes with high precision. Work is ongoing to learn more about what goes wrong in mitochondria in diabetes, and how that makes beta cells less able to do their job and leads to beta cell loss. It is possible that keeping mitochondria healthy can help to protect beta cells in diabetic patients. We further applied our diabetic zebrafish to study changes that occur in the eye after longstanding hyperglycemia. We found that our zebrafish show damage to retinal blood vessels and nerve cells which is similar to what is seen in human diabetic retinopathy. These zebrafish represent a new tool to learn more details about how diabetic retinopathy starts and progresses, which can suggest new ways to prevent or treat this serious diabetes complication.