Contribution of the Hepatic Cytoplasmic Lipid Droplet to the Development of Diabetes Mellitus Type 2
Abstract
Question to Be Addressed: The Department of Defense has chosen to add to this year s Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area list diabetes. Although insulin-dependent (or type 1) diabetes has been long known and can be relatively simply controlled, type 2 diabetes is far from understood and often leads to loss in quality of life, fitness, performance as well as years of life. Part of the reason of this lack of understanding is the complexity and the overlap with other conditions and disease states. Although percentages differ across the United States, as well as in the military family, it is widely recognized that at least 45% of the US population is either overweight or obese and at risk of developing chronic metabolic diseases and disease states. This includes cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver disease, the latter a condition due to fat accumulation in the liver in people who drink little or no alcohol, increasing the risk of liver inflammation, and potentially liver failure and liver cancer. Even though it is clear that an individual s genetic background controls whether he or she is likely to develop type 2 diabetes, overweight or obesity greatly enhances this risk. It is also clear that a steady intake of lipids (fat) plays a large role in the development of type 2 diabetes, although it is not exactly known how. This is the very question that we want to address in this proposal: If and how the liver cell (to be precise: the lipid droplets found in liver cells) is involved in the change of glucose, insulin, and fat metabolism leading to a type 2 diabetic state. Innovation of the Idea: Researchers tend to focus either on the glucose side, the insulin side or the lipid side of the metabolism. Part of the reason is that to address a research question, scientists choose a simplified model to get a clear insight in at least one portion of the problem. Combined research efforts with multiple models then potentially give views from different angles and of the total disease makeup. Given that the development of diabetes type 2 is likely complex and probably overlaps with several other disease states, mentioned above, we propose to analyze a small liver lipid organelle, termed the cytosolic lipid droplet, and to combine views on glucose and lipid metabolism. We want to study the lipid droplet in a set of existing liver samples from patients with nonalcoholic fatty liver disease and compare these data with studies in cell lines and studies in rats, which are either overfed with a high glucose and high-fat diet or fed with regular diet. In this way, we will be able to see if changes in the lipid droplets in human liver tissue, animals, and isolated cells can answer the direct question if the liver cell through its fat droplets can functions as a switchboard for type 2 diabetes. Applicability and Impact of the Research: The main outcome of proposed work will be to establish whether or not the liver lipid droplet has a catalyzing role in the development of type 2 diabetes. If this is correct, it would open up for entirely new types of diagnostics, preventive interventions, and possibly also a renewed focus on existing drugs that have not yet been tested for the purpose of diabetes. For example, administrating dietary supplements such as Food and Drug Administration-approved omega 3 lipids (e.g., Vascepa, EPA-only) or mTORC1 inhibitors (e.g., Sirolimus, Everolimus, Temsirolimus) that all help to lower liver lipid could be tested. We also predict that we will find new proteins that play a role in the liver metabolism of glucose, either for energy storage or for energy production that could become new therapeutic targets for intervention and/or prevention of type 2 diabetes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610081
Entities
People
- Tommy Nilsson
Organizations
- McGill University Health Centre
- United States Army