Hoppel, Charles L., MD
Diabetes Mellitus: Role of posttranslational modifications of mitochondrial carnitine palmitoyltransferase 1
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Liver, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Phosphatases-Kinases
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Diabetes mellitus, characterized by low insulin and high glucagon levels, is a major health care problem. With a lack of insulin the body's capacity to use glucose for energy production is limited resulting in increased fatty acid oxidation and ketone body production. The associated long term effects of abnormal fatty acid metabolism are related to the long term complications of diabetes. In this switch of fuel utilization for energy production, i.e., from carbohydrate to fatty acid oxidation, the liver plays a central role. The key step in mitochondrial fatty acid oxidation in the liver is the entry of activated fatty acids into mitochondria. Carnitine palmitoyltransferase-1 (CPT1a) is the rate-controlling enzyme and is critical in the pathway. In diabetes the enzyme becomes less sensitive to regulation by its physiological inhibitor resulting in excessive fatty acid oxidation. Our studies have identified a mechanism for the change in the enzyme's sensitivity to inhibition and should provide a new avenue for approaching treatment in diabetes. With the new understanding of the regulation of the enzyme, new therapeutic approaches can be undertaken to produce subtle changes in control without an effect on activity and thus limit adverse effects.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
We are working in the area of lipid metabolism, particularly the regulation of mitochondrial fatty acid oxidation. The study is focused on mitochondria in liver and hepatocytes, because the mitochondrial enzyme carnitine palmitoyltransferase 1 is the key step in the metabolic control of fatty acid oxidation. Disruption of the system is associated with increased fatty acid oxidation with hepatic production of ketone bodies as a major product. This results in ketosis and possibly acidosis from the excess hepatic mitochondrial fatty acid oxidation.
We believe that our work is focused on the metabolic complications of diabetes. Success should provide new opportunities to explore therapeutic targets to control fatty acid oxidation and possibly lipid-derived problems in diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
I would discuss the importance of basic science research in providing understanding of metabolic processes and pathophysiology that occur in diabetes. Even with all the knowledge and understanding that currently exists, there are still basic biological questions that have not been addressed. With the new technology, especially in studying proteins, newer approaches and, in particular, a deeper understanding of the changes that occur in these proteins during diabetes should lead to identifying new pathways and expanding existing pathways to bring new targets for consideration. With this understanding then there is hope to find/develop new therapeutic agents to change the step that is not working correctly. The power of the new biology resides in this deeper probing of our biological systems with a unique opportunity for resolving conflicts.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
During my clinical training in internal medicine a major clinical situation revolved around the care of patients in diabetic ketoacidosis. I had a number of patients that required heroic efforts to control their ketosis and acidosis. While the care of patients with diabetes has markedly improved and the clinical crises we encountered 40+ years ago have been almost eliminated the chronic complication surrounding abnormal lipid metabolism continue. I practiced general internal medicine on a part-time basis for 40 years and the great improvements in diabetes care still are not completely realized. I believe our work directly impacts the lipid metabolic issues in diabetes and continue to be enthusiastic about future possibilities.
Previously I have served as a member of the Diabetes Association of Greater Cleveland Board of Trustees, Executive Committee, and served as president for two years. I have been an active member of the Research Review Committee of the local organization and just recently completed a term of office.
The current award will allow us to use modern proteomic approaches to study why the enzyme that controls mitochondrial fatty acid oxidation becomes insensitive to the natural inhibitor. The post translational modifications that we uncover will then serve as focus points to understand the enzymes that produced the modification. With this information we can explore how to change that enzyme and affect the limiting step. In this way, possible new approaches and targets for therapy will arise.
In what direction do you see the future of diabetes research going?
My basic interest is in mitochondria. In addition to the metabolic changes that are specific to the liver and addressed in our current project I see the cardiomyopathy associated with diabetes as another area for detailed mitochondrial studies. Here the emphasis would be on integrated mitochondrial function that is measured as oxidative phosphorylation. Basic questions about oxidation of the end product of glucose metabolism versus fatty acid oxidation are of primary interest. Also, is one or both populations of heart mitochondria affected. We recently studied and have a paper in Diabetes on the reactive oxygen species that are generated from kidney tubular mitochondria during fatty acid oxidation and these do not come from the sites usually associated with mitochondrial reactive oxygen species generation. This is part of our view that the metabolic pathways in fatty acid oxidation are incompletely studied in diabetes.
From a general standpoint, the development of a glucose sensing system connected to insulin release for minute to minute control in diabetes or transplantation of islet cells to the appropriate splanchnic bed for mimicking the normal homeostasis are important.
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