Kibbey, Richard Glenn, PhD
Compartmentalized phosphenolpyruvate metabolism in insulin secretion
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Channels, Single Cell Studies, and Calcium Signaling, Islet Biology\Hormone Secretion and Exocytosis, Islet Biology\Metabolic Regulation
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Pancreatic beta-cells are crucial for maintaining control of blood glucose by the regulated secretion of insulin. The signal for these cells to release insulin comes from a metabolic message derived from the metabolism of glucose. For years it has been know that ATP, the energy currency of the cell, is important for the signaling process. Because mitochondrial metabolism is the predominant source of ATP and because mitochondria are also very important for the secretion of insulin, it has been assumed that the ATP coming from these mitochondria ultimately triggered the release of insulin.
Based on observations supported by a prior ADA award, Dr. Kibbey identified a metabolic signal that acts like a molecular tachometer telling the rest of the cell how fast the metabolic cycles in the mitochondria are turning. The product of this so-called mitochondrial GTP cycle is a metabolic signal called PEP. Because PEP can come from two different steps in the process of glucose metabolism (one mitochondrial and the other cytosolic), he proposes that it signals two separate and distinct events necessary for insulin release. Both of these events rely on the metabolism of PEP at distinct locations in the cytosol to make ATP. If we can harness these two metabolic pathways, this paradigm-changing hypothesis may lead to novel treatments for diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The proposed research for this award is to investigate the mechanism that insulin secreting cells "sense" glucose levels in the blood in order to secrete the appropriate amount of insulin. When this mechanism is disrupted diabetes can occur, therefore, understanding the normal physiological process is an essential step to understand how insulin-secreting cells fail and how to prevent such failure. Key to "sensing" glucose is the metabolism of the glucose inside of the cell in a specialized organelle known as the mitochondria. Mitochondria are the cellular energy factories that metabolize both glucose and amino acids by a cycle of chemical reactions known as the Krebs’s cycle (who’s description lead to the awarding of the Nobel Prize in 1953 to Sir Hans Krebs). A rare genetic disorder in children leading to low blood sugar from deranged glucose sensing in insulin secreting cells (Hyperinsulinemia Hyperammonemia) lead to my discovery of an alternative energy sensing mechanism in mitochondria. As metabolism turns the Krebs cycle it makes a fixed amount of the chemical mitochondrial GTP (mtGTP), and the faster it turns the more it produces.
I hypothesized that mtGTP was the chemical signal (a "molecular tachometer") to let the rest of the cell know how fast energy was being metabolized. I then demonstrated in insulin secreting cells that the faster mtGTP is made, the more insulin gets secreted- a mechanism quite different than described in most medical textbooks. Careful metabolic analyses of these cells surprisingly showed that the mtGTP signal told mitochondria to make less fuel for the cell and, instead, pump calcium that then led to insulin secretion. As a previous ADA award I connected the mtGTP signal to insulin secretion via the generation of a second carrier signal called phosphoenolpyuvate or PEP. This signal is generated by a mitochondrial GTPase that is, ironically, used in other tissues to make glucose. In this proposal we further characterize how this mtGTP-dependent PEP signal communicates with the rest of cell. These studies have potential not only to describe a completely new frontier in the physiological regulation of metabolism, but may also directly lead to new therapies for diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The studies that are supported for this grant will help to characterize the underlying mechanism that insulin-secreting cells sense glucose and secrete insulin. Previous studies on other components of the glucose sensing mechanism have lead to the discovery and or development of novel medications for treatment of diabetes by increasing the amount of insulin that is released in response to glucose. As part of the glucose-sensing mechanism that I have discovered, I identified a novel potential drug target. By increasing the production rate of this metabolic signal, insulin secretion rates dramatically increase their insulin secretion by 200-300%. Alternatively, reducing the production rate can severely reduce insulin secretion, a phenomenon that is known to occur during the progression to diabetes. Therefore further studies into this important energy sensory may lead to novel therapeutic strategies to prevent or treat diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My research efforts are focused upon identifying the potentially reversible factors that lead to type-2 diabetes mellitus (T2DM). Dysfunctional insulin secretion is central to the pathogenesis of T2DM. In the absence of appropriate insulin secretion in response to blood glucose, diabetes will not occur. It is now a disease of epidemic proportions worldwide (~194 million cases in 2003 expected to climb to 333 million by 2025- more than the current population of the U.S.). 132 billion dollars in direct costs alone was estimated for the U.S. in 2002 not including the social and emotional costs of complications of diabetes like neuropathy, blindness, amputation, kidney failure, heart disease, and stroke. Once a disease only rarely observed in children, now T2DM exceeds that of Type-1 diabetes in children in certain states emphasizing the growing problem of this epidemic. I personally believe that diabetes is preventable and potentially reversible and am dedicated to reducing the impact of this looming worldwide medical catastrophe. This award will allow me to follow my studies on the energy sensing mechanism involved in insulin secretion. In addition to providing the support to generate the necessary data to write manuscripts for publications and to receive future grants, this award will allow me to further develop my laboratory into this important new area of investigation
In what direction do you see the future of diabetes research going?
Diabetes is a disease that occurs when there is an imbalance between nutrient energy intake and sensing by the body with subsequent energy storage and utilization. Because mitochondria are the central component of this equation, much of the key insights to understand the physiology and path physiology of diabetes will be found in studies of mitochondria in all of the target tissues associated with diabetes. Largely because of recent improvements in metabolomics technologies there has been a resurgence in the appreciation of the importance of intracellular metabolism for metabolic diseases like Type-2 diabetes and this will likely identify dramatic new therapeutic targets as well as increase our understanding of diseases. Type 2 diabetes research has been largely focused on understanding insulin resistance, but the importance of the pancreatic islet in protecting against diabetes is now becoming apparent. Given how desperate a world-wide health problem diabetes is becoming, new innovations will be needed to augment insulin secretion, preserve beta-cell function and protect these crucial cells from injury and death.
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