Heart, Emma , PhD
Role of NQO1 and plasma membrane electron transport in pancreatic beta cell redox control and insulin secretion
General Research Subject: Type 2 Diabetes
Focus: Islet Biology, 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
Insufficient insulin secretion from pancreatic beta cells is one of the complications of type 2 diabetes. This application re-examines the mechanism of glucose stimulated insulin secretion from pancreatic beta cells, which is dependent on glucose metabolism via both cytosolic and mitochondrial metabolic pathways. A glucose-dependent increase in NADH, NADPH and ATP production are central to this process. We have identified a novel metabolic pathway in b-cells, which involves plasma membrane electron transport (PMET) and cytosolic oxidoreductase NQO1, and is responsible for the regulation of glucose metabolism and insulin secretion from pancreatic beta cells.
Based on our published and preliminary data, we propose that the PMET/NQO1 axis regulates beta cell redox environment, which plays an important role for the glucose-stimulated insulin secretion. PMET/NQO1 controls the ratio between reduced-to-oxidized nicotinamide nucleotides NADH and NADPH, and produces low levels of reactive oxygen intermediates (ROI), which recently have been recognized as mediators of insulin secretion. To test our hypothesis, we will use a combination of pharmacological, electrochemical, biochemical and gene manipulation approaches to address the mechanism and identify metabolic mediators by which PMET/NQO1 supports insulin secretion under elevated glucose. These studies will not only lead to better understanding of glucose stimulated insulin secretion, but will also help us to design new therapeutic strategies to enhance beta cell secretory response to help treat type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project aims to understand how metabolism of glucose, the most abundant metabolic fuel, is coupled to the insulin secretion from pancreatic beta cells. Insulin secretion is dependent on the metabolism of glucose within beta cells. While oxidation of glucose via mitochondrial pathways and subsequent rise in the ATP/ADP ratio is prerequisite for the secretion of insulin, it is not sufficient to account for the entire process. Furthermore, while mitochondria are important for the beta cell energetic and redox control, there are equally important systems which can engage in such processes. I have identified Plasma Membrane Electron Transport (PMET), as a novel extra-mitochondrial pathway, which regulates beta cell redox status and which activity and function are required for the beta cell heath, energy homeostasis and glucose-stimulated insulin secretion (GSIS). Integration of PMET with the rest of the beta cell metabolic networks can provide holistic model for stimulus-secretion coupling in pancreatic beta cells. The precise mechanism how PMET pathway operates and how it can modulate insulin secretion via nutrient and pharmacological interventions is the goal of this award.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Insufficient insulin secretion from pancreatic islet beta cells is a major contributor to the development of type 2 diabetes. The studies supported by this grant will help to elucidate the underlying mechanism by which pancreatic beta cells secrete insulin in response to glucose rise after a meal. In the past, important discoveries have been made to identify some of the key pathways which are activated by rise in glucose levels and which lead to glucose-stimulated insulin secretion. However, many of pathways critical for the process of insulin secretion are unknown. Identification of these pathways and understanding how they can be modulated by dietary or pharmacological interventions, will likely lead to development of potent therapeutic strategies to treat type 2 diabetes. I have identified a novel pathway, Plasma Membrane Electron Transport (PMET), which regulates glucose metabolism and insulin secretion from beta cells. The precise mechanism how this pathway operates and interacts with the rest of metabolic network in the beta cell is the goal of this award. These studies may lead to the development of pharmacological strategies and preventative measures to manage and 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?
Having a family member who suffered from type 2 diabetes helped me to realize the economical and psychological impact of this disease and its complications on the affected individual and his/her family. Type 2 diabetes is currently on the rise in all developed countries. In addition, type 2 diabetes strikes people at younger and younger age, and more and more adolescents develop this disease. Metabolic deregulation and other factors due to the lifestyle and diet likely play a crucial role in the development of this disease, and I am dedicated to help unravel underlying mechanisms. This grant will enable me to undertake my studies on the metabolic coupling mechanisms underlying glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells and how various metabolic conditions alter this process. I feel confident that the outcome of this work will provide useful insights into the mechanism by which glucose metabolism is linked to insulin secretion by pancreatic beta cells, and how this process can be modulated by nutritional and pharmacological interventions.
In what direction do you see the future of diabetes research going?
Diabetes type 2 is a metabolic disease, characterized by impairment in insulin secretion and resistance to insulin in the peripheral tissues. In healthy situation, glucose sensing by beta cells of pancreas leads to release of insulin. Insulin binds to insulin receptor on the plasma membrane of peripheral tissues (muscle, fat and liver), which offsets a signaling cascade leading to the enhancement of glucose transport and utilization in these tissues. Understanding how these processes are impaired in type 2 diabetic patients will help to design effective treatment strategies.
Many important discoveries have been made to identify individual signaling cascades on a single cell level in individual tissues. However, it is becoming clear that disruption of the whole body energy homeostasis, such as the communication between insulin secreting pancreas and insulin sensitive periphery plays an important role during development of diabetes. Thus, integrated physiological studies, rather than a single-gene knock out approaches, are needed to address the complexity of these metabolic interactions. I believe that future diabetes research will greatly benefit from integrated approach in order to understand how communication between pancreas and peripheral tissues is regulated. This approach will be necessary to complement existing knowledge of single-cell signaling cascades, and for development of effective therapies to treat type 2 diabetes and its complications.
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