Shisheva, Assia C., PhD
Striated muscle PIKfyve in systemic glucose metabolism
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology, Integrated Physiology\Insulin Resistance, Integrated Physiology\Muscle, Obesity, Obesity\Animal Models
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes Type: Type 2 diabetes
Type 2 diabetes (T2D) is the most common endocrine disorder, characterized by elevated blood glucose resulting from defects in body's ability to use and produce the hormone insulin. Inability to use insulin, called insulin resistance, is also a common characteristic of other diseases, including hypertension, obesity and atherosclerosis. These diseases are on an alarming rise, necessitating intensive research on elucidating the mechanisms of insulin resistance. In early stages of T2D, insulin resistance is greatest in skeletal muscle, the tissue responsible for blood glucose removal after a meal. Muscle's failure to respond to insulin results from defective intracellular molecular signals for glucose entry into cells. Studies in a test tube implicated >60 genes in this process. But only for a few has their whole-body metabolic role been verified, with limitations related to unavailability of appropriate experimental animal models. This proposal stems from our recent success in generating a unique mouse model with muscle-specific disruption of a gene, called pikfyve, implicated in intracellular glucose entry.
This projects aims to elucidate the metabolic defects and underlying molecular mechanisms. The innovation of the project lies in its preclinical focus to identify for the first time the role of a vital enzyme, exploiting the power of a novel genetically modified unique mouse model. The results of these studies will have a lasting impact because they will not only fundamentally advance knowledge for the pathogenesis of T2D but will also offer novel strategies for preventive and therapeutic intervention in patients with insulin resistance, obesity and T2D.
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 project will reveal the essential role of PIKfyve, a single mammalian enzyme synthesizing two rare phosphoinositides with signaling functions, in muscle and whole body insulin sensitivity and glucose homeostasis by using a unique genetically modified loss-of-function mouse models developed in our laboratory. Lack of muscle insulin sensitivity, a condition called insulin resistance, is a major risk factor in type 2 diabetes. This project will provide a new therapeutic target that is an enzyme, which by modulating its activity is expected to produce a beneficial outcome in individuals with prediabetes, i.e., subjects with insulin resistance who are likely to develop type 2 diabetes. Additionally, our project will provide to the research community a novel experimental insulin resistance mouse model for exploring more effective strategies against muscle insulin resistance and prediabetes in preclinical studies.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Type 2 diabetes (T2D) is caused by genetic predisposition interacting with obesity-promoting life style. The genetic predisposition in diabetic patients' relatives who are ostensibly healthy is functionally manifested as muscle insulin resistance, i.e., muscle failure to respond to insulin and take up glucose in order to clear it from the blood after meal. The molecular mechanism of insulin action leading to glucose uptake in muscle encompasses >60 gene products. Under muscle insulin resistance, anyone of these insulin-responsive molecules could be affected. In this preclinical study we will characterize the role for one of these genes, expecting to identify it as a critical regulator in whole-body glucose metabolism. Such a regulator could be used as a drug target in developing more effective medications to combat insulin resistance. In the case of PIKfyve, it is important to indicate that it exists in a physical complex with another enzyme (Sac3), which has opposing activity. The PIKfyve complex represents a fascinating candidate therapeutic target in that dual intervention to activate PIKfyve kinase and inhibit Sac3 phosphatase could lead to a robust and sustained impact in reversing insulin resistance. This novel paradigm will lead to novel and effective therapeutic/preventive modalities against progression to T2D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
The excitement for studying the mechanisms of insulin action and pathogenesis of diabetes started early in my career - while an undergraduate student, when, in a team of clinicians and basic researchers from the group of Diabetes in the Sofia Medical University, I was exploring the presence of insulin antibodies in sera of insulin-treated or untreated diabetic patients and their consequence in glucose and insulin homeostasis. My deep interests in the pathogenic mechanisms of insulin resistance and diabetes directed my choice of laboratories and research projects, when I moved West, first to The Weizmann Institute of Science in Israel and then to the University of Massachusetts in the US. When I took my independent position of Associate Professor in 1996 at WSU, Detroit, MI, I was well versed with knowledge and expertise to address insulin-regulated glucose metabolism at any level: from molecules and cells, to rodents and humans. I could proudly say that my whole research career has been solely devoted to better fundamental understanding of insulin-mediated postprandial control of glucose metabolism.
This award will play an enormous role in my research efforts because this is a preclinical study in genetically modified mouse models, expected to develop features similar to those seen in subjects with prediabetes. Furthermore, it is equally rewarding that this preclinical study will be conducted with ADA financial support, as the PIKfyve molecule was first identified under the auspices of my ADA Carrier Development Award.
In what direction do you see the future of diabetes research going?
The goal of the current and future research must include reversal of the current obesity and type 2 diabetes epidemics, together with improved treatment and disease management. The future fundamental research will probably define multiple critical nodes in insulin signaling and intracellular membrane trafficking underlying the disease. Understanding these potential pathogenic subgroups with the same diagnosis will allow better- directed treatment and call for new medications based on the characterization of novel druggable targets.
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