Yechoor, Vijay K., MD
Mechanisms underlying circadian control of beta-cell function
General Research Subject: Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Beta Cell Transcription Regulation, Islet Biology\Metabolic Regulation
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
There is increased risk of diabetes and obesity with a disruption of normal sleep/awake cycles in shift workers and with sleep disorders. Recent studies suggest an important role for molecular circadian clocks in glucose metabolism. There is a central clock in the brain that sets the rhythm and communicates with peripheral clocks present in every tissue. The molecular clock at its core has a complex of two proteins called 'Bmal1' and 'Clock'. Bmal1 is essential for the normal clock function and its disruption leads to complete loss of circadian rhythm. How the circadian clock controls beta-cell function and insulin secretion is not fully understood.
The underlying hypothesis of this proposal is that the beta-cell clock is essential for normal islet function and its ability to adapt to environmental circadian disturbances, and any disruption of this would lead to diabetes. Our preliminary studies reveal that deletion of Bmal1 gene only in beta-cells leads to diabetes due to altered mitochondrial function, oxidative stress and loss of glucose-stimulated insulin secretion in mice. The current proposal seeks to decipher mechanisms underlying regulation of beta-cell function by the molecular clock and its role in beta-cell energy metabolism, mitochondrial function and the ability of beta-cells to tolerate oxidative stress, using cellular and animal models of genetic and environmental circadian clock disruptions. This study will thus help unravel novel regulatory roles of the molecular clock in beta-cell function and uncover new targets to modulate this circadian-beta cell axis to prevent and treat beta-cell failure and diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Beta-cells maintain plasma glucose within a narrow physiological range despite large fluctuations in nutrient flux imposed by feeding/activity cycles that are driven by the circadian clock. This requires integrating circadian rhythm with stimulus-insulin secretion coupling mechanisms. Consistent with this, circadian misalignment is associated with metabolic syndrome and diabetes in shift workers. Our previous work has shown that the function of the circadian clock is critical for normal glucose homeostasis and a disruption of this leads to diabetes and that this is secondary to beta cell dysfunction. Preliminary studies indicate that this is secondary to a disruption of of mitochondrial energy metabolism in beta cells. The aim of this project is to identify the regulatory mechanisms underlying the circadian control of beta cell function. Specifically we will address the role of the intrinsic beta cell clock in regulating mitochondrial function in beta cells.
Results from this study will identify the mechanistic role of the circadian clock in beta cell function and unravel novel regulatory interactions between the circadian clock, mitochondrial bioenergetics and metabolism. This will allow identification of novel targets to modulate this circadian clock-ß-cell axis that can lead to new strategies to prevent and treat beta-cell failure and diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
There are many factors that trigger and perpetuate beta cell function, the hallmark of all diabetes. There has been an ever-increasing incidence of diabetes and obesity over the last few decades. One factor that has received some recent attention is disruptions of the biological clock associated with modern lifestyle.
Our research has identified the biological clock to be critically important to maintain normal beta cell function via regulation of energy metabolism and a disruption of this biological clock results in diabetes. With the proposed series of experiments we seek to fully understand the mechanisms underlying this regulation of beta cell function by the biological clock. This would allow identification of regulatory pathways would allow them to be specifically targeted for new drugs that may be useful in not only preventing but possibly reversing beta cell dysfunction in diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a physician, I treat patients and families who have been devastated by diabetes and its complications, many of which are largely preventable or treatable. This is a constant driver that motivates me to take advantage of the unique opportunity as a physician-scientist and specifically ask fundamental questions regarding the phathophysiological and molecular mechanisms underlying diabetes with the ultimate goal of translating them to transform patient care.
The current award and the proposed research that it will support will go a long way in not only establishing the definitive role the biological clocks play in normal beta cell function but also will help identify novel pathways that would be targets for new drug development. I firmly believe that it is only pure intellectual curiosity that prompts creative scientific discovery, the application of which ultimately improves patient care. Towards this end, this award will allow me to pursue basic questions in beta cell biology and develop this field of circadian clock regulation of energy metabolism in beta cells with the ultimate goal of preventing and reversing diabetes.
In what direction do you see the future of diabetes research going?
There has been enormous progress made, over the last few decades, in understanding the molecular basis of diabetes and its complications. However, the incidence of diabetes is ever increasing and the translation of basic research to prevention and therapy has lagged behind. To address this we need to not only continue our investigation into identifying and understanding the risk factors that initiate and perpetuate the progression to diabetes but step up efforts to translate this into patient-focused action.
Thus the two major thrusts would include: 1. Efforts to identify the risk factors for diabetes and fully elucidate molecular pathways they regulate including those that affect energy metabolism, insulin resistance and beta-cell function. 2. Translate these into effective prevention strategies and therapies using innovative cross-disciplinary approaches.
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