News & Research

Evanston Northwestern Healthcare Research Institute Evanston, Illinois

Circadian Clock in Diabetes: Role of the NAD/SIRT1 Pathway.

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Integrated Physiology\Muscle, Integrated Physiology\Regulation of Glucose Kinetics, Integrated Physiology\Liver

Type of Grant: Basic Science

Project Start Date: July 1, 2009

Project End Date: June 30, 2012

Research Description

The first biological clock gene was discovered in 1997 at Northwestern University and in 2005 our group discovered that mice with mutations in the clock develop type 2 diabetes mellitus and obesity. We have recently pinpointed an important genetic and molecular loop that explains the relationship between the clock and diabetes involving a family of 'aging enzymes' known as the sirtuins. The sirtuins appear to control the clock and enable feeding and glucose turnover to be coordinated with the availability of food. The proposed studies will seek to define the precise messages that connect the sirtuin and clock systems. Understanding how the body clock controls glucose metabolism will ultimately shed light on potential therapies that can be adjusted to match the daily variation in feeding, sleep, and activity that are critically altered in diabetes.

Reseacher Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes? 

The major goal of our research is to understand links between the internal biological clock, obesity and diabetes.  Our work is based upon a long-standing interest in the relationship between the internal body clock, glucose metabolism and appetite.  Most of us are aware of the strong daily variation in appetite, and those with diabetes are familiar with a parallel daily change in the handling of sugar.  Over the past 5 years, our laboratory and others have begun to systematically uncover the biological basis for this relationship between metabolism and timing.  A major key to this work has been the use of animals with genetically altered body clock-indeed, our studies have shown that disruption of the clock increases susceptibility to both diabetes and obesity.  Yet we still do not fully understand how the clock functions within central glucoregulatory pathways to impact diabetes, and how circadian systems also modulate appetite and energy balance.  During the course of this work we have also uncovered surprising evidence that one of the fundamental mechanisms through which the circadian clock impacts glucose metabolism involves the NAD-dependent deacetylase Sirt1, and the upstream control of NAD synthesis, a central 'nutrient sensing' pathway in mammalian cells. 

The central objective of our research under the ADA grant award will be to dissect the role of the NAD-Sirt1 pathway as a major link between the internal clock and metabolic homeostasis.  Throughout this work we will collaborate closely with the group of Dr Shin Imai (Washington Univ, St Louis), who was among the first to uncover a role for NAD in the control of the sirtuin system.  In the long-term, we hope that our studies will lead to a better understanding of the temporal control of both energy balance and metabolism and in so doing, to new therapeutic targets and strategies for management of diabetes and obesity.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

One of the hallmarks of modern life is the frequent disruption of normal cycles of rest and activity that is most severe in shift work, jet travel, and chronic sleep deprivation states. While it is further well known that certain adverse health events such as myocardial infarction and hypertension are increased at certain times of day, less is known about how and why pathologies linked to diabetes and cardiovascular disease exhibit such strong peaks across the day and night. 

Our work has uncovered a surprising explanation for this phenomenon: our internal body clock, present in nearly all tissues including the liver and pancreas, is crucial in controlling our fluctuation of blood sugar and many other aspects of metabolism.  Thus we seek to better understand a major contributing factor in the development of diabetes-that is, how the internal clock system may be important in disease initiation, progression and treatment.  In the long-term, by better understanding how damage to the clock damages our capacity to properly handle blood sugar and to control appetite, we hope to advance knowledge on existing treatments for disease and to uncover new possible targets for disease modification.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts? 

Diabetes research has been at the forefront of efforts to develop a 'mechanistic' approach to disease in man.  The model of diabetes therapies has captivated me for many years since it is an example of the powerful interrelation between basic science and clinical medicine.  It is inspiring to realize that insulin was the first protein drug, in addition to being the first recombinant drug.  Yet, as we now know, despite such remarkable advances, diabetes continues to spread around the globe. 

In my own family, diabetes has taken a toll, having led to the death of my great-grandmother shortly before Banting & Best's new 'insulin' became widely available (it was my grandmother who originally impressed upon me her own experience of loss from the disease).  I was particularly motivated to enter diabetes research because of the opportunity to apply new molecular approaches to clinical medicine and I was fortunate to benefit from the stimulating mentorship offered at the University of Chicago when I was in training.  At present I believe that our opportunity to define not only the pathways involved in glucose metabolism, but to also understand how these pathways affect behavior, continues to provide stimulation and hope for treatments.

In what direction do you see the future of diabetes research going? 

Many factors will influence the course of diabetes research and in particular, as our science becomes more sophisticated, it will be necessary to foster collaboration amongst diverse scientists and disciplines.  Clearly epidemiology and public health issues are paramount-including efforts to educate and make available proper nutrition and improved exercise.   From our own vantage point, improved knowledge of the biological basis for control of both appetite and glucose metabolism will be a centerpiece in the effort to approach diabetes.  Whereas much research in the past has taken a focused biochemical and molecular approach, it will be important to combine such studies with those focused on physiology and behavior. 

Just as neurobehavioral studies represent a 'final frontier' in life-sciences research overall, the allure of studies on the 'brain', and the potential to gain greater insight into the contribution of brain pathways to metabolism, represents one of the most exciting areas for diabetes investigation.  Our focus on the link between biological clocks and metabolism can be considered an example of such interdisciplinary efforts that will be increasingly important for the future of diabetes research.