Cherrington, Alan D., PhD
Regulation of glucose metabolism in vivo
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications\Hypoglycemia, Insulin Action, Metabolism, Integrated Physiology\Liver
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
Hyperglycemia, a hallmark of diabetes, results both from overproduction of glucose and impairment in glucose utilization. The overproduction of glucose results from excessive rates of glycogen breakdown in the liver but, more importantly, from excessive rates of gluconeogenesis (the conversion of non-glucose molecules to glucose by the liver). We have developed a unique animal model along with various experimental tools, to allow us to study the regulation of glucose production by hormones, neural mediators and new drug candidates in the normal and insulin resistant whole animal.
Following feeding, intricate signals from various organs (pancreas, liver, fat) and the brain interact to carefully direct the disposition of nutrients in the various tissues of the body. We have found that signals emanating from the portal vein (the blood vessel into which absorbed nutrients flow) control the distribution of glucose between the liver, muscle and fat. We are now trying to understand the way in which these signals are relayed to the brain and the means by which the brain then communicates with muscle, liver and the pancreas to bring about the desired outcome.
Finally, we are carrying out well controlled studies related to non-invasive glucose monitoring, as well as to development of new drugs and insulin analogues for treatment of individuals with both types 1 and type 2 diabetes.
Mentor: Alan Cherrington, PhD Postdoctoral Fellow: Christopher J. Ramnanan, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project is focused on the role of the liver in regulating glucose metabolism both in the fed and fasted states. Insulin action in the brain will be a major interest. Work in rodents has suggested that insulin action in the CNS plays an important role in glucoregulation. It is not clear whether it also does so in larger mammals, such as the dog or human. Our work will endeavor to answer this question. In addition we will examine the significance of the route of insulin delivery to the development of hypoglycemia, a critical issue for individuals with diabetes. If the frequency of hypoglycemia is reduced by portal vein insulin delivery then it will add impetus to the development of oral insulins or insulins that are hepatoselective. We will also examine the control of post-prandial hepatic glucose uptake and storage. It is known that liver glucose uptake is markedly abnormal in people with type 1 or type 2 diabetes. We have developed a diet induced canine model of hepatic insulin resistance that we will use to explain the hepatic dysfunction. The hope is that by identifying the first temporal defect and the dietary insult which causes it, we can develop strategies to intervene therapeutically.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project has the potential to lead to new insulin molecules, as well as new drugs to treat people with type 1 or type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been involved with diabetes research my whole career. Frankly, my choice of disease focus was random and made long before the Mentor Based Grant program existed. Having said that, however, the program is vitally important to me. It has allowed me to support a series of high quality fellows who have themselves gone on to careers in diabetes research.
In what direction do you see the future of diabetes research going?
I see diabetes research going in a number of directions:1) Beta cell biology will continue to be a focus given that it is ultimately failure of the beta cell which pushes the person from glucose intolerance to diabetes.2) Obesity will be come an even more important topic of study given its role in the explaining the number of people with diabetes.3) The power of metabolomics and genome wide associations will be explored and should lead to an ability to predict disease or even more likely to predict the response to a given treatment thereby leading to personalized medicine.4) Perhaps the most important research will be done in the translation area. Creating effective treatment paradigms for people who are overweight and/or have diabetes will be critical to any health care system that is developed in this country and to the health of the nation.5) Ultimately we have to develop strategies to prevent the disease if we are to win the war against diabetes
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