Lowell, Bradford Barr
Glucose sensing neurons in the brain: important regulators of peripheral glucose homeostasis.
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Regulation of Food Intake, Other, Signal Transduction (Non-Insulin Action)\Transgenic Models
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Type 2 diabetes is a major health problem. Prior work has suggested that type 2 diabetes is caused by the simultaneous occurrence of two problems: dysfunction of insulin-secreting pancreatic beta-cells and impaired insulin action on target tissues. Work being supported by an ADA Mentor-Based Postdoctoral Fellowship is investigating if there is a third, previously unrecognized abnormality - dysfunction of glucose sensing by the brain. ÒGlucose-excitedÓ neurons sense increases in glucose and then initiate, via neural circuits, responses aimed at returning blood glucose levels to normal. Importantly, the capability of these neurons to sense glucose is lost in obesity-induced type 2 diabetes. These studies strongly suggest that an important component of type 2 diabetes may actually be located within the brain. The ADA-supported postdoctoral fellow will use a variety of mouse genetic engineering approaches to determine the importance of glucose sensing in the brain, and to delineate the neural processes that underlie it.
Mentor: Lowell, Bradford, MD, PhD Postdoctoral Fellow: Shah, Bhavik
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
For many years, it has been known that discrete groups of neurons (such as POMC neurons) in the brain have the ability to sense levels of glucose in the blood. However, the importance of this has been largely unknown. My laboratory specializes in genetically engineering mice to assess the role of a given gene within a given group of neurons in controlling behavior and physiology. Recently, we have begun a large effort to study the importance of glucose-sensing by neurons. Towards these ends, we have generated mutant mice in which glucose-sensing in POMC neurons (in the arcuate nucleus of hypothalamus) is defective. We discovered that this leads to glucose-intolerance. This finding demonstrates that glucosesensing by POMC neurons plays an important role in controlling blood glucose levels. We have also discovered that glucose-sensing in POMC neurons (in the brain) becomes defective in states of obesity and type 2 diabetes. Given that glucose-sensing in neurons plays an important role in controlling blood glucose, this could be a previously unknown mechanism contributing importantly to the pathogenesis of type 2 diabetes. All in all, it is becoming clear that glucosesensing in the brain is extremely important for regulation of blood glucose levels.
Preliminary data from our lab indicates that POMC neurons consist of two functionally diverse subpopulations (glucose regulating versus body-weight regulating). Currently, we have identified molecular markers that are uniquely present in glucose-sensing versus body-weight regulating POMC subpopulations. Using the molecular markers, we will investigate anatomy and function of glucose-sensing versus body-weight regulating POMC subpopulations. Eventually, this will lead to much better understanding of neurocircuits that regulate blood glucose and body weight. These findings may open up new avenues for treating type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Using genetic engineering approaches, we are identifying novel brain based mechanisms that play an important role in controlling blood glucose. We believe that these brain-based mechanisms become defective in type 2 diabetes. A complete understanding of these novel mechanisms could lead to new approaches for treating type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research?
The major focus of research in my group is to uncover mechanisms of diseases, with the ultimate goal of identifying new therapeutic approaches to disease. This award will make it possible for me to mentor a post doctoral scientist in techniques used to genetically investigate the importance of glucose-sensing by the brain.
In what direction do you see the future of diabetes research going?
Evidence is mounting form numerous sources and many different lines of investigation that the brain plays a very important role in controlling blood glucose. The importance of these brain-based mechanisms has not been appreciated in the past. Given the complexity of the brain (100 billion neurons making trillions of neural connections), unique approaches, in particular, neuron-specific gene manipulation in mice, will be necessary to 'unlock' the secrets of how the brain controls blood glucose levels and metabolism. I believe that such approaches will play a key role in diabetes research going forward. My lab is generating many different genetic reagents (modified mice) that will facilitate the performance of such studies.
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