Accili, Domenico , MD
Role of GLUT4-expressing Neurons in Diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Insulin Action\Glucose Transport, Insulin Action\Insulin Resistance, Insulin Action\Transgenic Models
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Insulin resistance plays a key role in the pathogenesis of type 2 diabetes. The PI has made the novel and potentially important observation of a new cell type in the brain, a neuron, that shares common features with other cell types that are important for insulin action in muscle and fat. This neuron is characterized by the expression of the insulin-dependent glucose transporter Glut4. The PI has shown that this 'Glut4 neuron' is important for insulin action, and that rendering this neuron insulin-resistant contributes to diabetes. In studies outlined in the proposal, the PI proposes genetic and cell biology experiments to understand the contribution of Glut4 neurons to peripheral insulin sensitivity. The PI will use transgenic mice and fluorescent markers to identify these neurons and study the consequences of their inactivation on metabolism. Using advanced microscopy techniques, the PI will investigate how insulin affects Glut4 in neurons, and the consequences of Glut4 modulation on the Central Nervous System. The proposal will contribute to identifying a novel site of insulin resistance that can be targeted for diabetes therapy.
Mentor: Accili, Domenico, MD Postdoctoral Fellow: Ren, Hongxia
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This laboratory studies the pathogenesis of insulin resistance and attempts to identify new therapeutic approaches for this condition. Insulin resistance remains the cornerstone of diabetes pathogenesis and, despite decades of intensive research efforts, few new treatment options are available for it. Over the past decade, this laboratory has been at the forefront of studies to map genetic, biochemical, cell biological, and integrated physiological mechanisms that regulate various aspects of insulin resistance, including liver glucose production and lipoprotein turnover, fat cell function, and regulation of food intake. Studies from this laboratory have identified mechanisms linking altered gene expression with common abnormalities of glucose and lipid metabolism in diabetes. Current work is focused on mechanisms linking insulin action and insulin resistance with the central nervous system. The laboratory has recently identified a discrete neuron population in the brain, and has demonstrated that insulin resistance in these neurons has widespread consequences for insulin sensitivity in liver, causing alterations of liver glucose production that resemble those of patients with type 2 diabetes. Thus, work supported by this Award will allow the laboratory to characterize this interesting neuron population and to define mechanisms whereby these cells affect glucose production by the liver. The ultimate goal of this research is to develop agents that improve insulin sensitivity by acting through the central nervous system.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We are trying to understand the mechanism by which glucose and lipid production in the liver of diabetic patients is increased. This abnormality is the main cause of diabetic complications and of the worsening of diabetes control over time. By understanding why the diabetic produces excess glucose and lipids in the liver, we are more likely to find a cure that is effective at combating both hyperglycemia and dyslipidemia (high 'bad' cholesterol and triglycerides).
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is a major threat to public health worldwide. Current treatment options are limited and imperfect. As a physician/scientist, I believe that new cures are necessary and that they can only be found through research and development. I was fortunate enough that my life circumstances made it possible for me not to limit myself to treat patients with the available tools, but to devote my academic career to devising new treatments through research. This award will further my efforts by allowing me to recruit and retain an uncommonly gifted scientist to work under my guidance. In addition to providing much needed support for ongoing research that we hope will result in better treatments for diabetes, this award will serve an educational/training purpose that will hopefully entice the recipient fellow, Dr. Hongxia Ren, to join the ranks of become independent academic investigators who are trying to make a difference in the lives of patients affected with diabetes.
In what direction do you see the future of diabetes research going?
Diabetes research is at a crossroads. On the one hand, the need for more
resources and more talent to be applied to finding new treatments for
diabetes has never been more urgent. On the other, the converging
pressures of a dwindling funding base, difficulties in attracting and
retaining skilled young workers into the field, complexities of clinical
development, mounting regulatory hurdles and marketing/financial
realities have combined to make the future of our endeavors uniformly
grim across academia, industry, government, and non-profit funders. It's
important that diabetes researchers band together with an eye to
solving the outstanding clinical problems that our patients face daily:
more effective, rational and scientific approaches to prevention and
lifestyle modification, safer and more effective drugs to combat insulin
resistance and obesity, durable approaches to preservation of beta cell
function, and effective strategies to lower the cardiovascular risk in
patients with over disease.
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