Research Description
While the goal of diabetes treatment is normoglycemia, most therapeutics (especially insulin and insulin secretagogues) carry with them a significant risk of potentially life-threatening hypoglycemia; this risk increases with the intensity of therapy. Hypoglycemic shock is the cause of 282,000 emergency room visits a year and the death of about 1 in every 20 patients with type 1 diabetes. In addition to the financial burden of complications due to hypoglycemic episodes, the risk of hypoglycemia limits diabetes treatment. From information gathered in previous studies, we defined a novel subset of neurons within the ventromedial hypothalamus (VMN) that, when silenced, lowers baseline blood glucose, decreased the CRR to both insulin-induced hypoglycemia and glucoprivation, and eliminates hypoglycemia associated autonomic failure (HAAF)-like responses. This preliminary data suggests a role for these neurons and the overall neurocircuitry in glucose homeostasis, the CRR, and HAAF. We will further evaluate the role of these cells in the CRR to understand the mechanisms, define the site and mechanisms responsible for HAAF, and understand the role of these cells in diabetes. By understanding the mechanisms underlying the CRR, and the failure of the CRR in HAAF, we will identify potential targets for interventions to prevent or mitigate HAAF. These studies also have the potential to reveal mechanisms that contribute to hyperglycemia in diabetes- either via the dysfunction of non-CCKBR VMN cells that control glucose disposal or via the inappropriate action of the CRR neural circuitry.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?My project will investigate the role of the brain in hypoglycemia. I am interested in determining how the brain receives the signal of low blood glucose and generates a response in order to restore normal levels of glucose in the blood. We are particularly interested in understanding how these brain systems change following repeated hypoglycemia and contribute to hypoglycemia associated autonomic failure. By revealing these underlying mechanisms, we will uncover novel therapeutic targets for diabetes treatment.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?Currently, we do not have a strong grasp on the mechanisms responsible for hypoglycemia associated autonomic failure that exacerbates the risk of diabetic shock and seizures in type 1 and advanced type 2 diabetic patients. Without understanding the underlying mechanisms, there is little hope for significant advances in treatment. My project will attempt to reveal the brain systems that no longer function properly in patients with hypoglycemia associated autonomic failure. We hope to eventually override and/or prevent the adaptations associated with hypoglycemia associated autonomic failure in order to ameliorate the risk of hypoglycemia and associated diabetic shock diabetic patients. By studying these brain systems, we may also reveal novel mechanisms that ameliorate hyperglycemia, which may be relevant for type 2 diabetes.
Why important for you, personally, to become involved in diabetes research? What role will this award play?As a trained neuroscientist, I entered science in order to understand how the brain functions and have recently become interested in diabetes research during postdoctoral training at the Brehm Center for Diabetes Research at the University of Michigan. This award will help me begin my career as an academic scientist at a major research institution, as I start my lab that will investigate the neural systems that control blood glucose levels throughout my career.
In what direction do you see the future of diabetes research going?From my perspective as a neuroscientist, I think we will soon better understand and appreciate the importance of the interplay between the nervous system and the periphery in glucose management. While admittedly I am biased, I think that the advancement of neuroscience tools and teasing out individual neurons and circuits will allow us to reveal in greater detail and confidence the role(s) for the brain in glycemic control. On a more general level, I see more and more therapeutic targets revealed for diabetes treatment. As a result, this may lead to more focal and specialized treatment to re-establish proper glycemic control in diabetic patients.