Cryer, Philip E., MD
Hypoglycemia in Diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
Hypoglycemia (low blood sugar levels) is a problem for people with diabetes that has not been solved. It causes repeated episodes that range from distracting to devastating. It makes it very difficult for people with diabetes to maintain near-normal blood sugar levels. It is the result of treatment (e.g., insulin) and impaired body defenses against falling blood sugar levels. We study the mechanisms of the impaired defenses. Those include loss of the blood sugar raising hormones glucagon and epinephrine (adrenaline) and loss of the warning symptoms that used to allow the person to recognize and self-treat falling sugar levels (by eating) before sugar levels get too low. Coupled with more applied studies, insight into the causes of impaired defenses against falling blood sugar levels can be expected to lead to clinical strategies that will minimize the risk of hypoglycemia and, thus, improve the lives of all people affected by diabetes.
Mentor: Philip Cryer, MD Postdoctoral Fellow: Nadia Khoury, MD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Hypoglycemia is a problem for people with diabetes that has not been solved. Its pathogenesis involves defective glucose counterregulation and hypoglycemia unawareness - impaired physiological and behavioral defenses against falling glucose levels. The key feature of both is an attenuated sympathoadrenal response; thus, we call it Hypoglycemia-Associated Autonomic Failure (HAAF) in diabetes. Although HAAF can be caused by recent antecedent hypoglycemia, prior exercise or sleep, its mechanism(s) is unknown. Therefore, we are testing the hypothesis that adrenergic activation, cholinergic activation, or both mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal and symptomatic responses to hypoglycemia (Aim 13). To do so we will contrast the effects of 1) saline, 2) combined adrenergic blockade with the nonselective a- adrenergic antagonist phentolamine and the nonselective ß-adrenergic antagonist propranolol, and 3) combined adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine during antecedent hypoglycemia on the sympathoadrenal and symptomatic responses to hypoglycemia the following day in healthy subjects.
It is also anticipated that Dr. Ramanathan will test the hypothesis that suppression of the ß-cell secretory response with the KATP channel agonist (opener) diazoxide, compared with placebo, (producing a model of type 2 diabetes) permits emergence of direct a-cell stimulation of glucagon secretion by the contents of a mixed meal and by the sulfonylurea glimepiride (with glucose infused to prevent hypoglycemia) (Aim 15). Loss of glucagon secretion is a feature of defective glucose counterregulation in diabetes. We suspect it is due to ß-cell failure.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our long-term goal is to eliminate treatment-induced hypoglycemia from the lives of all people affected by diabetes. Our premise is that insight into the pathogenesis of treatment-induced hypoglycemia will lead to better understanding of the frequency and impact of, risk factors for and elimination of hypoglycemia. Therefore, we have designed a series of experiments that will provide insight into the mechanisms of treatment-induced hypoglycemia in people with diabetes. Two of those experiments are mentioned here.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Dr. Ramanathan is gaining critical experience in the performance of hypothesis-driven research in humans. She has committed to this type of translational research, between clinical trials and bench science. She has reviewed the literature, participated in the design of her studies, and has started to perform them. She will continue to learn from her studies, interpret her findings, and present and publish the results. The Mentor-Based Postdoctoral Fellowship Award will allow her to gain this training.
In what direction do you see the future of diabetes research going?
Research into the basic aspects of the treatment of diabetes, including treatment that improves glycemic control while reducing the risk of hypoglycemia, will continue to be important pending the prevention and cure of diabetes. That will happen, but we don't know when and we must not wait until then to improve the lives of all people affected by diabetes.
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