Glaser, Nicole , MD
Mechanism of cerebral injury in pediatric diabetic ketoacidosis
General Research Subject: Type 1 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Pediatrics, Pediatrics\Type 1
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Diabetic Ketoacidosis (DKA) is a frequent complication of type 1 diabetes in children. DKA occurs when insulin levels are insufficient to suppress fat breakdown, resulting in toxic levels of ketones. DKA can cause brain swelling and injury. In 1% of DKA episodes, severe, life-threatening brain swelling occurs, but many more children with DKA have milder forms of brain swelling. Recent data suggest that DKA may be an important and previously unrecognized diabetes-related cause of brain injury. Children who have experienced DKA perform more poorly on memory tests compared with children with diabetes without DKA history.
Previous studies suggest that DKA-related brain injury may be similar to injury resulting from reduced brain blood flow and/or oxygen supply. Previous studies also suggest that activation of ion transporters that bring salts and water into brain cells may cause injury during DKA and that blocking these transporters may protect the brain. The proposed studies aim to investigate mechanisms of brain injury during DKA. Microscopic examination of rat brains during/after DKA and measurements of blood proteins that increase with brain injury will determine the timing of brain injury in relation to DKA treatment, the cell types involved, and potential protective effects of medications that inhibit ion transporters. These studies will further our ultimate goal of developing strategies to prevent DKA-related brain injury. These data are also important for understanding how conditions present during DKA affect other neurological disorders (i.e. stroke and traumatic brain injury) that may occur in individuals with diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project involves the investigation of brain injury caused by diabetic ketoacidosis (DKA) in children. DKA occurs commonly in children with new-onset of type 1 diabetes (25-40%). In addition, DKA can occur in children with known diabetes during episodes of illness or insulin pump malfunction, or with insulin omission for any reason. Recent data suggest that brain swelling (cerebral edema) occurs commonly in children with DKA both before and during treatment. A small sub-set of children with DKA (~1%) develop severe, life-threatening brain swelling, but most develop mild or subtle brain swelling. Recent studies, however, suggest that even mild brain swelling during DKA may be associated with subtle brain injury, affecting cognitive functions in these children, particularly memory function. Although there is considerable data suggesting that brain swelling and brain injury occur during DKA, the cause of brain injury is not understood. Our project will investigate the cause of DKA-related brain injury and will lay the foundation for future trials aimed at preventing this injury from occurring.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic ketoacidosis (DKA) can develop in anyone with diabetes, especially during episodes of illness or occasionally with malfunction of diabetes care equipment such as insulin pumps. Previous research suggests that subtle or more severe brain injury can occur during DKA and that children are particularly vulnerable to this injury. Although it has been known for decades that DKA can cause brain injury, very little is known about how this occurs and what can be done to prevent it. Our work will investigate the mechanism of this injury and will provide essential data to plan future studies aimed at preventing brain injury caused by DKA. In addition, people with diabetes may develop brain injuries due to other causes, such as stroke or trauma. Previous research suggests that high blood glucose levels may worsen these types of injuries, but the reasons for this are only partially understood. Our work will also provide data relevant to the care of people with diabetes who have strokes or traumatic brain injuries and will help us to determine how treatment of brain injuries in these people might be improved.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a pediatric resident, I witnessed the tragic death of a two year-old boy due to complications of diabetic ketoacidosis (DKA). The patient, a beautiful little boy, arrived in the pediatric intensive care unit with what appeared to be routine DKA. During his treatment, he unexpectedly developed neurological symptoms and then became unresponsive. We determined that he had developed cerebral edema (brain swelling). Despite the best efforts of our medical team, his brain injury progressed and he died one day later. This event was tragic beyond belief. I recall asking the critical care and endocrine specialists for explanations about why it had occurred, but found that very little was known about this complication of DKA. I spent hours in the medical library reading through the literature about cerebral edema caused by DKA and still found no clear explanation. This issue continued to bother me throughout my residency. When I chose to specialize in pediatric endocrinology, it was easily clear to me which area of research I should pursue. The current award will further the work of my laboratory in determining the cause of DKA-related brain injury. It is my hope that my work will eventually prevent other tragic events like the one that affected me so greatly during my residency.
In what direction do you see the future of diabetes research going?
Several recent studies, including some from our laboratory, suggest that insulin and glucose play much more important roles in the brain than previously recognized. Our work and that of others suggests that hyperglycemia and ketosis (during DKA) may make the brain particularly vulnerable to injury. In addition, the important role of insulin in the brain is just recently beginning to be recognized. Abnormalities in insulin effects in the brain have been implicated in several degenerative neurological diseases and data from our laboratory suggest that lack of insulin may also play a role in DKA-related brain injury. I believe that the roles of insulin and glucose metabolism in the brain will be very important areas of future investigation with relevance not only to individuals with diabetes but also to patients with multiple other types of brain disorders.
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