New research aims to lessen the possibility of brain swelling in diabetic ketoacidosis patients
By Stephen Whelan, PhD and Emeritus Professor William Hoffman, MD of Medical College of Augusta University
Edited by Molly Gluck
Diabetic ketoacidosis (DKA) is a serious metabolic/immunologic complication of Type 1 diabetes (T1D) and the most common chronic medical condition in children. It results due to the body producing high levels of ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA’s dysregulation by the body results in a lowered pH and an increase of a low-grade systemic inflammation. The latter can lead to a cerebral inflammation and subclinical brain edema, a term to describe when fluids build up in the brain (i.e. brain swelling). In the early stages of the insulin deficit and its metabolic/immunologic deregulation, there is a progression of oxidative stress and systemic inflammation that is hypothesized to contribute to brain edema — which causes morbidity and mortality, particularly in young people with DKA.
For clinical brain edema — where the patient has recognizable clinical signs and symptoms — morbidity and/or mortality is over 50 percent, and occurs in approximately one in every 1,000 episodes of DKA. Around 60 percent of children with DKA will have subclinical brain edema (BE) — meaning that the individual has minimally recognizable clinical signs and symptoms — and it resolves possibly with no sequela. Hoffman et al. have reported that after a severe episode of DKA, subclinical neurocognitive defects continue to advance for at least three months in some children. It is also important to note that clinical BE does not appear to develop in adults as often as those under the age of 21 years.
In collaboration with Dr. Norman Lee, director of the Chemical Instrumentation Center at Boston University, we wanted to explore the levels of neurotoxins and neuroprotective molecules in the well-recognized tryptophan/kynurenine pathway that has not been investigated in young patients being treated for DKA/T1D; beginning during treatment (at 6–12 hours), at two weeks and at three months after treatment. Our hope is that this investigation of molecular changes will lead to more effective personalized treatment of DKA to lessen the possibility of brain edema. For some quick background, the tryptophan/kynurenine pathway is vital for cellular energy — and the neurotoxins and neuroprotective molecules as well as other molecules produced along the kynurenine pathway are key regulators of the immune system, inflammation and neurological conditions.
Our research methodology included analyzing metabolites in patient blood samples, in which we first extracted the metabolites then identified their specific molecular mass signatures and fragmentation masses. We discovered that there are several neurotoxins and also neuroprotective molecules formed during DKA and its treatment. Interestingly, we also discovered differences in molecules associated with neuroprotection and neurotoxicity between genders and race during treatment. At this time, we can only say the differences are quantitative between these groups — but in the future, the differences we observed between male and female patients as well as differences between African American and Caucasian patients may be important for developing personalized treatment for more effective outcomes. As part of personalized medical intervention, treatment may also include any combination of nutritional intake, supplementation (vitamin B which are cofactors in the tryptophan/kynurenine pathway, carnitine/acetylcarnitine, amino acids, etc.) and fitness regime.
Treatment technology has a come a long way — including continuous glucose monitoring (CGM), in which a tiny sensor is placed under the skin and a signal can automatically activate an insulin pump to administer a calculated dose of insulin. Currently, developing rapid and cost-effective mass spectrometry technology driven methods — such as metabolomic (small molecules), proteomic (proteins) and lipidomic (lipids/fats) biomarker platforms where hundreds of molecules and lipids to thousands of proteins can be analyzed at a single time point in a single patient — will help the development of customized personal treatment, in turn improving patient outcomes.
We hope that our study and other population-level and disease “Omics” studies will help inform the future development of sensors, similar to the CGM, that can detect other key metabolic changes and inform a program of specific action or treatment to restore balance in DKA patients.
Both academia and pharma are using and developing mass spectrometry biomarker platforms to improve patient care which takes significant upfront financial and time investment. There is significant hope for personalized medicine.
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