Abstract
Diabetic ketoacidosis (DKA) is a serious complication of complete insulin deficiency and insulin resistance in Type 1 diabetes (T1D). This results in the body producing high levels of serum ketones in an attempt to compensate for the insulin deficiency and decreased glucose utilization. DKA’s metabolic and immunologic dysregulation results in gradual increase of systemic and cerebral oxidative stress, along with low grade systemic and cerebral inflammation and the development of pretreatment subclinical BE. During treatment the early progression of oxidative stress and inflammation is hypothesized to advance the possibility of occurrence of crisis of clinical brain edema (BE), which is the most important cause of morbidity and mortality in pediatric DKA. Longitudinal neurocognitive studies after DKA treatment show progressive and latent deficits of cognition and emphasize the need for more effective DKA treatment of this long-standing conundrum of clinical BE, in the presence of systemic osmotic dehydration, metabolic acidosis and immune dysregulation. Candidate biomarkers of several systemic and neuroinflammatory pathways prior to treatment also progress during treatment, such as the neurotoxic and neuroprotective molecules in the well-recognized tryptophan (TRP)/kynurenine pathway (KP) that have not been investigated in DKA. We used LC-MS/MS targeted mass spectrometry analysis to determine the presence and initiation of the TRP/KP at three time points: A) 6–12 hours after initiation of treatment; B) 2 weeks; and C) 3 months following DKA treatment to determine if they might be involved in the pathogenesis of the acute vasogenic complication of DKA/BE. The Trp/KP metabolites TRP, KYN, quinolinic acid (QA), xanthurnenic acid (XA), and picolinic acid (PA) followed a similar pattern of lower levels in early treatment, with subsequent increases. Time point A compared to Time points B and C were similar to the pattern of sRAGE, lactate and pyruvic acid. The serotonin/melatonin metabolites also followed a similar pattern of lower quantities at the early stages of treatment compared to 3 months after treatment. In addition, glutamate, n-acetylglutamate, glutamine, and taurine were all lower at early treatment compared to 3 months, while the ketones 3-hydroxybutaric acid and acetoacetate were significantly higher in the early treatment compared to 3 months. The two major fat metabolites, L-carnitine and acetyl-L-carnitine (ALC) changed inversely, with ALC significantly decreasing at 2 weeks and 3 months compared to the early stages of treatment. Both anthranilic acid (AA) and 3-OH-anthranilic acid (3OH-AA) had overall higher levels in the early stages of treatment (A) compared to Time points (B and C). Interestingly, the levels of AA and 3OH-AA early in treatment were higher in Caucasian females compared to African American females. There were also differences in the metabolite levels of QA and kynurenic acid (KA) between genders and between races that may be important for further development of custom targeted treatments. We hypothesize that the TRP/KP, along with the other inflammatory pathways, is an active participant in the metabolic and immunologic pathogenesis of DKA’s acute and chronic insults.
Highlights
A total of 43 samples were assayed for the major tryptophan/kynurenine pathway metabolites (e.g. 3-OH-anthranilic acid, anthranilic acid, kynurenic acid, kynurenine, picolinic acid, quinolinic acid, tryptophan, and xanthurenic acid), as well as other metabolites mentioned in this manuscript
Our study indicates kynurenine pathway (KP) is an early participant in the inflammation/ perturbation of Diabetic ketoacidosis (DKA) and likely begins prior to treatment
We extend the observation that DKA’s metabolic and immune inflammation are significantly interrelated with the KP as an important perturbation component likely prior to, during and after DKA correction
Summary
Diabetic ketoacidosis (DKA) in type 1 diabetes (T1D) is an acute, complicated, metabolic/ immunologic condition that involves: dehydration [1]; transient hypertension [2, 3]; oxidative stress [4, 5]; and numerous recognizable metabolic [6,7,8,9,10,11,12] and immunologic dysregulations [13,14,15,16], in addition to a prothrombotic state [17]. While the research is limited, we believe that early inflammatory DKA pathways, prior to and during treatment, are important candidates for involvement in the pathogenesis of BE/ DKA, a life-threatening insult for children with T1D/DKA. An additional candidate for inflammation is the kynurenine pathway (KP), with the newly formed tryptophan (TRP)/ kynurenine (KP) metabolites that are likely initiated prior to DKA treatment. This activation can result in dysregulation or over activation with production of both neurotoxic and neuroprotective molecules. The complexity and progression of the dysregulation increases the potential value of early study and biomarker identification [25] for studying the pathogenesis of the neurological crisis, and the goal of identifying potential metabolic as well as immunological molecular target(s) for intervention
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