Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Abstract

A common complication of type 1 diabetes mellitus is diabetic ketoacidosis (DKA), a state of severe insulin deficiency. A potentially harmful consequence of DKA therapy in children is cerebral edema (DKA-CE); however, the mechanisms of therapy-induced DKA-CE are unknown. Our aims were to identify the DKA treatment factors and membrane mechanisms that might contribute specifically to brain cell swelling. To this end, DKA was induced in juvenile mice with the administration of the pancreatic toxins streptozocin and alloxan. Brain slices were prepared and exposed to DKA-like conditions in vitro. Cell volume changes were imaged in response to simulated DKA therapy. Our experiments showed that cell swelling was elicited with isolated DKA treatment components, including alkalinization, insulin/alkalinization, and rapid reductions in osmolality. Methyl-isobutyl-amiloride, a nonselective inhibitor of sodium-hydrogen exchangers (NHEs), reduced cell swelling in brain slices elicited with simulated DKA therapy (in vitro) and decreased brain water content in juvenile DKA mice administered insulin and rehydration therapy (in vivo). Specific pharmacological inhibition of the NHE1 isoform with cariporide also inhibited cell swelling, but only in the presence of the anion transport (AT) inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid. DKA did not alter brain NHE1 isoform expression, suggesting that the cell swelling attributed to the NHE1 was activity dependent. In conclusion, our data raise the possibility that brain cell swelling can be elicited by DKA treatment factors and that it is mediated by NHEs and/or coactivation of NHE1 and AT.

Brain injury in children with diabetic ketoacidosis: Review of the literature and a proposed pathophysiologic pathway for the development of cerebral edema

“…However, improved understanding of the underlying mechanisms of CE and its early identification may ultimately help guide therapeutic interventions aimed at specific molecular targets, with the aim of preventing fatalities and irreversible neurologic sequelae (Table 4). 32,33,44,47,54,85,159,160 The role of genetic factors in susceptibility to CE is another area of interest, but without data.…”

A Rare and Lethal Complication: Cerebral Edema in the Adult Patient with Diabetic Ketoacidosis

“…Treatment strategies, including bolus administration of insulin and bicarbonate, appear to play a significant role in development of CE as well. Administration of medications that depress respiratory drive, such as morphine, can decrease a protective hyperventilation that could further worsen an acidotic state; these medications and standard mechanical ventilation settings in patients who are intubated should be avoided [ 3 , 6 ].…”

“…A combination of elevated blood glucose in the setting of depleted insulin availability creates an acidic environment from the production of β -hydroxybutyric acid and acetoacetic acid [ 1 ]. DKA has been linked to several devastating metabolic derangements including osmotic diuresis, depletion of intracellular potassium, accumulation of toxic ketoacids, and dysregulation of sodium hydrogen exchanger mechanisms [ 2 , 3 ]. A destructive consequence secondary to these abnormalities is cerebral edema (CE) that has been documented throughout the pediatric literature, but more sporadically in the adult literature.…”

Inhibition of the Sodium–Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2

“…The ketone hypothesis is under study for cardiovascular and renal benefit and is potentially positioned to explore the proclivity for T2DM patients who are ketosis prone, to develop DKA while administered SGLT2i in the absence of hyperglycemia or insulinopenia (Lopaschuk and Verma, 2016). The NHE family of channels may be influenced by ketogenesis, for example, NHE1 appears to mediate the brain swelling that occurs in preclinical models of DKA (Rose et al, 2015).…”