Combined insulin and bicarbonate therapy elicits cerebral edema in a juvenile mouse model of diabetic ketoacidosis

Cerebral edema in diabetic ketoacidosis (DKA-CE) occurs primarily in children and can develop during DKA therapy. The treatment factors contributing to DKA-CE remain elusive. Our objectives were to characterize an age-appropriate DKA mouse model and to determine which DKA therapies contribute to DKA-CE. Juvenile mice were briefly fed a high-fat diet and injected with two pancreatic β-cell toxins: streptozocin and alloxan. Severe insulin and leptin deficiencies associated with hyperosmolar ketoacidosis rapidly developed, indicating DKA. DKA mice were treated with re-hydration ± insulin and brain water content (BWC) measured as an indicator of DKA-CE. As expected, glucose and β-OH-butyrate corrected in DKA mice that received rehydration and insulin. BWC significantly increased above control levels only in DKA mice that received combined insulin and bicarbonate therapy, indicating the development of DKA-CE. Microscopically, DKA-CE brains had perineuronal and perivascular edema, with microvacuolation in the white matter tracts. These results indicate that insulin-deficient juvenile mice develop biochemical changes that are similar to those of DKA in children. Increased BWC was observed only in DKA mice that received combined insulin and bicarbonate therapy, suggesting that rapid systemic alkalinization in the presence of insulin may contribute to DKA-CE.