Cerebral Metabolic Alterations in Rats with Diabetic Ketoacidosis: Effects of Treatment with Insulin and Intravenous Fluids and Effects of Bumetanide

  1. Nicole Glaser, MD (nsglaser{at},
  2. Natalie Yuen, B.S.2,
  3. Steven E. Anderson, Ph.D.2,
  4. Daniel J. Tancredi, Ph.D.1 and
  5. Martha E. O'Donnell, Ph.D.2
  1. 1Department of Pediatrics and
  2. 2Department of Physiology and Membrane Biology, University of California, One Shields Avenue, Davis, CA 95616


Objective: Cerebral edema is a life-threatening complication of diabetic ketoacidosis (DKA) in children. Recent data suggest cerebral hypoperfusion and activation of cerebral ion transporters may be involved, but data describing cerebral metabolic alterations during DKA are lacking.

Research design and methods: We evaluated 50 juvenile rats with DKA and 21 normal control rats using proton and phosphorus magnetic resonance spectroscopy (MRS). MRS measured cerebral intracellular pH and ratios of metabolites including ATP/inorganic phosphate (Pi), phosphocreatine (PCr)/Pi, N-acetyl aspartate (NAA)/creatine (Cr), and lactate/Cr, before and during DKA treatment. We determined the effects of treatment with insulin and intravenous saline ± bumetanide, an inhibitor of Na-K-2Cl cotransport, using analysis of covariance with a 2 X 2 factorial study design.

Results: Cerebral intracellular pH was decreased during DKA compared to control (mean [± SE] difference = −0.13±0.03, p<0.001), and lactate/Cr was elevated (mean difference = 0.09±0.02, p<0.001). DKA rats had lower ATP/Pi and NAA/Cr (mean differences −0.32±0.10, p=0.003 and −0.14±0.04, p<0.001, respectively) compared to controls, but PCr/Pi was not significantly decreased. During two hours treatment with insulin/saline, ATP/Pi, PCr/Pi and NAA/Cr declined significantly, despite an increase in intracellular pH. Bumetanide treatment increased ATP/Pi and PCr/Pi, and ameliorated the declines in these values with insulin/saline treatment.

Conclusions: These data demonstrate that cerebral metabolism is significantly compromised during DKA, and further deterioration occurs during early DKA treatment, consistent with possible effects of cerebral hypoperfusion and “reperfusion injury”. Treatment with bumetanide may help to diminish the adverse effects of initial treatment with insulin/saline.


    • Received April 29, 2009.
    • Accepted December 9, 2009.

This Article

  1. Diabetes
  1. All Versions of this Article:
    1. db09-0635v1
    2. 59/3/702 most recent