Acetoacetate and beta-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells

J Diabetes Complications. Mar-Apr 1999;13(2):91-7. doi: 10.1016/s1056-8727(99)00030-6.


Insulin-dependent diabetes mellitus (IDDM), is characterized by a lack of insulin production from beta cells in the pancreas. One of the metabolic consequences of this insulin deficit is an increased hepatic synthesis of ketone bodies, resulting in a serious medical complication, diabetic ketoacidosis (DKA). DKA, in turn, has been associated with the development of cerebral edema. The severity of this complication ranges from death to a subclinical presentation, but seems to be invariably present to some degree. The etiology of the cerebral edema is unknown, but changes in osmolality, pH, and insulin effects on the blood-brain barrier have all been suggested as possible culprits. Blood-brain barrier impermeability is maintained by the endothelial cells (EC) lining the blood vessels. Thus, it would seem likely that alterations in EC function would be necessary for the development of cerebral edema. However, no studies have examined the effects of ketone bodies on brain endothelial cells. The two major ketone bodies in DKA are acetoacetate (AcAc) and beta-hydroxybutyrate (BOHB). In the present study we examined the effect of these ketone bodies on a major intracellular signalling pathway. The changes in intracellular calcium concentration, and the production of two vasoactive peptides, endothelin-1 (ET-1) and vascular permeability factor (VPF/VEGF) in mouse brain microvascular endothelial cells (MBMEC). The present studies demonstrate the BOHB can increase vascular permeability factor. In contrast, AcAc increases the production of the potent vasoconstrictor, endothelin-1. This data would suggest that brain ECs are potential targets of the metabolic alterations in DKA.

Publication types

  • Comparative Study

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Acetoacetates / pharmacology*
  • Animals
  • Blotting, Western
  • Brain / metabolism*
  • Brain Edema / etiology*
  • Calcium / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / complications
  • Diabetic Ketoacidosis / metabolism*
  • Endothelial Growth Factors / biosynthesis*
  • Endothelin-1 / biosynthesis*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Lymphokines / biosynthesis*
  • Mice
  • Protein Isoforms
  • Time Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Acetoacetates
  • Endothelial Growth Factors
  • Endothelin-1
  • Lymphokines
  • Protein Isoforms
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • acetoacetic acid
  • Calcium
  • 3-Hydroxybutyric Acid