Reversal of hyperglycemic-induced defects in myo-inositol metabolism and Na+/K+ pump activity in cultured neuroblastoma cells by normalizing glucose levels.
myo-Inositol accumulation and incorporation into phosphoinositides was decreased in neuroblastoma cells chronically exposed to medium containing 30 mmol/L glucose or 30 mmol/L galactose. In addition, the intracellular content of myo-inositol and phosphatidylinositol was decreased and the sorbitol or galactitol content increased in cells cultured for 2 weeks in medium containing 30 mmol/L glucose or 30 mmol/L galactose, respectively. Na+/K+ adenosine triphosphatase (ATPase) transport activity was also significantly decreased by long-term exposure of neuroblastoma cells to medium containing 30 mmol/L glucose or 30 mmol/L galactose. When glucose-conditioned cells were placed in medium containing a normal glucose concentration for 24 hours, myo-inositol metabolism and content, phosphatidylinositol levels, and Na+/K+ pump activity were restored or completely returned to normal values. These functions were also significantly improved, except for the phosphatidylinositol content, which was increased by 55%, when galactose-conditioned cells were incubated for 24 hours in unsupplemented medium. The polyol content of the glucose- or galactose-conditioned cells was also significantly reduced. Returning the cells to normal glucose levels for 1 to 3 hours did not completely restore myo-inositol metabolism. Improved myo-inositol metabolism and content, sorbitol levels, and Na+/K+ ATPase transport activity were also obtained within 24 hours when cells chronically exposed to medium supplemented with 30 mmol/L glucose were placed in medium containing 30 mmol/L glucose and 0.4 mmol/L sorbinil. The phosphatidylinositol content of these cells was improved by approximately 30%. Cells prelabeled for 24 hours with [U-14C]sorbitol metabolize more than 50% of the [U-14C]sorbitol during a 24-hour incubation in unsupplemented medium. These studies conducted at the cellular level suggest that restoration of normal myo-inositol metabolism, polyol content, and Na+/K+ pump activity altered by hyperglycemic conditions occurs rapidly following normalization of glucose concentration.
Yorek
M A
MA
Department of Internal Medicine, Veterans Administration Medical Center, Iowa City, IA 52246.
Dunlap
J A
JA
Stefani
M R
MR
Davidson
E P
EP
D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D005690:Galactose / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009994:Osmolar Concentration; D012016:Reference Values; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D001786:Blood Glucose; D007294:Inositol; D013012:Sorbitol; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D005690:Galactose