New aspects of lactate metabolism: IGF-I and insulin regulate mitochondrial function in cultured brain cells during normoxia and hypoxia.
Using 13C nuclear magnetic resonance spectroscopy in combination with conventional biochemical techniques, effects of insulin and IGF-I on energy metabolism and cell viability were studied in cerebral cortical neurons, astrocytes and cocultures thereof during normoxia and hypoxia. Lactate dehydrogenase leakage was used to monitor the cytoprotective effects of IGF-I and insulin. Thus, during normoxia both peptides decreased LDH leakage from neurons. During hypoxia, however, this protection was only observed when insulin was present. Interestingly, neurons showed much less LDH leakage during hypoxia than astrocytes or cocultures. A possible explanation could be an increased glycolysis in neurons. Thus, lactate production and glucose consumption were increased severalfold in neurons during hypoxia whereas astrocytes and cocultures only showed a slight increase. Both insulin and IGF-I increased glucose metabolism during normoxia in astrocytes but not in neurons, whereas during hypoxia this increase was less pronounced. Using [1-13C]glucose it could be demonstrated that production of lactate from mitochondrial precursors was, in the presence of insulin or IGF-I, down regulated in astrocytes but increased in neurons during normoxia. This route for lactate production was not used during hypoxia and incorporation into the C-3 position of lactate approached the theoretical maximum of 50%.
Sonnewald
U
U
MR-Center, SINTEF UNIMED, Trondheim, Norway.
Wang
A Y
AY
Schousboe
A
A
Erikson
R
R
Skottner
A
A
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012016:Reference Values
D007328:Insulin; D019344:Lactic Acid; D007334:Insulin-Like Growth Factor I; D007770:L-Lactate Dehydrogenase; D005947:Glucose