Glutamate Metabolism Is Coupled to Lactate Production from Astrocytes under Low-GlucoseGlucose Conditions

Recurrent hypoglycemia (RH) results in elevated lactate levels in the ventromedial hypothalamus that impair the counter-regulatory responses to hypoglycemia. While the mechanisms that enhance lactate production are not clear, our previous data suggests that astrocytic glycogen is the major source of lactate resulting from RH. A number of different inputs regulate glycogen turnover in astrocytes and the interaction between metabolic and neurotransmitter signals may alter glycogenolytic capacity and ultimately, lactate production. The current study investigates how the interaction between norepinephrine and glutamate influence lactate production from astrocytes in the setting of hypoglycemia. We cultured primary rat astrocytes in normal (2.5mM) and low (0.1mM) glucose medium in the presence and absence of norepinephrine and/or glutamate for 3 hours and quantified lactate in the culture media. We also examined the contribution of glutamate oxidation using the glutamate dehydrogenase inhibitor, hexachlorophene. Our data indicates that under low glucose conditions, glutamate alone dramatically enhances lactate production in astrocytes compared to controls (P<0.0001). Of note, the inhibition of glutamate oxidation also increased lactate secretion, but not to the same extent as glutamate alone (P<0.01). In contrast, the addition of norepinephrine and glutamate significantly reduced lactate secretion (P<0.05). Our data suggests that glutamate uptake during acute hypoglycemia likely plays a large role in driving astrocytic lactate production, a metabolic deficit that is offset by the oxidation of glutamate and by norepinephrine. In conclusion, our data suggests that under low glucose conditions, the metabolism of glutamate is tightly coupled to lactate production in astrocytes. Disclosure D. A. Appadurai: None. O. Chan: None. Funding National Institutes of Health (DK099315)