Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia

Abstract

Hypoglycemia occurs frequently during intensive insulin therapy in patients with both type 1 and type 2 diabetes and remains the single most important obstacle in achieving tight glycemic control. Using a rodent model of hypoglycemia, we demonstrated that exposure to antecedent recurrent hypoglycemia leads to adaptations of brain metabolism so that modest increments in circulating lactate allow the brain to function normally under acute hypoglycemic conditions. We characterized 3 major factors underlying this effect. First, we measured enhanced transport of lactate both into as well as out of the brain that resulted in only a small increase of its contribution to total brain oxidative capacity, suggesting that it was not the major fuel. Second, we observed a doubling of the glucose contribution to brain metabolism under hypoglycemic conditions that restored metabolic activity to levels otherwise only observed at euglycemia. Third, we determined that elevated lactate is critical for maintaining glucose metabolism under hypoglycemia, which preserves neuronal function. These unexpected findings suggest that while lactate uptake was enhanced, it is insufficient to support metabolism as an alternate substrate to replace glucose. Lactate is, however, able to modulate metabolic and neuronal activity, serving as a "metabolic regulator" instead.

Insights from Neuroenergetics into the Interpretation of Functional Neuroimaging: An Alternative Empirical Model for Studying the Brain's Support of Behavior

“…1,20 13 C Magnetic resonance spectroscopy measurements of the relationship between the glutamate/glutamine cycle and neuronal glucose oxidation To determine the energetic cost of brain function 13 C MRS studies have been performed in rats over a wide range of activities from isoelectric pentobarbital anesthesia under which there is no cortical signaling to awake states with high levels of cortical signaling. The original results by Sibson et al 24 have been reproduced in several laboratories, 25-38 demonstrating a tight correlation between V cycle and CMR glc(ox),N (Figure 2; see Supplementary Table 1 for both rat [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] and human 23,40-52 results). This neurometabolic coupling in the rat somatosensory cortex spanning awake to deeply anesthetized conditions has several consequences.…”

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

“…36 All of these studies point to an increased ability of the brain to sustain its metabolic needs following recurrent hypoglycemia.…”

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…61 Lactate infusions that caused only a small increase in brain lactate metabolism were found to result in maintenance of brain glucose metabolism during subsequent hypoglycemia in rats subjected to recurrent hypoglycemia. 62 …”