Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise

Abstract

We studied the role of lactate in gluconeogenesis (GNG) during exercise in untrained fasting humans. During the final hour of a 4-h cycle exercise at 33-34% maximal O 2 uptake, seven subjects received, in random order, either a sodium lactate infusion (60 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or an isomolar sodium bicarbonate infusion. The contribution of lactate to gluconeogenic glucose was quantified by measuring 2 H incorporation into glucose after body water was labeled with deuterium oxide, and glucose rate of appearance (Ra) was measured by [6,6-2 H2]glucose dilution. Infusion of lactate increased lactate concentration to 4.4 Ϯ 0.6 mM (mean Ϯ SE). Exercise induced a decrease in blood glucose concentration from 5.0 Ϯ 0.2 to 4.2 Ϯ 0.3 mM (P Ͻ 0.05); lactate infusion abolished this decrease (5.0 Ϯ 0.3 mM; P Ͻ 0.001) and increased glucose Ra compared with bicarbonate infusion (P Ͻ 0.05). Lactate infusion increased both GNG from lactate (29 Ϯ 4 to 46 Ϯ 4% of glucose Ra, P Ͻ 0.001) and total GNG. We conclude that lactate infusion during low-intensity exercise in fasting humans 1) increased GNG from lactate and 2) increased glucose production, thus increasing the blood glucose concentration. These results indicate that GNG capacity is available in humans after an overnight fast and can be used to sustain blood glucose levels during low-intensity exercise when lactate, a known precursor of GNG, is available at elevated plasma levels. lactate; hyperlactatemia; stable isotopes GLUCONEOGENESIS (GNG) is regulated by hormones (such as glucagon and insulin) and requires three-carbon substrates, i.e., pyruvate (from lactate and alanine) or glycerol. The relationship among substrate availability, the rate of GNG, and the concentration of the product, glucose, in the blood is not yet fully understood. Increased lactate concentration in blood is known to occur in a number of metabolic disorders, e.g., respiratory chain disorders, pyruvate dehydrogenase deficiency, and diabetes mellitus (13). The role of GNG under the condition of increased substrate availability in these disorders is of pathophysiological interest. In patients with a respiratory chain disorder, plasma lactate concentrations are substantially increased at low-intensity levels of exercise (35,36); in patients with mitochondrial myopathy due to complex I deficiency, we observed steady-state plasma lactate concentrations of between 4 and 7 mM during prolonged low-intensity cycle exercise at 15% of their maximal workload (W max ). Their mean lactate rate of appearance (R a ) was 73 Ϯ 12 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 during exercise, which was more than double their resting lactate R a (35,36). In another low-intensity exercise study in mitochondrial myopathy patients with complex I deficiency during fasting, plasma lactate concentrations increased from 1 mM at rest to ϳ4 mM during exercise and were associated with an increased fractional contribution of lactate to glucose production as well as increased rates of glucose production (37).In healthy human subjects in the resting condition...

Fructose and glucose co-ingestion during prolonged exercise increases lactate and glucose fluxes and oxidation compared with an equimolar intake of glucose

“…Increased lactate availability, produced by exogenous lactate infusion, increases fractional (42,43) and total gluconeogenesis from lactate (GNG L ) during prolonged exercise in fasted conditions (43). In contrast, our results show that GNG L was very low, most likely as a consequence of carbohydrate intake and suppression of gluconeogenesis by hyperinsulinemia (44), although our subjects were well trained and had high GNG capacity (27).…”

Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors

“…Interestingly, MCT1 expressed in red oxidative muscle fibres will in turn facilitate the uptake of lactate which will be used after conversion into pyruvate as an alternate carbohydrate fuel source (6,7). Similar lactate exchange and uptake through MCT1 is reported in the heart (8), red blood cells (9), and even in the liver, to support gluconeogenesis (10). Within tumors also, we and others recently documented that cancer cells could import lactate through MCT1 from the most glycolytic tumor cells (11)(12)(13)(14) or tumor-associated fibroblasts (15,16) to fuel mitochondrial respiration and thereby spare glucose for hypoxic tumor cells.…”

Hypoxia stimulates lactate disposal in rainbow trout

“…More research will be needed to show whether this same mechanism also activates gluconeogenesis in fish. Finally, it has been demonstrated that high blood lactate concentration (maintained via a lactate clamp) stimulates gluconeogenesis in exercising humans ( Roef et al, 2003). Overall, therefore, the increase in R d lactate observed in trout is probably jointly supported by an increase in lactate oxidation caused by a switch in fuel preference and by the activation of gluconeogenesis that might be required to sustain glucose supply to the nervous system.…”