Lactate-Protected Hypoglycemia (LPH)

Abstract

Here, we provide an overview of the concept of a lactate-protected hypoglycemia ("LPH"), originally proposed as lowering glucose while simultaneously increasing lactate concentration as a method by which tumors might be targeted. Central to this hypothesis is that lactate can act as a critical salvage fuel for the central nervous system, allowing for wide perturbations in whole body and central nervous system glucose concentrations. Further, many tumors exhibit "the Warburg" effect, consuming glucose and producing and exporting lactate despite adequate oxygenation. While some recent data have provided evidence for a "reverse-Warburg," where some tumors may preferentially consume lactate, many of these experimental methods rely on a significant elevation in lactate in the tumor microenvironment. To date it remains unclear how various tumors behave in vivo, and how they might respond to perturbations in lactate and glucose concentrations or transport inhibition. By exploiting and targeting lactate transport and metabolism in tumors (with a combination of changes in lactate and glucose concentrations, transport inhibitors, etc.), we can begin developing novel methods for targeting otherwise difficult to treat pathologies in the brain and spinal cord. Here we discuss evidence both experimental and observational, and provide direction for next steps in developing therapies based on these concepts.

Keywords: hyperlactatemia; hypoglycemia; lactate; lactate dehydrogenase; monocarboxylate transporter; shuttle.

FIGURE 1

During normal conditions (A,B), circulating glucose is taken up by normal (A) and tumor (B) cells, with tumor cells being more glucose-avid (represented by the thicker black line denoting glucose from blood to the cell) and exporting more lactate (represented by the thicker black line denoting lactate from cell to blood). Note the relative increase in ATP production from glycolysis in tumor cells and the concomitant slightly less ATP from oxidative phosphorylation (represented by size of ATP in box). During lactate-protected hypoglycemia (LPH) (C,D), circulating glucose is dramatically lowered and glucose uptake into both normal (C) and tumor (D) cells is impaired (dotted lines from blood to cell glucose). At the same time hyperlactatemia serves as a salvage fuel for normal cells, while tumor cells, accustomed to lactate export, have a less robust ability to import and use lactate. Note decreased ATP production via glycolysis from both cells with an increase in oxidative phosphorylation ATP production from lactate import in normal cells and an overall impaired ATP production from tumor cells. Note that LPH alone, while elegant in its use of lactate as a salvage fuel for the CNS, may prove to be problematic as tumor cells may adjust and begin taking up lactate when (1) glucose becomes limiting, and/or (2) lactate becomes abundant. Further, MCT expression profiles in tumors often differ when compared to non-tumor tissues, suggesting that the use of LPH in conjunction with selective targeting of tumor MCTs may be more effective than LPH alone.

FIGURE 2

In anesthetized canines, hypoglycemia without a salvage fuel is not well tolerated (A); isoelectric brain death is seen around 30 min after hypoglycemia. When lactate is provided as a salvage fuel (B), brain activity is maintained for 6–8 h after hypoglycemia induction. Note the difference in scale of the X and Y axes of the two figures. Used with permission from Ferguson et al. (2018).