An increased capacity of the retina for glycolysis/lactate production, or a shift from oxidative metabolism to glycolysis, in the presence of high glucose could be called a Crabtree effect, which was first demonstrated in yeast. We argue that such a change may occur in diabetics and may explain the increase in [H
+]
o that we found here. However, the previous literature is complex because methods and rat strains have differed, so there is uncertainty about whether an increase in glycolysis in the retina occurs with acute or chronic hyperglycemia
17,20,21 or not.
5,18,22,23 Some in vitro experiments where increased glucose led to greater lactate production
20 have been challenged on the grounds that the initial level of glucose may not have been sufficient for normal metabolism,
22 even though bath levels of glucose were similar to those normally found in the blood. The diffusion limitation caused by unstirred layers in in vitro preparations frequently causes substrate concentrations at the tissue to be lower than in the bath, so the “control” condition may have been partial starvation and the “high” glucose condition was not really high. Other work, in which concentrations of lactate rather than rates of lactate production were measured, has been criticized because the isolation of the retina may have been slow enough that hypoxia, rather than a Crabtree effect, caused the increased glycolysis. Ola et al.,
18 who found no dependence of lactate production or retinal lactate concentration on glucose in control or diabetic Sprague-Dawley rats, argued that hypoxia may have distorted the data of Heath et al.
21 and was responsible for the higher retinal lactate-to-pyruvate concentration ratio (L/P) that Heath et al.
21 found in normal animals (21 ± 2.9 in Heath et al.
21 and 17.1 ± 0.9 in Ola et al.
18). But if the control and diabetic rats were treated similarly during experiments, then some component of any increase in the L/P ratio could have been due to hypoxia, but a difference between control and diabetic groups would have been due to diabetes. This difference between groups was substantial. Heath et al.
21 found that after 3 weeks on a starch diet, diabetic Wistar rats had 40% higher retinal lactate and 52% higher retinal L/P than control rats. The results of Salceda et al.
17 in diabetic Long-Evans rats were similar at a similar time point.
17 A further complication is that lactate concentrations and L/P ratios do not necessarily reflect metabolic rates, and it is possible that higher L/P in diabetics resulted from a reduced ability of the retina to clear lactate. Significantly, plasma lactate increased by 100% in the diabetics in the study by Heath et al.,
21 so the energetics of moving lactate from the retina to the blood would have been less favorable and lactate transport could have been reduced. We did not measure blood lactate; however, the blood acidified equally during hyperglycemia in our control and diabetic rats, so we do not believe that blood lactate in our diabetic animals could have been much higher than in controls. We conclude that there is evidence for a Crabtree effect that takes time to develop, but that it may be small and therefore difficult to measure directly, and it may vary among rat strains. With pH recordings, we can see that most of the increased [H
+]
o comes from the outer retina, whereas all the other studies referred to could not differentiate inner and outer retina. All these things may contribute to the divergence in results.