Retinal Neurovascular and Neuronal Dysfunction in Type 1 Diabetes

Introduction

We read with interest the article by Lasta and associates, “Neurovascular dysfunction precedes neural dysfunction in the retina of patients with type 1 diabetes.” ¹ The authors found that flicker light–induced retinal vasodilation and blood velocity were reduced in people with well-controlled type 1 diabetes compared with healthy controls. No significant differences in the amplitude and implicit time of the pattern electroretinogram (PERG) P50 and N95 responses were found between the two groups. The authors concluded that impaired neurovascular coupling in the retina of patients with type 1 diabetes, characterized by reduced vasodilation and blood velocity during light stimulation compared with nondiabetic subjects, may occur in the absence of neuronal dysfunction. 

The authors used a similar methodology as Lecleire-Collet and coworkers, ² who found a moderate correlation between light-induced arteriolar vasodilation, and PERG N95 amplitudes (r = −0.27) and implicit times (r = −0.35). However, the PERG reduction found in the study by Lecleire-Collet et al. needs to be interpreted with caution due to the presence of outer retinal dysfunction in their subjects as shown by a reduction in the full-field ERG and the PERG P50 response. Although the N95 component of the PERG reflects the activity of the inner retinal neurons, its amplitude is also reduced if outer retinal dysfunction is present. To compensate for the outer retinal neuronal contribution, an N95/P50 amplitude ratio is commonly used, but it was not analyzed in this study. 

The authors implied that PERG responses in diabetic subjects might indicate normal neuronal function; however, the current evidence suggests that PERG is not the most sensitive test to detect functional changes in the early stages of diabetes or diabetic retinopathy. Our group and others have shown that the oscillatory potential (OP) is sensitive in detecting changes in the retinal circulation, ^3,4 and OP abnormality has been reported to occur early in the diabetic eye before retinopathy is detected clinically. ^5,6 In addition, the OP has been shown to be more sensitive than PERG in detecting functional changes in patients with background diabetic retinopathy. ⁷ Thus, we suggest that OP analysis would be preferable to PERG to investigate the role of neurons in neurovascular dysfunction in human diabetes studies. 

The N95 component of the PERG is derived largely from the retinal ganglion cells; however, we wish to point out that ganglion cells may not be essential for neurovascular coupling in the retina. Previous studies in rats have shown that glial cells are critical mediators of light-induced arteriolar vasomotor responses, and action potential blockade with tetrodotoxin prevents light-induced glial calcium increases. ^8,9 Because action potentials can be generated only by ganglion and amacrine cells in the retina, it is also possible that amacrine cells could mediate neurovascular coupling without a significant contribution from ganglion cells. 

Reduced vasodilation to light has been well described in diabetes and occurs before the onset of typical diabetic retinopathy lesions. ^10–12 The extent to which this process reflects neuronal, vascular, or glial dysfunction remains a controversial subject. At best, the results of the present study indicate that neurovascular dysfunction in early and well-controlled type 1 diabetes is not due to ganglion cell dysfunction. We do not believe it is possible to draw accurate conclusions on the role of other neurons from the results of this study.