March 2013
Volume 54, Issue 3
Letters to the Editor  |   March 2013
Retinal Neurovascular and Neuronal Dysfunction in Type 1 Diabetes
Author Affiliations & Notes
  • Jonathan E. Noonan
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia; and the
  • Chi D. Luu
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia; and the
  • Ryan E. K. Man
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia; and the
  • Ecosse L. Lamoureux
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, VIC, Australia; and the
    Singapore Eye Research Institute, National University of Singapore, Singapore.
Investigative Ophthalmology & Visual Science March 2013, Vol.54, 1838. doi:10.1167/iovs.13-11847
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      Jonathan E. Noonan, Chi D. Luu, Ryan E. K. Man, Ecosse L. Lamoureux; Retinal Neurovascular and Neuronal Dysfunction in Type 1 Diabetes. Invest. Ophthalmol. Vis. Sci. 2013;54(3):1838. doi: 10.1167/iovs.13-11847.

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      © ARVO (1962-2015); The Authors (2016-present)

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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. 1012 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. 
Lasta M Pemp B Schmidl D Neurovascular dysfunction precedes neural dysfunction in the retina of patients with type 1 diabetes. Invest Ophthalmol Vis Sci . 2013; 54: 842–847. [CrossRef] [PubMed]
Lecleire-Collet A Audo I Aout M Evaluation of retinal function and flicker light-induced retinal vascular response in normotensive patients with diabetes without retinopathy. Invest Ophthalmol Vis Sci . 2011; 52: 2861–2867. [CrossRef] [PubMed]
Luu CD Szental JA Lee S-Y Lavanya R Wong TY. Correlation between retinal oscillatory potentials and retinal vascular caliber in type 2 diabetes. Invest Ophthalmol Vis Sci . 2010; 51: 482–486. [CrossRef] [PubMed]
Moller A Eysteinsson T. Modulation of the components of the rat dark-adapted electroretinogram by the three subtypes of GABA receptors. Vis Neurosci . 2003; 20: 535–542. [CrossRef] [PubMed]
Yonemura D Aoki T Tsuzuki K. Electroretinogram in diabetic retinopathy. Arch Ophthalmol . 1962; 68: 19–24. [CrossRef] [PubMed]
Holopigian K Seiple W Lorenzo M Carr R. A comparison of photopic and scotopic electroretinographic changes in early diabetic retinopathy. Invest Ophthalmol Vis Sci . 1992; 33: 2773–2780. [PubMed]
Coupland SG. A comparison of oscillatory potential and pattern electroretinogram measures in diabetic retinopathy. Doc Ophthalmol . 1987; 66: 207–218. [CrossRef] [PubMed]
Metea MR Newman EA. Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J Neurosci . 2006; 26: 2862–2870. [CrossRef] [PubMed]
Newman EA. Calcium increases in retinal glial cells evoked by light-induced neuronal activity. J Neurosci . 2005; 25: 5502–5510. [CrossRef] [PubMed]
Garhofer G Zawinka C Resch H Kothy P Schmetterer L Dorner GT. Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. Br J Ophthalmol . 2004; 88: 887–890. [CrossRef] [PubMed]
Nguyen TT Kawasaki R Wang JJ Flicker light-induced retinal vasodilation in diabetes and diabetic retinopathy. Diabetes Care . 2009; 32: 2075–2080. [CrossRef] [PubMed]
Mandecka A Dawczynski J Vilser W Abnormal retinal autoregulation is detected by provoked stimulation with flicker light in well-controlled patients with type 1 diabetes without retinopathy. Diabetes Res Clin Pract . 2009; 86: 51–55. [CrossRef] [PubMed]

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