Rod phototransduction and light signal transmission during type 2 diabetes

Abstract

IntroductionDiabetic retinopathy is a major complication of diabetes recently associated with compromised photoreceptor function. Multiple stressors in diabetes, such as hyperglycemia, oxidative stress and inflammatory factors, have been identified, but systemic effects of diabetes on outer retina function are incompletely understood. We assessed photoreceptor physiology in vivo and in isolated retinas to better understand how alterations in the cellular environment compared with intrinsic cellular/molecular properties of the photoreceptors, affect light signal transduction and transmission in the retina in chronic type 2 diabetes.Research design and methodsPhotoreceptor function was assessed in BKS.Cs-Dock7m+/+Lepr db/J mice, using homozygotes for Leprdb as a model of type 2 diabetes and heterozygotes as non-diabetic controls. In vivo electroretinogram (ERG) was recorded in dark-adapted mice at both 3 and 6 months of age. For ex vivo ERG, isolated retinas were superfused with oxygenated Ames’ media supplemented with 30 mM glucose or mannitol as iso-osmotic control and electrical responses to light stimuli were recorded.ResultsWe found that both transduction and transmission of light signals by rod photoreceptors were compromised in 6-month-old (n=9–10 eyes from 5 animals, ***p<0.001) but not in 3-month-old diabetic mice in vivo (n=4–8 eyes from 2 to 4 animals). In contrast, rod signaling was similar in isolated retinas from 6-month-old control and diabetic mice under normoglycemic conditions (n=11). Acutely elevated glucose ex vivo increased light-evoked rod photoreceptor responses in control mice (n=11, ***p<0.001), but did not affect light responses in diabetic mice (n=11).ConclusionsOur data suggest that long-term diabetes does not irreversibly change the ability of rod photoreceptors to transduce and mediate light signals. However, type 2 diabetes appears to induce adaptational changes in the rods that render them less sensitive to increased availability of glucose.

Diabetic photoreceptors: Mechanisms underlying changes in structure and function

“…Likewise, reduced photoreceptor amplitudes and delayed implicit times are observed in Ins2 Akita mice at 9 months, but not up to 6 months of age (Hombrebueno et al, 2014). Similarly, decreased photoreceptor amplitudes and delayed implicit times were previously observed at 12 weeks, but not at 8 weeks of age (Bogdanov et al, 2014) and at 6 months, but not at 3 months of age in db/db mice (Becker et al, 2020).…”

“…No changes in photoreceptor amplitude or implicit time were observed in a high fat diet model up to 12 months of age, although these mice displayed obesity, glucose intolerance and insulin resistance typically associated with pre-diabetes (Rajagopal et al, 2016). In fact, 13-week-old Zucker diabetic fatty rats and 3-month-old db/db mice are both reported to show increased amplitude and maximal slope of the photoreceptor response (Johnson et al, 2013;Becker et al, 2020), indicating augmented photoreceptor function, possibly due to increased availability of glucose in the absence of photoreceptor damage. While differences between and within the clinical data and various animal models of diabetes may appear complex, it is important to consider differences in glycemic control and disease duration, which likely greatly influence photoreceptor health.…”

“…These findings in patients with diabetes are complemented by studies in animal models of diabetes. We recently showed that while acute elevation of glucose augments rod photoreceptor function in nondiabetic mouse retinas, this effect is abrogated in retinas from diabetic db/db mice (Becker et al, 2020). Although these findings are in contrast to those in patients with diabetes, the discrepancies may be due to adaptations in uncontrolled diabetes in diabetic mice, but regulated glucose levels in human patients.…”

“…As noted above, acute hyperglycemia can in fact improve retinal light responses in both diabetic and nondiabetic subjects (Dawson et al, 2000;Klemp et al, 2004;Kurtenbach et al, 2006;Holfort et al, 2010a;Holfort et al, 2010b;Johnson et al, 2013;Becker et al, 2020). However, the development of persistent hyperglycemia is known to rapidly overwhelm glucose demand, causing glucose to be diverted away from its normal intracellular glycolytic function.…”

Two‐photon AMPK and ATP imaging reveals the bias between rods and cones in glycolysis utility

“…The photoreceptor component was isolated using the blocker cocktail as described previously. 30 Dim flash responses were periodically recorded for 70 min. In the control recordings, the response amplitude declined gradually, while the response waveform did not change (Figure 4B,C, WT rod control).…”