PURPOSE. Electroretinograms (ERGs) are abnormal in diabetic retinas before the appearance of vascular lesions, providing a possible biomarker for diabetic vision loss. Previously, we reported that decreased retinal dopamine (DA) levels in diabetic rodents contributed to early visual and retinal dysfunction. In the current study, we examined whether oscillatory potentials (OPs) could serve as a potential marker for detecting early inner retinal dysfunction due to retinal DA deficiency. METHODS. Retinal function was tested with dark-adapted ERGs, taken at 3, 4, and 5 weeks after diabetes induction with streptozotocin. Electrical responses were analyzed and correlations were made with previously reported retinal DA levels. The effect of restoring systemic DA levels or removing DA from the retina in diabetic mice on OPs was assessed using L-3,4-dihydroxyphenylalanine (L-DOPA) treatments and retina-specific tyrosine hydroxylase (Th) knockout mice (rTHKO), respectively. RESULTS. Diabetic animals had significantly delayed OPs compared to control animals in response to dim, but not bright, flash stimuli. L-DOPA treatment preserved OP implicit time in diabetic mice. Diabetic rTHKO mice had further delayed OPs compared to diabetic mice with normal retinal Th, with L-DOPA treatment also providing benefit. Decreasing retinal DA levels significantly correlated with increasing OP delays mediated by rod pathways. CONCLUSIONS. Our data suggest that inner retinal dysfunction in early-stage diabetes is mediated by rod-pathway deficits and DA deficiencies. OP delays may be used to determine the earliest functional deficits in diabetic retinopathy and to establish an early treatment window for DA therapies that may prevent progressive vision loss.
PURPOSE. Electroretinograms (ERGs) are abnormal in diabetic retinas before the appearance of vascular lesions, providing a possible biomarker for diabetic vision loss. Previously, we reported that decreased retinal dopamine (DA) levels in diabetic rodents contributed to early visual and retinal dysfunction. In the current study, we examined whether oscillatory potentials (OPs) could serve as a potential marker for detecting early inner retinal dysfunction due to retinal DA deficiency. METHODS. Retinal function was tested with dark-adapted ERGs, taken at 3, 4, and 5 weeks after diabetes induction with streptozotocin. Electrical responses were analyzed and correlations were made with previously reported retinal DA levels. The effect of restoring systemic DA levels or removing DA from the retina in diabetic mice on OPs was assessed using L-3,4-dihydroxyphenylalanine (L-DOPA) treatments and retina-specific tyrosine hydroxylase (Th) knockout mice (rTHKO), respectively. RESULTS. Diabetic animals had significantly delayed OPs compared to control animals in response to dim, but not bright, flash stimuli. L-DOPA treatment preserved OP implicit time in diabetic mice. Diabetic rTHKO mice had further delayed OPs compared to diabetic mice with normal retinal Th, with L-DOPA treatment also providing benefit. Decreasing retinal DA levels significantly correlated with increasing OP delays mediated by rod pathways. CONCLUSIONS. Our data suggest that inner retinal dysfunction in early-stage diabetes is mediated by rod-pathway deficits and DA deficiencies. OP delays may be used to determine the earliest functional deficits in diabetic retinopathy and to establish an early treatment window for DA therapies that may prevent progressive vision loss.
Purpose
To evaluate the utility of low luminance stimuli to functionally probe inner retinal rod pathways in the context of diabetes mellitus in both rat and human subjects.
Methods
Inner retinal dysfunction was assessed using oscillatory potential (OP) delays in diabetic rats. Scotopic electroretinograms (ERGs) in response to a series of increasing flash luminances were recorded from streptozotocin (STZ)-treated and control Sprague-Dawley rats after 7, 14, 20, and 29 weeks of hyperglycemia. We then evaluated OP delays in human diabetic subjects with (DR) and without (DM) diabetic retinopathy using the International Society for Clinical Electrophysiology in Vision (ISCEV) standard scotopic protocol and two additional dim test flashes.
Results
Beginning 7 weeks after STZ, OP implicit times in diabetic rats were progressively delayed in response to dim, but not bright stimuli. In many diabetic subjects the standard ISCEV dim flash failed to illicit measureable OPs. However, OPs became measurable using a brighter, nonstandard dim flash (Test Flash 1, −1.43 log cd s/m2), and exhibited prolonged implicit times in the DM group compared with control subjects (CTRL).
Conclusions
Delays in scotopic OP implicit times are an early response to hyperglycemia in diabetic rats. A similar, inner retinal, rod-driven response was detected in diabetic human subjects without diabetic retinopathy, only when a nonstandard ISCEV flash intensity was employed during ERG testing.
Translational Relevance
The addition of a dim stimulus to standard ISCEV flashes with assessment of OP latency during ERG testing may provide a detection method for early retinal dysfunction in diabetic patients.
Diabetic retinopathy (DR) is diagnosed clinically by directly viewing retinal vascular changes during ophthal-moscopy or through fundus photographs. However, electroretinography (ERG) studies in humans and rodents have revealed that retinal dysfunction is demonstrable prior to the development of visible vascular defects. Specifically, delays in dark-adapted ERG oscillatory potential (OP) implicit times in response to dim-flash stimuli (<21.8 log cd $ s/m2) occur prior to clinically recognized DR. Animal studies suggest that retinal dopamine deficiency underlies these early functional deficits. In this study, we randomized individuals with diabetes, without clinically detectable retinopathy, to treatment with either low-or high-dose Sinemet (levodopa plus carbidopa) for 2 weeks and compared their ERG findings with those of control subjects (no diabetes).
We assessed dim-flash–stimulated OP delays using a novel handheld ERG system (RETeval) at baseline and 2 and 4 weeks. RETeval recordings identified significant OP implicit time delays in individuals with diabetes without retinopathy compared with age-matched control subjects (P < 0.001). After 2 weeks of Sinemet treatment, OP implicit times were restored to control values, and these improvements persisted even after a 2-week washout. We conclude that detection of dim-flash OP delays could provide early detection of DR and that Sinemet treatment may reverse retinal dysfunction.
Purpose.
Although diabetic retinopathy (DR) is clinically diagnosed based on vascular pathology, diabetic patients with angiographically normal retinas have been found to exhibit subtle defects in vision. This has led to the theory that diabetes-associated metabolic abnormalities directly impair neural retinal function before the development of vasculopathy, thereby resulting in visual deficits. In this study, we sought to delineate the temporal relationship between retinal dysfunction and visual deficits in a rat model of Type 1 diabetes. Moreover, we investigated the relative contribution of retinal dysfunction versus diabetes-induced lens opacity, to the visual deficits found in early-stage DR.
Methods.
Pigmented Long Evans rats were rendered diabetic with streptozotocin (STZ). Control and diabetic rats were assessed across 12 weeks of hyperglycemia for visual function with optokinetic tracking weekly visual acuity and monthly contrast sensitivity, retinal function with dark-adapted electroretinograms (monthly electroretinograms [ERGs]), and cataract formation with slit lamp exam (biweekly).
Results.
Diabetic rats exhibited significantly reduced visual function and delayed ERG responses by 1 month post-STZ. Significant cataracts did not develop until 6 weeks post-STZ. Moreover, increases in lens opacity (r = −0.728) and ERG implicit times (r = −0.615 for rod-dominated response and r = −0.322 for rod/cone mixed response) showed significant correlations with reductions in visual acuity in diabetic rats.
Conclusions.
STZ-induced hyperglycemia reduces visual function, affecting both visual acuity and contrast sensitivity. The data suggest that visual defects found in early-stage DR may initially involve abnormalities of the neural retina and worsen with later development of cataracts.
Purpose
To evaluate the utility of low luminance stimuli to functionally probe inner retinal rod pathways in the context of diabetes mellitus in both rat and human subjects.
Methods
Inner retinal dysfunction was assessed using oscillatory potential (OP) delays in diabetic rats. Scotopic electroretinograms (ERGs) in response to a series of increasing flash luminances were recorded from streptozotocin (STZ)-treated and control Sprague-Dawley rats after 7, 14, 20, and 29 weeks of hyperglycemia. We then evaluated OP delays in human diabetic subjects with (DR) and without (DM) diabetic retinopathy using the International Society for Clinical Electrophysiology in Vision (ISCEV) standard scotopic protocol and two additional dim test flashes.
Results
Beginning 7 weeks after STZ, OP implicit times in diabetic rats were progressively delayed in response to dim, but not bright stimuli. In many diabetic subjects the standard ISCEV dim flash failed to illicit measureable OPs. However, OPs became measurable using a brighter, nonstandard dim flash (Test Flash 1, −1.43 log cd s/m2), and exhibited prolonged implicit times in the DM group compared with control subjects (CTRL).
Conclusions
Delays in scotopic OP implicit times are an early response to hyperglycemia in diabetic rats. A similar, inner retinal, rod-driven response was detected in diabetic human subjects without diabetic retinopathy, only when a nonstandard ISCEV flash intensity was employed during ERG testing.
Translational Relevance
The addition of a dim stimulus to standard ISCEV flashes with assessment of OP latency during ERG testing may provide a detection method for early retinal dysfunction in diabetic patients.