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Acute Hypoglycemia Decreases Central Retinal Function in the Human Eye
Abstract
The goal of this pilot study was to assess the effects of acute hypoglycemia on retinal function and contrast sensitivity in individuals with and without diabetes. Hyperinsulinemic hypoglycemic and euglycemic clamp procedures were performed in subjects without diabetes (n=7) and with controlled type 1 diabetes (n=5). Mean age was 28 years, and none had retinal disease. During euglycemia (glucose 95-110 mg/dl) and acute hypoglycemia (glucose 50-55 mg/dl), contrast sensitivity was measured and spatial retinal responses were recorded with multifocal electroretinograms (mfERG), a rapid technique for mapping sensitivity from the foveal, macular and peripheral areas of the retina. During hypoglycemia, retinal responses (mfERG P1 wave) were decreased in both type 1 diabetes subjects and subjects without diabetes. The dominant effect was in the amplitude of the responses in the central macular retina, not in their temporal properties. Responses from the central region, central 10(0), were on average 1.8-fold lower than those from the periphery for both groups. All diabetes subjects and 3/7 without diabetes reported central scotoma. Decreases in mfERG amplitude were accompanied by decreases in contrast sensitivity. These changes were immediately reversed with the restoration of euglycemia. Overall, this study demonstrates that the acute effects of hypoglycemia in the human eye predominantly involve central vision, and these visual effects originate, at least in part, in the retina. The association between low blood glucose levels and impaired central vision underscores the importance of avoiding when possible and promptly treating hypoglycemia, particularly in individuals with diabetes.
... Chronic hyperglycaemia induces an adaptational response that tends to normalise retinal implicit time at a higher level of habitual glycemia (Klemp et al., 2005). During hypoglycaemia, mfERG was found to decrease, both in subjects with type 1 diabetes and subjects without diabetes (Khan et al., 2011). The dominant effect was in the amplitude of the responses in the central macular retina and not in their temporal properties (Khan et al., 2011). ...
... During hypoglycaemia, mfERG was found to decrease, both in subjects with type 1 diabetes and subjects without diabetes (Khan et al., 2011). The dominant effect was in the amplitude of the responses in the central macular retina and not in their temporal properties (Khan et al., 2011). Responses from the central region were approximately 1.8-fold lower than from the periphery for both groups (Khan et al., 2011). ...
... The dominant effect was in the amplitude of the responses in the central macular retina and not in their temporal properties (Khan et al., 2011). Responses from the central region were approximately 1.8-fold lower than from the periphery for both groups (Khan et al., 2011). ...
Multifocal electroretinogram (mfERG) is an important diagnostic tool in the clinical evaluation of central electro-retinal function of the macula. To enhance the diagnostic values and to improve its accuracy and internal consistency, it is crucial to examine carefully the endogenous and exogenous factors that affect mfERG recordings and clinical interpretations. This mini review focuses on three aspects of exogenous factors including (1) physiological variations pertaining to age and gender; (2) systemic changes owing to oxygen, blood pressure and glucose levels; (3) individual variables due to refractive status, pupil size, luminance and viewing condition.
... The retina is one of the major energy consuming tissues within the body, and its energetic source for normal functioning comes mainly from glucose metabolism. This necessity for glucose is evidenced by alteration in electroretinogram (ERG) responses and altered neurotransmitter release as described in ischemic and hypoglycemic conditions (Khan et al., 2011;Mukaida et al., 2004;Napper et al., 2001;Neal et al., 1994;Skrandies and Heinrich, 1992;Umino et al., 2006). Among the alterations observed after metabolic stress, reductions in GABA neuronal content could be noticed concomitant with a higher extracellular GABA availability and Müller cell localization (Napper et al., 2001;Osborne and Herrera, 1994;Zeevalk and Nicklas, 1991). ...
... Therefore, modifications in GABAergic signaling are observed in the context of DR whose pathophysiology is characterized by significant alterations in glucose supply to the retina. Moreover, recurrent hypoglycemic episodes are considered a worrying condition for insulin-treated diabetic patients' health, including retinal and visual deficits (Frier, 1993;Khan et al., 2011) and there is no evidence whether short-term and consecutive variations in glucose offering to the retina can modify GABAergic signaling. Although in vivo studies have evidenced modifications in retinal GABAergic signaling (Ishikawa et al., 1996;Kajiura et al., 1994;Vilchis and Salceda, 1996), they do not rule out the possibility of a vascular component. ...
... The knowledge that hypoglycemia and hyperglycemia severely impair diabetic patients' vision (Frier, 1993;Khan et al., 2011;Umino et al., 2006) calls the attention for the need of studies that help to elucidate DR pathogenesis. The present study contributes to this body of evidence and sheds light on the necessity to further investigate the early effects of glycemic disturbs. ...
... Type 1 diabetes mellitus (DM) is a chronic disease with decreased pancreatic insulin production caused by an auto immune reaction destroying the b-cells of the pancreas. The disease can progress sub-clinically for many years but is usually diagnosed before age 30 years [8]. The reduced ability of the body to control levels of blood glucose (glycemic control) can, over time, lead to many complications affecting major body organs including the cardiac and vascular systems, nervous system, visual system and kidneys [9]. ...
... The oscillatory potentials (OPs), a complex response that is thought to originate with the amacrine cells of the middle retina layers, seem to be particularly sensitive [14, 15]. Studies using the mfERG have revealed that changes to the retinal electrophysiology are spatially localised [16– 18], correlate with glycemic control [8, 19], and may predict areas that later develop clinically significant features of DR202122. The analysis techniques of these previously published studies required summarising the data. ...
... The analysis techniques of these previously published studies required summarising the data. In the spatial domain, this involved averaging rings, quadrants or zones of responses together [8, 16, 18], or selecting an exemplary, 'most abnormal', response from a spatial area212223. In the temporal domain, several techniques were used to reduce the data; several studies used a template-fitting algorithm that reduces the data to two values representing the amplitude and implicit times, respec- tively [17,19202122, other studies used signal-to-noise ratios that have the effect of reducing the entire waveform of interest to one value [16]. ...
Spatial-temporal partial least squares (ST-PLS) is a multivariate statistical analysis that has improved the analysis of modern imaging techniques. Multifocal electroretinograms (mfERGs) contain a large amount of data, and averaging and grouping have been used to reduce the amount of data to levels that can be handled using traditional statistical methods. In contrast, using all acquired data points, ST-PLS enables statistically rigorous testing of changes in waveform shape and in the distributed signal related to retinal function. We hypothesise that ST-PLS will improve analysis of the mfERG. Two mfERG protocols, a 103 hexagon clinical protocol and a slow-flash mfERG (sf-mfERG) protocol, were recorded from an adolescent population with type 1 diabetes and an age similar control population. The standard mfERGs were analysed using a template-fitting algorithm and the sf-mfERG using a signal-to-noise measure. The results of these traditional analysis techniques are compared with those of the ST-PLS analysis. Traditional analysis of the mfERG recordings revealed changes between groups for implicit time but not amplitude; however, the spatial location of these changes could not be identified. In contrast, ST-PLS detected significant changes between groups and displayed the spatial location of these changes on the retinal map and the temporal location within the mfERG waveforms. ST-PLS confirmed that changes to diabetic retinal function occur before the onset of clinical pathology. In addition, it revealed two distinct patterns of change depending on whether the multifocal paradigm was optimised to target outer retinal function (photoreceptors) or middle/inner retinal function (collector cells).
... Hypoketotic hypoglycemia, developed by patients having severely impaired β-oxidation of fatty acids (Taroni and Uziel, 1996) and 3-hydroxyacyl-CoA dehydrogenase deficiencies (Eaton et al., 2003;Tyni et al., 2004) have been reported to result in retinitis pigmentosa and peripheral neuropathy (Schrijver-Wieling et al., 1997;Tyni et al., 2004). Khan et al. (2011) showed that there is a close clinical effect of hypoglycemia on retinal function as detected by multifocal electroretinogram. This occurs in both normal subjects and those suffering from Type 1 diabetes, whereby, the central retina is preferentially affected (Khan et al., 2011). ...
... Khan et al. (2011) showed that there is a close clinical effect of hypoglycemia on retinal function as detected by multifocal electroretinogram. This occurs in both normal subjects and those suffering from Type 1 diabetes, whereby, the central retina is preferentially affected (Khan et al., 2011). In another study, Adijanto et al. (2014) referred to a novel metabolic coupling between the RPE and the photoreceptors, by which, the photoreceptor outer segment membrane components get recycled back into ketones, to be fed into the oxidative phosphorylation of the photoreceptors (Adijanto et al., 2014). ...
Derivatives of the vitamin riboflavin, FAD and FMN, are essential cofactors in a multitude of bio-energetic reactions, indispensable for lipid metabolism and also are requisites in mitigating oxidative stress. Given that a balance between all these processes contributes to the maintenance of retinal homeostasis, effective regulation of riboflavin levels in the retina is paramount. However, various genetic and dietary factors have brought to fore pathological conditions that co-occur with a suboptimal level of flavins in the retina. Our focus in this review is to, comprehensively summarize all the possible metabolic and oxidative reactions which have been implicated in various retinal pathologies and to highlight the contribution flavins may have played in these. Recent research has found a sensitive method of measuring flavins in both diseased and healthy retina, presence of a novel flavin binding protein exclusively expressed in the retina, and the presence of flavin specific transporters in both the inner and outer blood-retina barriers. In light of these exciting findings, it is even more imperative to shift our focus on how the retina regulates its flavin homeostasis and what happens when this is disrupted.
... Intensive systemic insulin therapy rescues retinal neurons from apoptosis in diabetic rats [6], and intensive metabolic control with systemic insulin therapy reduces the risk of the retinopathy and progression in diabetic human patients [7]. However, acute hypoglycemia induced by insulin treatment generally contributes to subsequent decline of visual function [8]. Due to rapid degradation rate of insulin, diabetic patients require daily injections of insulin, causing reduced quality of life. ...
... However, the device did not suppress the expression of PKC-β1 and VEGF. Acute hypoglycemia is known to affect visual function [8]. The blood glucose level in insulin-DDS-treated rats showed acute decrease at day 4 and the blood glucose level tended to be lower than in nontreated healthy rats [insulin DDS (STZ+), 63 (day 7) to 110 (day 28) mg/dL; non-treated (STZ−), 74 (day 7) to 153 (day 14) mg/dL], which might affect the retinal gene expression. ...
In this study, we developed a subcutaneous insulin-releasing device consisting of a disk-shaped capsule and drug formulation comprised of poly(ethylene glycol) dimethacrylates, then evaluated its efficacy on retinal function in streptozotocin (STZ)-induced diabetic rats. In vitro release studies showed that recombinant human insulin was released with a constant rate for more than 30 days. The device was able to maintain a basal level of blood glucose in diabetic rats for a prolonged period of more than 30 days, simultaneously preventing a decrease in body weight. For assessing the pharmacological effect of the device on retinal function in diabetic rats, electroretinograms were conducted for 12 weeks. The reduction in amplitude and delay in implicit time were attenuated by the device during the initial 4 weeks of application. The increase in gene expression of protein kinase C (PKC)-γ and caspase-3 in the diabetic retina was also attenuated by the device. Immunohistochemistry showed that the increase in glial fibrillary acidic protein expression in the diabetic retina was attenuated by the device. Histological evaluation of subcutaneous tissue around the device showed the biocompatibility of the device. In conclusion, the insulin-releasing device attenuated the reduction of retinal function in STZ-induced diabetic conditions for 4 weeks and the efficacy of the device might be partially related to PKC signaling in the retina. The long-term ability to control the blood glucose level might help to reduce the daily frequency of insulin injections.
... Future research should identify the adoption, use, and benefits of CGM in adults aged > 65. Hautala et al. [11] Longer duration of type 1 diabetes and poor glycemic management from childhood to young adulthood may contribute to visual impairment Fong et al. [12] Longer duration of diabetes is strong predictor of retinopathy Khan et al. [13] Retinal responses and central vision is impaired during episodes of hypoglycemia (glucose 50-55 mg/dL) Fine motor skills and falls ADA [5], Kimbro [14] Older adults with diabetes greater risk of depression, falls, and other geriatric syndromes Skeletal and muscular system problems, including frozen shoulder and trigger finger, are associated with type 1 and type 2 diabetes Pfützner et al. [18] Type 1 diabetes patients performed similar to healthy controls on hand dexterity Shah et al. [19] Greater fall frequency in older adults (age > 65) with type 1 diabetes compared with younger age group (age 55-64) Cognitive functioning ...
... In addition, longer type 1 diabetes duration is one of the strongest predictors of retinopathy [12]; thus, older adults with type 1 diabetes are already at great risk for visual impairment. Furthermore, older adults with type 1 diabetes are at increased risk of severe hypoglycemia, and episodes of hypoglycemia (50-55 mg/dL) negatively affect vision of people with type 1 diabetes [10,13]. The combination of these conditions can make it increasingly difficult to not only effectively treat low blood glucose but also deliver correct insulin doses for higher blood glucose levels. ...
Purpose of review:
Due to treatment advancements, individuals with type 1 diabetes (T1D) are living longer, presenting a unique understudied population with advanced complex needs. This article is a review of the aging literature in T1D and identifies existing gaps while serving as a call to the research community.
Recent findings:
Recent studies have identified an association between cognitive impairment and glycemic variability, as well as increased risk and frequency of hypoglycemia in older adults with T1D. However, limited research exists about additional physical and mental health conditions and barrier to successful treatment in this population. Older adults may experience both age- and diabetes-related barriers to diabetes management. Due to the scarcity of aging T1D research, current treatment guidelines for this age group are based on type 2 diabetes research. There is a critical need to further investigate the physical and mental effects of T1D and aging as well as public health policy; insurance challenges; and needs for support and interventions for older adults with T1D.
... Microvascular complications leading to nephropathy, cardiovascular diseases, neuropathy and retinopathy are serious consequences of both type I and II diabetes [1]. Diabetic retinopathy is generally linked to hyperglycemia [2], but recently we [3][4][5]and other [6][7][8][9][10] have described the key role of hypoglycemia in retinal visual dysfunction and cell death. There are several different causes of hypoglycemia, including inappropriate diet, irregular physical activity and unsuitable insulin treatment of diabetes. ...
... Diverse in vivo studies showed that chronic moderate hypoglycemia observed in glucagon receptor-deficient mice (Gcgr -/-) led to loss of vision and possible retinal degeneration [6], long-term exposure of this mouse model to carbohydrate diet normalized glycemia and partially restored retinal function [9]. In human, acute effect of hypoglycemia involve principally central vision [8] . More generally, Punzo et al. recently suggested that cone death in retinitis pigmentosa could be, at least in part, the result of the starvation of cones via the insulin/mTOR pathway [7]. ...
Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining "normal" GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.
... In earlier work using glucose-insulin clamp experiments, we demonstrated that acute hypoglycemia can affect central vision in individuals with normal glucose tolerance and diabetes mellitus (12). The current study was conducted to better understand the visual symptoms that e33 commonly occur during hypoglycemic episodes in patients with insulin-requiring diabetes mellitus in real-world ambulatory settings. ...
... Blood glucose monitoring device downloads were examined, and for those using a continuous glucose monitoring system (CGMS), downloads of the CGMS were performed. The survey used to record visual symptoms was adapted from Hepburn et al (13) and our earlier work (12). Participants were asked if they experienced blurred vision, dimness of vision, double vision, a black hole in the middle of their vision, black spots, floaters, loss of vision, or other visual symptoms, as well as questions concerning the presence of adrenergic and neuroglycopenic symptoms. ...
Objective: To recognize visual symptoms that occur during hypoglycemia to help patients avoid severe hypoglycemic events.
Methods: A series of adults with insulin-requiring diabetes were asked to complete questionnaires concerning visual symptoms during hypoglycemia (blood glucose <70 mg/dL). For patients using a continuous glucose monitoring system (CGMS), glucose levels during the time of symptoms were confirmed from downloads of their devices and meter readings when available. Pregnant women and those with an inability to complete the survey were excluded. Demographic information and type, duration, and complications of diabetes were obtained from medical record review.
Results: Participants (n = 107) were 68.6% female, with a mean age of 50.4 years, duration of diabetes of 9 to 46 years, 59.2% of participants had type 1 diabetes (39% pump users) and 22 participants were using CGMS (2 of these 22 participants were excluded because of incomplete data). Of the CGMS users, 75.0% had ≥1 visual symptom, and 86.6% had glucose levels <60 mg/dL with visual symptoms. Blurred vision was the most common visual symptom reported during hypoglycemia (73.3% of all participants and 65.0% using CGMS), followed by dimness of vision (44.7%), “black spots” (37.1%), central black hole (34.3%), double vision (15.3%), and transient complete loss of vision (2.8%). Time from onset to resolution of symptoms was less than 30 minutes in 80.0% of participants.
Conclusion: Visual symptoms are common during hypoglycemia but not widely appreciated. Blurred vision, common with hyperglycemia, is also seen during hypoglycemia. It is especially important for patients with poor hypoglycemic awareness to be educated to better recognize that changes in vision may indicate hypoglycemia.
... It requires constant supply of blood glucose to sustain its function and its energy demand is normally met through the uptake of glucose and oxygen [2,3]. Glucose movement across the blood-retinal barrier occurs mainly through the glucose transporter 1 (GLUT1) [4,5] and the need for glucose is evidenced by alterations in electroretinogram (ERG) responses and altered neurotransmitter release observed in hypoglycemic conditions [6,7,8]. It has been shown that acute hypoglycemia decreases rod and cone vision, blurs central vision, and produces temporary central scotomas in humans [6,[9][10][11]. ...
... Glucose movement across the blood-retinal barrier occurs mainly through the glucose transporter 1 (GLUT1) [4,5] and the need for glucose is evidenced by alterations in electroretinogram (ERG) responses and altered neurotransmitter release observed in hypoglycemic conditions [6,7,8]. It has been shown that acute hypoglycemia decreases rod and cone vision, blurs central vision, and produces temporary central scotomas in humans [6,[9][10][11]. The consequence of sustained hypoglycemia on retinal function is less clear. ...
The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod and cone photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin.
... This may reflect how retinal function became dependent on high glucose levels during chronic hyperglycemia. Clinical electrophysiological and psychophysical studies of retinal function in patients with diabetes[6],[7],[47]suggest that relative hypoglycemia (normoglycemia after prolonged hyperglycemia) may be comparable to hypoglycemia in a healthy subject[48]. In the normal retina, small reductions in glycemia have little effect on photoreceptoral activity, which is maintained by a balance between both glycolysis and oxidative phosphorylation[49],[50]. ...
... In the normal retina, small reductions in glycemia have little effect on photoreceptoral activity, which is maintained by a balance between both glycolysis and oxidative phosphorylation[49],[50]. In contrast, a diabetic retina appears not to utilize aerobic respiration to the same extent as a normal retina[51],[52],[48], perhaps due to a reduction in mitochondrial activity or number[53]. The prompt reduction of ZDF awave amplitudes in response to lowered glucose levels could reflect a similar shift in energy metabolism which rendered the retina abnormally dependent on glycolysis[51],[52]. ...
Purpose
Glucose concentrations are elevated in retinal cells in undiagnosed and in undertreated diabetes. Studies of diabetic patients suggest that retinal function adapts, to some extent, to this increased supply of glucose. The aim of the present study was to examine such adaptation in a model of type 2 diabetes and assess how the retina responds to the subsequent institution of glycemic control.
Methods
Electroretinography (ERG) was conducted on untreated Zucker diabetic fatty (ZDF) rats and congenic controls from 8–22 weeks of age and on ZDFs treated with daily insulin from 16–22 weeks of age. Retinal sections from various ages were prepared and compared histologically and by immunocytochemistry.
Principal Findings/Conclusions
Acute hyperglycemia did not have an effect on control rats while chronic hyperglycemia in the ZDF was associated with scotopic ERG amplitudes which were up to 20% higher than those of age-matched controls. This change followed the onset of hyperglycemia with a delay of over one month, supporting that habituation to hyperglycemia is a slow process. When glycemia was lowered, an immediate decrease in ZDF photoreceptoral activity was induced as seen by a reduction in a-wave amplitudes and maximum slopes of about 30%. A direct effect of insulin on the ERG was unlikely since the expression of phosphorylated Akt kinase was not affected by treatment. The electrophysiological differences between untreated ZDFs and controls preceded an activation of Müller cells in the ZDFs (up-regulation of glial fibrillary acidic protein), which was attenuated by insulin treatment. There were otherwise no signs of cell death or morphological alterations in any of the experimental groups. These data show that under chronic hyperglycemia, the ZDF retina became abnormally sensitive to variations in substrate supply. In diabetes, a similar inability to cope with intensive glucose lowering could render the retina susceptible to damage.
... This suggests that retinal health may not strongly correlate with awareness of hypoglycemia. This finding contrasts with the possibility raised by Khan et al. [28], who suggested that individuals with retinal disease might have greater sensitivity to hypoglycemia. Additionally, Singh et al. [29] reported that a significant percentage of study participants were aware of the link between diabetes and eye damage, including the risk of blindness. ...
Diabetes is considered one of the most prevalent endocrine metabolic diseases. Monitoring hypoglycemia unawareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycaemic event. This study aimed to evaluate the frequency of hypoglycemia unawareness and identify the factors contributing to its occurrence. A sample of 390 patients diagnosed with type 1 and type 2 diabetes was interviewed in an endocrine and diabetes center in Al-Ahsa city. Sociodemographic data, risk factors, and Clarke scores were used to evaluate the impairment of hypoglycemia awareness. Reduced awareness of hypoglycemia was found in 93 patients (23.8%). There were no statistically significant differences in the age of the patients, mean age of diagnosis, or cumulative glucose level between patients with awareness and those with reduced awareness (P > 0.05). Patients with type 2 diabetes mellitus (T2DM) showed significantly reduced awareness compared to type 1 diabetes (T1DM) (P = 0.038). Additionally, there were no statistically significant differences in hypoglycemia awareness between patients who underwent nephropathy screening and those who did not (P = 0.523). In conclusion, our study revealed reduced hypoglycemia awareness in 93 patients. However, there was no statistically significant difference related to various factors, including age and cumulative glucose levels. Patients with T2DM showed significantly lower hypoglycaemic awareness compared to patients with T1DM. Further research is needed to evaluate other factors of hypoglycemia unawareness.
... This latter parameter needs also to be considered in predicting retinopathy. There is a substantial body of evidence, although mainly from preclinical studies, linking this complication of diabetes to hypoglycemia [25][26][27]. ...
... Known diabetic microvascular complications have been identifed as aggravating factors due to hypoglycemia [10]. Studies in subjects with type 1 diabetes have documented that acute hypoglycemia decreases retinal responses to stimuli and increases retinal neurodegeneration [13,14]. In vivo studies evaluating the retinal vascular repercussion during an episode of acute hypoglycemia and after glucose normalization in subjects with and without diabetes have not, to our knowledge, been carried out. ...
Aim
To evaluate retinal vascular perfusion and density by optical coherence tomography angiography (OCTA) before, during, and after hypoglycemia in individuals with diabetes mellitus with or without diabetic retinopathy (DR).
Methods
A focused clinical history was performed, followed by an ophthalmological examination to document retinopathy status. OCTA was performed at baseline, at hypoglycemia, and at glucose normalization. Eye tracking and eye alignment devices on the platform were used to obtain a macular thickness cube (512 × 128) and vascular perfusion and density protocols of 3 × 3 mm. Retinal vascular reactivity was analyzed with superficial plexus vascular perfusion and density protocols on OCTA.
Results
Fifty-two participants encompassing 97 eyes fulfilled the eligibility criteria. Their mean age was 42.9 ± 15.1 years (range, 22 to 65), and 20 (38.2%) were men. We found a statistically significant difference in vascular perfusion and density when comparing all groups at baseline. The controls had higher vascular perfusion and density values than the cases. Vascular perfusion and density were significantly reduced in all groups during the hypoglycemia episode, except for vascular density in DR cases.
Conclusion
Acute hypoglycemia significantly alters the retinal vascularity in DM patients with and without DR, suggesting that repeated episodes of acute hypoglycemia could exacerbate retinopathy in the long term.
... Another potential confound was that we did not measure glucose levels at the time of testing, hence it is possible that some of the variability in performance in the diabetic group could be explained by variations in glucose levels. 50 We opted to use increment and decrement Gabor stimuli to measure the perceptual output of ON and OFF pathways (inspired by Luo-Li et al. 2016s 20 original experiments), reasoning that any damage to ON RGC would impact on the ON-signaling pathway and cortical responses to increments. These Gabor stimuli were specifically designed with a mean luminance background and were ramped across 200 ms to avoid stimulating the opposite contrast. ...
Purpose:
Animal models suggest that ON retinal ganglion cells (RGCs) may be more vulnerable to diabetic insult than OFF cells. Using three psychophysical tasks to infer the function of ON and OFF RGCs, we hypothesized that functional responses to contrast increments will be preferentially affected in early diabetes mellitus (DM) compared to contrast decrement responses.
Methods:
Fifty-two people with DM (type 1 or type 2) (mean age = 34.8 years, range = 18-60 years) and 48 age-matched controls (mean age = 35.4 years, range = 18-60 years) participated. Experiment 1 measured contrast sensitivity to increments and decrements at four visual field locations. Experiments 2 and 3 measured visual temporal processing using (i) a response time (RT) task, and (ii) a temporal order judgment task. Mean RT and accuracy were collected for experiment 2, whereas experiment 3 measured temporal thresholds.
Results:
For experiment 1, the DM group showed reduced increment and decrement contrast sensitivity (F (1, 97) = 4.04, P = 0.047) especially for the central location. For experiment 2, those with DM demonstrated slower RT and lower response accuracies to increments and decrements (increments: U = 780, P = 0.01, decrements: U = 749, P = 0.005). For experiment 3, performance was similar between groups (F (1, 91) = 2.52, P = 0.137).
Conclusions:
When assessed cross-sectionally, nonselective functional consequences of retinal neuron damage are present in early DM, particularly for foveal testing. Whether increment-decrement functional indices relate to diabetic retinopathy (DR) progression or poorer visual prognosis in DM requires further study.
... The highly metabolically active neurosensory retina is particularly vulnerable to episodes of low glucose due to the strict dependence of retinal cells on glycolysis. 17 To interrogate the response of the retina to hypoglycemia, we isolated neurosensory retinal explants from 8-to 10-week-old mice and cultured them in vitro ( Figure S1A). Hematoxylin and eosin staining of these retinal explants cultured for 24 h demonstrates preservation of the normal retinal architecture ( Figure S1B) and the presence of the major inner retinal cell types ( Figure S1C). ...
Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.
... The effects of acute hypoglycaemia on the retina of subjects with or without diabetes were investigated for the first time in 2011 by Khan et al. They found decreased central retinal function in all subjects with diabetes after acute hypoglycaemia, hypothesising that during this period cells are unable to meet their metabolic demands due to an insufficient glucose supply [30]. Hypoglycaemia is not to be ignored for diabetic patients, with the average type 1 diabetic patient estimated to suffer two episodes of symptomatic hypoglycaemia per week, leading to thousands of such episodes over a lifetime, and at least one episode of severe hypoglycaemia per year [31]. ...
Glucose is one of the most important metabolic substrates of the retina, and glycaemic imbalances can lead to serious side effects, including retinopathy. We previously showed that hypoglycaemia induces retinal cell death in mice, as well as the implication of glutathione (GSH) in this process. This study aimed to analyse the role of low glucose-induced decrease in GSH levels in endoplasmic reticulum (ER) stress. We cultured 661W photoreceptor-like cells under various glucose conditions and analysed ER stress markers at the mRNA and protein levels. We used the ERAI (“ER stress-activated indicator”) mouse model to test ER stress in both ex vivo, on retinal explants, or in vivo, in mice subjected to hypoglycaemia. Moreover, we used buthionine sulfoximine (BSO) and glutamate cysteine ligase (Gclm)-KO mice as models of low GSH to test its effects on ER stress. We show that the unfolded protein response (UPR) is triggered in 661W cells and in ERAI mice under hypoglycaemic conditions. Low GSH levels promote cell death, but have no impact on ER stress. We concluded that low glucose levels induce ER stress independently of GSH levels. Inhibition of ER stress could prevent neurodegeneration, which seems to be an early event in the pathogenesis of diabetic retinopathy.
... Besides the HbA 1clowering effect known to be related to complications, it is essential to notice that time in hypoglycemia (,3.0 mmol/L [54 mg/dL]), during which cognitive impairment appears, was dramatically reduced by ;70% by CGM. It is essential to see the full picture of CGM for understanding effects that also include less glycemic variability and reduction of very high glucose levels (1,2,(26)(27)(28). ...
Objective:
Continuous glucose monitoring (CGM) reduces HbA1c and time spent in hypoglycemia in people with type 1 diabetes (T1D) treated with multiple daily insulin injections (MDI) when evaluated over shorter time periods. It is unclear to what extent CGM improves and helps to maintain glucose control, treatment satisfaction, diabetes distress, hypoglycemic concerns, and overall well-being over longer periods of time.
Research design and methods:
The GOLD trial was a randomized crossover trial performed over 16 months of CGM treatment in people with T1D treated with MDI. People completing the trial (n = 141) were invited to participate in the current SILVER extension study in which 107 patients continued CGM treatment over 1 year along with the support of a diabetes nurse every 3 months.
Results:
The primary end point of the change in HbA1c over 1.0-1.5 years CGM use compared with previous self-monitoring of blood glucose during GOLD showed a decrease in HbA1c of 0.35% (95% CI 0.19-0.50%, P < 0.001). Time spent in hypoglycemia <3.0 mmol/L (54 mg/dL) and <4.0 mmol/L (72 mg/dL) decreased from 2.1 to 0.6% (P < 0.001) and from 5.4 to 2.9% (P < 0.001), respectively. Overall well-being (World Health Organization 5-item well-being index, P = 0.009), treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire, P < 0.001), and hypoglycemic confidence (P < 0.001) increased, while hypoglycemic fear (Hypoglycemia Fear Survey-Worry, P = 0.016) decreased and diabetes distress tended to decrease (Problem Areas in Diabetes Scale, P = 0.06). From randomization and screening in GOLD, HbA1c was lowered by 0.45% (P < 0.001) and 0.68% (P < 0.001) after 2.3 and 2.5 years, respectively.
Conclusions:
The SILVER study supports beneficial long-term effects from CGM on HbA1c, hypoglycemia, treatment satisfaction, well-being, and hypoglycemic confidence in people with T1D managed with MDI.
... Besides the HbA 1clowering effect known to be related to complications, it is essential to notice that time in hypoglycemia (,3.0 mmol/L [54 mg/dL]), during which cognitive impairment appears, was dramatically reduced by ;70% by CGM. It is essential to see the full picture of CGM for understanding effects that also include less glycemic variability and reduction of very high glucose levels (1,2,(26)(27)(28). ...
CGM reduces A1c and time in hypoglycemia in persons with T1D treated with MDI evaluated over short time periods. It’s unclear to what extent CGM improves glucose control, treatment satisfaction, hypoglycemia fear and diabetes-related QoL long term.
The GOLD trial was a 16 month randomized crossover trial of CGM use in persons with T1D treated with MDI. The SILVER study is an extension in which patients continued CGM use (DexcomG4/G5) for 1 year with clinical visits every 3 months.
The primary endpoint, A1c change during long-term CGM use compared with SMBG during GOLD (from end of SMBG in GOLD until end of SILVER study/1.0-1.5 years), showed decreased A1c of 0.35% (95% CI 0.19-0.50), p<0.001. TIR increased by 8.6% (95% CI 5.1-12.0,p<0.001), from 43.0 -51.0%. Time in hypoglycemia <54 and <70 mg/dl decreased from 2.1- 0.6%, p<0.001 and from 5.4- 2.9%, p<0.001, respectively. From randomization and screening in GOLD, A1c decreased by 0.45% (p<0.001) and 0.68% (p<0.001) after 2.5 years, respectively. Wellbeing WHO-5, p<0.001, treatment satisfaction DTSQ, p<0.001 and hypoglycemia confidence, p<0.001 increased. Diabetes-distress decreased PAID, p=0.006 over the time period.
The SILVER study supports beneficial long-term effects by CGM use on A1c, TIR, hypoglycemia, treatment satisfaction, wellbeing, hypoglycemia confidence and diabetes distress in persons with T1D treated with MDI.
Disclosure
M. Lind: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Consultant; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Research Support; Self; Dexcom, Inc., Novo Nordisk Inc. A.F. Olafsdottir: None. I.B. Hirsch: Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care. Research Support; Self; Medtronic, Omnipod. J. Bolinder: Advisory Panel; Self; Abbott. Consultant; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca. S. Dahlqvist: None. A. Pivodic: None. J. Hellman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. M.O. Wijkman: None. E. Schwarcz: Advisory Panel; Self; Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H. Albrektsson: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. W. Polonsky: Advisory Panel; Self; Intarcia Therapeutics, Roche Diabetes Care. Consultant; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Onduo, Sanofi US, Xeris Pharmaceuticals, Inc.
Funding
Dexcom, Inc.
... 4 Acute hypoglycemia induced by insulin treatment generally contributes to subsequent decline of visual function. 5 Moreover, diabetic patients require insulin injections at least once a day owing to its rapid degradation rate and extremely short half-life, causing considerable pain and reduced quality of life. ...
Background
To pursuit effective sustained release systems for insulin to treat diabetic retinopathy (DR), a novel insulin delivering system was developed via loading onto chitosan nanoparticles/poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) hydrogel (ICNPH).
Methods and materials
Examinations including electroretinography, HE staining, transmission electron microscopy, terminal deoxynucleotidyl transferased UTP nick-end labeling, immunofluorescence, Western blot, and real-time polymerase chain reaction were performed to evaluate the neuroprotective efficacy of ICNPH on DR by a single subconjunctival injection.
Results
Compared with the insulin, blank, and sham treatment groups, subconjunctival injection of ICNPH significantly reduced the decrease of scotopic B-wave amplitude, alleviated retinal micro- and ultrastructural changes, and reduced retinal cell apoptosis caused in DR rats. Meanwhile, a significant reduction of vascular endothelial growth factor and glial fibrillary acidic protein expression as well as a remarkable increase in Occludin expression was also found in retinas in ICNPH group compared with the sham treatment group.
Conclusion
The results indicate that ICNPH has sufficient neuroprotective effect on retinas through subconjunctival injection in DR rats and facilitates controlled insulin delivery. It might be one of the therapeutic strategies for DR in the near future.
... Even though hypoglycemia itself has a potential adverse influence on the risk of death, transient hypoglycemia in the hospital setting over a short period (several days to weeks) might not have a significant impact. However, hypoglycemia could cause other harms that are less obvious than death, but may well be clinically significant, such as cognitive and vision-related sequelae [58,59]. Complex trade-offs may occur between tight glycemic control and hypoglycemia in critically ill patients. ...
Purpose:
It is unclear whether tight glycemic control is warranted in all critically ill adults. We employed network meta-analysis to examine the risk of mortality and hypoglycemia associated with different glycemic control targets in critically ill adults.
Methods:
Electronic databases were searched up to 2016 for randomized controlled trials comparing various insulin regimens in critically ill adults with hyperglycemia. Two reviewers independently extracted information and evaluated quality with the Cochrane risk-of-bias tool. Four glycemic control groups were compared: tight (blood glucose: 4.4 < 6.1 mmol/l), moderate (6.1 < 7.8 mmol/l), mild (7.8 < 10.0 mmol/l), and very mild (10.0 to < 12.2 mmol/l). Network meta-analysis was performed by a frequentist approach with multivariate random effects meta-analysis.
Results:
Thirty-six randomized trials (17,996 patients) were identified. Compared with very mild control, tight control did not reduce the risk of short-term mortality [relative risk (RR) 0.94 (95 % CI 0.83-1.07, p = 0.36)], and neither did mild control [RR 0.88 (0.73-1.06), p = 0.18] or moderate control [RR 1.1 (0.66-1.84), p = 0.72]. However, severe hypoglycemia (<2.2 mmol/l) was more frequent with tight control than very mild control [RR 5.49 (3.22-9.38), p < 0.001] or mild control [RR 4.47 (2.5-8.03), p < 0.001]. Stratified analyses (cause of death, ICU type, time period, or diabetes) did not find significant between-group differences. Ranking analysis revealed the following hierarchy for avoiding death (highest to lowest rank): mild control, tight control, and very mild control.
Conclusions:
Network meta-analysis showed no mortality benefit of tight glycemic control in critically ill patients, but fivefold more hypoglycemia versus mild or very mild control.
... During the United Kingdom Prospective Diabetes Study [1], people with type 2 diabetes mellitus who reduced their glycaemic levels to within the recommended levels demonstrated a lower risk of microvascular complications than did those receiving conventional dietary therapy. Post-trial monitoring to determine whether the therapy had a long-term effect on macrovascular outcomes found that despite an early loss of glyceamic differences (with 1 year of the therapy), a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up [18]. ...
Rationale, aims and objectives:
Self-management of type 2 diabetes through diet, exercise and for many medications, are vital in achieving and maintaining glycaemic control in type 2 diabetes. A number of interventions have been designed to improve self-management, but the outcomes of these are rarely explored from a qualitative angle and even fewer through a process evaluation.
Method:
A process evaluation was conducted using a qualitative design with participants randomized to an intervention. Seventy-three people living with type 2 diabetes and hyperglycaemia for a minimum of 1 year, randomized to one of two interventions (n = 34 to an education intervention and n = 39 to an education and acceptance and commitment therapy intervention) completed stage one of the process evaluation, immediately following the intervention through written feedback guided by open-ended questions. A purposive sample of 27 participants completed semi-structured interviews at 3 and 6 months post intervention. Interview data were transcribed and data analysed using a thematic analysis.
Results:
The majority of participants described an increase in knowledge around diabetes self-management and an increased sense of personal responsibility. Participants also described changes in self-management activities and reflected on the challenges in instigating and maintaining change to improve diabetes management.
Conclusion:
The complexities of implementing change in daily life to improve glycaemic control indicate the need for ongoing support post intervention, which may increase and maintain the effectiveness of the intervention.
... No obstante, el aporte de glúcidos de la bebida deportiva, consigue mantener sin cambios significativos los niveles de glucemia en la CcB, a pesar de la baja tasa de ingesta de líquido. Valores tan bajos de glucosa en sangre como los obtenidos en nuestro estudio han demostrado tener efectos negativos en el rendimiento cognitivo 30-32 e incluso en la capacidad visual y el procesamiento de la información sensitiva 33 , debido a la sensibilidad del cerebro humano a los cambios en esta variable 34 . ...
Introduction: 21 K and 1 000 m ascent trail-running races can be dangerous if an appropriate liquid replace- ment isn’t maintained.
Objectives: know trail-runners level of dehydration and assess the differences between ad libitum water (CcA) and sport drink (CcB) hydration after a trail run- ning race.
Methods: 18 subjects, mean age 31.9 (±2.8) and %MG 10.53 (±2.8), completed CcA or CcB. CcA and CcB effects on Weight (P), Fat Mass (MG), Glucose (GL), Lacta- te (LT), Systolic (TAS) and Diastolic Arterial Tension (TAD), Heart Rate (PPM) and Tympanic Temperature (Ta) were assessed. All measurements were taken at the start (T1) and the finish (T2) of each race. A Friedman ANOVA test was used to calculate the effect of CcA and CcB on each variable. Differences between race time (TC), % bodyweight loss (%PP) and liquid ingestion (LI) were assessed with a Wilcoxon test. All statistical analysis were conducted with SPSS version 20.0 (IBM, Somers, NY, USA).
Results: mean %PP was 2.967 (± 0.969) and 2.883 (± 0.730) for CcA and CcB respectively. No significant differences were found between %PP and LI (p > .05) be- tween races. Significant changes were found in P, %MG, GL, L, TAS and PPM between T1 and T2 in CcA condi- tion. While only significant changes in P and PPM were stabilised between T1 and T2 in CcB condition.
Conclusions: neither water or sport drink ingestion avoid trail-runners to reach a dehydrated state. Howe- ver, dehydration effects seems to be more serious when only water is ingested.
... The possibility of decrease in myocardial blood flow reserve might lead to cardiovascular mortality in hypoglycaemic patients [50,51]. Khan et al. [52] assessed effect of acute hypoglycaemia on retinal function which showed decrease in retinal response in T1DM with reduced amplitude of response in central macular retina and central scotoma. ...
Glycaemic control is often disturbed by iatrogenic hypoglycaemia as a result of intensive treatment and can be a major barrier to optimal glycaemic management. This risk of hypoglycaemia acts like a deterrent to the patient from achieving euglycaemia. The fear of hypoglycaemia leads to “defensive snacking” which further disrupts achievement of euglycaemia and leads to weight gain. Obesity by itself carries a major risk for adverse cardiovascular outcomes and coupled with hypoglycaemia significantly increases the cardiovascular risk in patients with diabetes. “Hyp-obesity” is a new term that effectively conveys the present challenges in achieving euglycaemia due to hypoglycaemia and obesity and would help facilitate therapeutic strategies to optimise diabetes management. Newer drugs targeting the incretin pathway such as glucagon-like peptide-1 (GLP-1) mimetic and dipeptidyl peptidase-4 (DPP-4) inhibitors would be beneficial in minimising the risk of hypoglycaemia and obesity.
... [76] More recently, Khan et al., demonstrated that acute effects of hypoglycemia in human eye led to signifi cant reduction of central retinal function and contrast sensitivity. [77] Figure 2 summarizes the physiological impact of hypoglycemia on different systems and their counter-regulatory responses. ...
Hypoglycemia is an important complication of glucose-lowering therapy in patients with diabetes mellitus. Attempts made at intensive glycemic control invariably increases the risk of hypoglycemia. A six-fold increase in deaths due to diabetes has been attributed to patients experiencing severe hypoglycemia in comparison to those not experiencing severe hypoglycemia Repeated episodes of hypoglycemia can lead to impairment of the counter-regulatory system with the potential for development of hypoglycemia unawareness. The short- and long-term complications of diabetes related hypoglycemia include precipitation of acute cerebrovascular disease, myocardial infarction, neurocognitive dysfunction, retinal cell death and loss of vision in addition to health-related quality of life issues pertaining to sleep, driving, employment, recreational activities involving exercise and travel. There is an urgent need to examine the clinical spectrum and burden of hypoglycemia so that adequate control measures can be implemented against this neglected life-threatening complication. Early recognition of hypoglycemia risk factors, self-monitoring of blood glucose, selection of appropriate treatment regimens with minimal or no risk of hypoglycemia and appropriate educational programs for healthcare professionals and patients with diabetes are the major ways forward to maintain good glycemic control, minimize the risk of hypoglycemia and thereby prevent long-term complications.
... Recently, Umino et al. showed that chronic moderate hypoglycemia in mouse led to loss of vision and eventual retinal degeneration [5], while Punzo et al. suggested that cones death in retinitis pigmentosa could be, at least in part, the result of starvation via the insulin/mTOR pathway [6] . A recent publication , showing a decrease of central retinal function in human during acute hypoglycemia, strengthened the importance of glycemic excursion in patients [7]. Programmed cell death, also called apoptosis, has been analyzed in various cell systems, stimulated by multiple stimuli. ...
Glucose is an important metabolic substrate of the retina and diabetic patients have to maintain a strict normoglycemia to avoid diabetes secondary effects, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Others and we recently demonstrated the potential role of hypoglycemia in diabetic retinopathy. We showed acute hypoglycemia to induce retinal cell death both in vivo during an hyperinsulinemic/hypoglycemic clamp and in vitro in 661W photoreceptor cells cultured at low glucose concentration. In the present study, we showed low glucose to induce a decrease of BCL2 and BCL-XL anti-apoptotic proteins expression, leading to an increase of free pro-apoptotic BAX. In parallel, we showed that, in retinal cells, low glucose-induced apoptosis is involved in the process of autophagosomes formation through the AMPK/RAPTOR/mTOR pathway. Moreover, the decrease of LAMP2a expression led to a defect in the autophagosome/lysosome fusion process. Specific inhibition of autophagy, either by 3-methyladenine or by down-regulation of ATG5 or ATG7 proteins expression, increased caspase 3 activation and 661W cell death. We show that low glucose modifies the delicate equilibrium between apoptosis and autophagy. Cells struggled against low nutrient condition-induced apoptosis by starting an autophagic process, which led to cell death when inhibited. We conclude that autophagy defect is associated with low glucose-induced 661W cells death that could play a role in diabetic retinopathy. These results could modify the way of addressing negative effects of hypoglycemia. Short-term modulation of autophagy could be envisioned to treat diabetic patients in order to avoid secondary complications of the disease.
... In addition, Glut 4-mediated glucose sensing is postulated to be important under hypoglycemic conditions [44]. Glut 4 might function in the retina to deliver glucose to meet energy expenditures of particular retinal processes associated with the maintenance of glucose supply under hypoglycemic conditions, despite the abundance of retinal Glut 1, since the affinity of Glut 1 for glucose is lower than that of Glut 4. In this regard, recent evidence shows that under hypoglycemic conditions retinal energy supply may be compromised [45], [46], [47]. Expression of Glut 4 in the retina thus opens new roles for insulin in retinal physiology.Figure S1 Western blots of muscle and retinal homogenates (100 mg protein) using two different anti Glut 4 monoclonal antibodies (1:100, Cell Signaling, left and 1:500, Bio-Trend right). ...
The vertebrate retina is a very metabolically active tissue whose energy demands are normally met through the uptake of glucose and oxygen. Glucose metabolism in this tissue relies upon adequate glucose delivery from the systemic circulation. Therefore, glucose transport depends on the expression of glucose transporters. Here, we show retinal expression of the Glut 4 glucose transporter in frog and rat retinas. Immunohistochemistry and in situ hybridization studies showed Glut 4 expression in the three nuclear layers of the retina: the photoreceptor, inner nuclear and ganglionar cell layers. In the rat retina immunoprecipitation and Western blot analysis revealed a protein with an apparent molecular mass of 45 kDa. (14)C-glucose accumulation by isolated rat retinas was significantly enhanced by physiological concentrations of insulin, an effect blocked by inhibitors of phosphatidyl-inositol 3-kinase (PI3K), a key enzyme in the insulin-signaling pathway in other tissues. Also, we observed an increase in (3)H-cytochalasin binding sites in the presence of insulin, suggesting an increase in transporter recruitment at the cell surface. Besides, insulin induced phosphorylation of Akt, an effect also blocked by PI3K inhibition. Expression of Glut 4 was not modified in retinas of a type 1 diabetic rat model. To our knowledge, our results provide the first evidence of Glut4 expression in the retina, suggesting it as an insulin- responsive tissue.
... In this respect, it is remarkable that decrease in retinal function was found in chronic hypoglycemia produced in an animal model [31]. Moreover, during the revision of this manuscript, acute hypoglycemia was reported to induce retinal cells death in mouse [32] and significant reduction of central retinal function in humans [33]. ...
Retinal tissue is exceptional because it shows a high level of energy metabolism. Glycogen content represents the only energy reserve in retina, but its levels are limited. Therefore, elucidation of the mechanisms controlling glycogen content in retina will allow us to understand retina response under local energy demands that can occur under normal and pathological conditions. Thus, we studied retina glycogen levels under different experimental conditions and correlated them with glucose-6-phosphate (G-6-P) content and glycogen synthase (GS) activity.
Glycogen and G-6-P content were studied in ex vivo retinas from normal, fasted, streptozotocin-treated, and insulin-induced hypoglycemic rats. Expression levels of GS and its phosphorylated form were also analyzed. Ex vivo retina from normal rats showed low G-6-P (14±2 pmol/mg protein) and glycogen levels (43±3 nmol glycosyl residues/mg protein), which were increased 6 and 3 times, respectively, in streptozotocin diabetic rats. While no changes in phosphorylated GS levels were observed in any condition tested, a positive correlation was found between G-6-P levels with GS activity and glycogen content. The results indicated that in vivo, retina glycogen may act as an immediately accessible energy reserve and that its content was controlled primarily by G-6-P allosteric activation of GS. Therefore, under hypoglycemic situations retina energy supply is strongly compromised and could lead to the alterations observed in type 1 diabetes.
Hypoglycemia is a condition where blood glucose concentration decreases below 70 mg/dL with or without signs or symptoms. Hypoglycemia symptoms may vary from mild to life-threatening conditions, or be classified based on the severity as mild-moderate and severe hypoglycemia. Mortality in patients with severe hypoglycemia was 3 times greater than in patients who experienced mild-moderate hypoglycemia. Management of hypoglycemia is classified based on its severity. Appropriate therapy is needed for hypoglycemia patients because untreated hypoglycemia will reduce the patient's quality of life. Understanding symptoms, prevention, and the management of hypoglycemia is needed, especially in patients who have experienced severe hypoglycemia so that it does not lead to recurrence or fatal condition.
Clinical Relevance
Visual function impairment from diabetic retinopathy can have a considerable impact on patient’s quality of life. Best-corrected visual acuity (BCVA) is most commonly used to assess visual function and guide clinical trials. However, BCVA is affected late in the disease process, is not affected in early disease, and does not capture some of the visual disturbances described by patients with diabetes. The goal of this report is to evaluate the relationship between diabetic retinal disease (DRD) and visual function parameters to determine which if any of them may be used in a future DRD staging system.
Methods
The visual functions working group was 1 of 6 areas of DRD studied as part of the DRD staging system update, a project of the Mary Tyler Moore Vision Initiative. The working group identified 12 variables of possible interest, 7 of which were judged to have sufficient preliminary data to suggest an association with DR to warrant further review: microperimetry, static automated perimetry, electroretinogram (ERG) oscillatory potentials, flicker ERG, low luminance visual acuity (LLVA), contrast sensitivity (CS), and BCVA. The objective field analyzer (OFA) was added after subsequent in-person workshops.
Results
Currently, the only visual function test available for immediate use is BCVA; the remaining tests are either promising (within 5 years) or have potential (>5 years) use. Besides BCVA, most visual function tests had a limited role in current clinical care; however, LLVA, CS, flicker ERG, and OFA demonstrated potential for screening and research purposes.
Conclusions
Although current visual function tests are promising, future prospective studies involving patients with early and more advanced retinopathy are necessary to determine if these tests can be used clinically or as endpoints for clinical studies.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Defects in the light-evoked responses of the retina occur early in the sequalae of diabetic retinopathy. These defects, identified through the electroretinogram, represent dysfunction of retinal neurons and the retinal pigment epithelium and are commonly identifiable at the timing of, or almost immediately following, diabetes diagnosis. Recently we demonstrated that systemic reduction of Glut1 in Type 1 diabetic mice reduced retinal sorbitol accumulation, mitigated ERG defects, and prevented retinal oxidative stress and inflammation. Here, we investigated whether systemic reduction of Glut1 also diminished hallmarks of diabetic retinopathy in Type 2 diabetic mice. Transgenic nondiabetic Leprdb/+ and spontaneously diabetic Leprdb/db mice that expressed wildtype (Glut1+/+) or systemically reduced levels of Glut1 (Glut1+/-), were aged and underwent standard strobe flash electroretinography and c-wave analysis prior to evaluation of inflammatory cytokines and oxidative stress molecules. Although Leprdb/dbGlut1+/- mice still displayed overt obesity and diabetes, no scotopic, photopic or c-wave ERG defects were present through 16 weeks of age and expression of inflammatory cytokines and oxidative stress molecules were also normalized. These findings suggest that systemic reduction of Glut1 is sufficient to prevent functional retinal pathophysiology in Type 2 diabetes. Targeted, moderate reductions of Glut1 or inhibition of Glut1 activity in the retina of diabetics should be considered as a novel therapeutic strategy to prevent development and progression of diabetic retinopathy.
One hundred years on from the initial discovery of insulin, we take this opportunity to reflect on the scientific discoveries that have improved so many lives. From its original crude form, insulin therapy has improved significantly over the past century. Despite this, hypoglycaemia remains an ever‐present fear for people with Type 1 diabetes. As such, it is essential that research now looks to minimise the frequency and severity of insulin‐induced hypoglycaemia and its complications, some of which can be life‐threatening. Over the last century, one thing that has become apparent is the success and need for translational diabetes research. From its origin in dogs, insulin treatment has revolutionised the lives of those with Type 1 diabetes through the coordinated effort of scientists and clinicians. In this review, we recount the more recent research that uses a mouse‐to‐man approach, specifically in hypoglycaemia research.
Background and purpose:
Although diabetes is associated with multiple ocular complications, there are limited data on the incidence and predictors of visual acuity (VA) loss in type 2 diabetes. The aim of this study was to determine the 4-year cumulative incidence of visual impairment and blindness, and the predictors of vision loss, in a representative community-based cohort.
Methods:
The longitudinal Fremantle Diabetes Study Phase II recruited 1551 participants with type 2 diabetes between 2008 and 2011. Participants attended biennial face-to-face assessments including VA measurement. Multivariable logistic regression was used to determine the predictors of vision loss (defined as a decrease in VA by >10 letters at the Year 4 assessment), excluding those with visual impairment (VA >6/19 and ≤6/48) and blindness (VA >6/48) at baseline.
Results:
882 participants with normal/near normal vision at baseline had VA data at Year 4 available. During a median [interquartile range] 4.1 [4.0-4.4] years of follow-up, the cumulative incidences of visual impairment and vision loss were 0.9% (n = 8) and 2.9% (n = 26), respectively. No participants developed blindness and 1.9% (n = 17) improved their VA. Multivariable logistic regression showed baseline smoking (OR: 3.17 (95% CI: 1.15-8.76)), prior severe hypoglycemia (5.59 (1.32-23.61)) and urinary albumin:creatinine ratio (uACR) (1.42 (1.09-1.84) for an increase of 1 in ln(uACR)) had higher odds of vision loss during follow-up.
Conclusions:
Smoking cessation and management strategies that avoid severe hypoglycemia and preserve kidney function may potentially prevent vision loss in people with type 2 diabetes.
Objective
To evaluate if the lowest target level for glycated haemoglobin (HbA 1c ) of <6.5% is associated with lower risk for retinopathy and nephropathy than less tight control in children and adults with type 1 diabetes.
Design
Population based cohort study.
Setting
Swedish National Diabetes Registry, 1 January 1998 to 31 December 2017.
Participants
10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017.
Main outcome measures
Relative risk (odds ratios) for retinopathy and nephropathy for different mean levels of HbA 1c .
Results
Mean age of participants was 14.7 years (43.4% female), mean duration of diabetes was 1.3 years, and mean HbA 1c level was 8.0% (63.4 mmol/mol). After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index, and smoking, the odds ratio for mean HbA 1c <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) for any retinopathy (simplex or worse) was 0.77 (95% confidence interval 0.56 to 1.05, P=0.10), for preproliferative diabetic retinopathy or worse was 3.29 (0.99 to 10.96, P=0.05), for proliferative diabetic retinopathy was 2.48 (0.71 to 8.62, P=0.15), for microalbuminuria or worse was 0.98 (0.60 to 1.61, P=0.95), and for macroalbuminuria was 2.47 (0.69 to 8.87, P=0.17). Compared with HbA 1c levels 6.5-6.9%, HbA 1c levels 7.0-7.4% (53-57 mmol/mol) were associated with an increased risk of any retinopathy (1.31, 1.05 to 1.64, P=0.02) and microalbuminuria (1.55, 1.03 to 2.32, P=0.03). The risk for proliferative retinopathy (5.98, 2.10 to 17.06, P<0.001) and macroalbuminuria (3.43, 1.14 to 10.26, P=0.03) increased at HbA 1c levels >8.6% (>70 mmol/mol). The risk for severe hypoglycaemia was increased at mean HbA 1c <6.5% compared with 6.5-6.9% (relative risk 1.34, 95% confidence interval 1.09 to 1.64, P=0.005).
Conclusions
Risk of retinopathy and nephropathy did not differ at HbA 1c levels <6.5% but increased for severe hypoglycaemia compared with HbA 1c levels 6.5-6.9%. The risk for severe complications mainly occurred at HbA 1c levels >8.6%, but for milder complications was increased at HbA 1c levels >7.0%.
Diabetic retinopathy (DR) is a major microvascular complication of diabetes, resulting in neuronal dysfunction, retinal vascular leakage, and apoptosis within the retina. Innate immunity plays an important role in the pathogenesis of type 2 diabetes (T2D) and related complications. The toll-like receptors (TLRs), central to innate immunity, are essential participants in the progression and pathogenesis of the disease and its complications. In the study, streptozotocin (STZ) was combined with whole-body hypoxia for quicker induction of early-stage diabetic retinopathy (DR) in the wild type (WT) and TLR7-knockout (KO) C57BL/6 mice. The effects of TLR7 were also investigated in fructose-treated retinal pigment epithelial (RPE) cells. In the retinas of WT/DR mice, abnormal a-wave and b-wave activity, hyperfluorescence, and reduced retinal thickness were observed. DR development was associated with enhanced TLR7 expression, whose deletion dramatically reduced VEGF expression levels. And the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-18 and IL-12, was highly reduced by TLR7-deficiency in DR mice. Consistently, WT/DR mice exhibited higher phosphorylation of IκB kinase α (IKKα), inhibitor of NF-κB α (IκBα) and nuclear factor κB (NF-κB), which were found to be down-regulated in KO/DR mice. Similarly, DR-induced mitogen-activated protein kinases (MAPKs) activation was blocked by TLR7-knockout. In vitro, fructose incubation-triggered inflammation was reversed by TLR7 knockdown, accompanied with inactivated NF-κB and MAPKs pathways. And reduced reactive oxygen species (ROS) generation was observed in TLR7-knockdown cells with fructose treatment. Together, inhibiting TLR7 suppressed diabetic retinopathy by reducing inflammation and suggested a potential application in clinics.
Cones comprise only a small portion of the photoreceptors in mammalian retinas. However, cones are vital for color vision and visual perception, and their loss severely diminishes the quality of life for patients with retinal degenerative diseases. Cones function in bright light and have higher demand for energy than rods; yet, the mechanisms that support the energy requirements of cones are poorly understood. One such pathway that potentially could sustain cones under basal and stress conditions is macroautophagy. We addressed the role of macroautophagy in cones by examining how the genetic block of this pathway affects the structural integrity, survival, and function of these neurons. We found that macroautophagy was not detectable in cones under normal conditions but was readily observed following 24 h of fasting. Consistent with this, starvation induced phosphorylation of AMPK specifically in cones indicating cellular starvation. Inhibiting macroautophagy in cones by deleting the essential macroautophagy gene Atg5 led to reduced cone function following starvation suggesting that cones are sensitive to systemic changes in nutrients and activate macroautophagy to maintain their function. ATG5-deficiency rendered cones susceptible to light-induced damage and caused accumulation of damaged mitochondria in the inner segments, shortening of the outer segments, and degeneration of all cone types, revealing the importance of mitophagy in supporting cone metabolic needs. Our results demonstrate that macroautophagy supports the function and long-term survival of cones providing for their unique metabolic requirements and resistance to stress. Targeting macroautophagy has the potential to preserve cone-mediated vision during retinal degenerative diseases.
The burden of hypoglycaemia is important, particularly in elderly type 2 diabetes (T2D) patients. Unfortunately, however, few studies are available concerning this population. GERODIAB is a prospective, multicentre, observational study that aims to describe the 5-year morbidity and mortality of 987 T2D patients aged 70years and older. After analyzing the frequency of and factors associated with hypoglycaemia in the 6months prior to study inclusion, it was found that hypoglycaemia was associated with retinopathy, lower levels of LDL cholesterol and altered mini-Geriatric Depression Scale (GDS) scores.
Copyright © 2015. Published by Elsevier Masson SAS.
In Brief
Older adults with type 1 diabetes are at high risk for severe hypoglycemia and may have serious comorbid conditions. Problems with cognition, mobility, dexterity, vision, hearing, depression, and chronic pain interfere with the ability to follow complex insulin regimens. With the development of geriatric syndromes, unpredictable eating, and frailty, treatment regimens must be modified with the goal of minimizing hypoglycemia and severe hyperglycemia and maximizing quality of life.
Purpose:
It is unknown which regions of the retina are most susceptible to damage by diabetes mellitus. We hypothesized that the standard and slow-flash (sf-) multifocal electroretinogram (mfERG) will localize retinal regions of greatest vulnerability.
Methods:
A total of 55 adolescents and young adults with type 1 diabetes and without diabetic retinopathy (DR) or with mild nonproliferative DR and 54 typically-developing, age-similar control participants underwent mfERG and sf-mfERG testing. The amplitude and implicit time of the first order response of the standard mfERG and of three multifocal oscillatory potentials (mfOPs) of the sf-mfERG were compared between groups at the level of hexagons, quadrants, and rings using separate mixed model ANOVAs. Spatial mapping of the P values from post hoc pairwise comparisons illustrated patterns of retinal dysfunction.
Results:
Delays in mfERG implicit times were evident across the tested retinal areas in the diabetes group. Delays in sf-mfERG implicit times were found at different eccentricities for each mfOP in the diabetes group. The greatest delays were noted in the periphery for mfOP1, in the midperiphery for mfOP2, and in the macular region for mfOP3. There were no significant group differences in amplitude for the mfERG and sf-mfERG protocols.
Conclusions:
Delays in mfERG and sf-mfERG responses suggest that the inner retina is particularly vulnerable to diabetes. Localizing regions of early dysfunction will help guide future studies to examine early structural damage associated with DR.
Multifocal visual electrophysiology, consisting of multifocal electroretinography (mfERG) and multifocal visual evoked potential (mfVEP), can objectively evaluate retina function and retina-cortical conduction pathway status by stimulating many local retinal regions and obtaining each local response simultaneously. Having many advantages such as short testing time and high sensitivity, it has been widely used in clinical ophthalmology, especially in the diagnosis of retinal disease and glaucoma. It is a new objective technique in clinical forensic medicine involving visual function evaluation of ocular trauma in particular. This article summarizes the way of stimulation, the position of electrodes, the way of analysis, the visual function evaluation of mfERG and mfVEP, and discussed the value of multifocal visual electrophysiology in forensic medicine.
Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr-/- mice.
Gcgr-/- mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry.
Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr-/- mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr-/- retinas have 20% fewer synaptic pairings than Gcgr+/- retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts.
Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.
We thank Dr. Clark and concur with his appropriate comments about the severity of hypoglycemic symptoms in type 1 diabetic subjects (1,2). The glycemic thresholds to activate the neuroendocrine, autonomic nervous …
This study allocated the symptoms identified during acute hypoglycemia objectively to the autonomic or neuroglycopenic groups of symptoms by the use of factor analysis.
Twenty-five nondiabetic subjects, 14 newly diagnosed insulin-dependent diabetic patients, and 16 insulin-dependent diabetic patients with diabetes greater than 4 yr duration were studied. Acute hypoglycemia was induced with insulin (2.5 mU.kg-1 body wt.min-1 i.v.), and symptoms of hypoglycemia were recorded with a seven-point scale at regular time points throughout the studies. Factor analysis of the symptom scores at the time of the acute autonomic reaction with principal component analysis followed by Varimax rotation was used to separate those symptoms that might belong to neuroglycopenic and autonomic groups.
Hypoglycemia was induced to a mean +/- SE plasma glucose nadir of 1.3 +/- 0.1 mM in nondiabetic subjects, to 2.0 +/- 0.3 mM in newly diagnosed diabetic patients, and 1.4 +/- 0.2 mM in patients with diabetes of greater than 4 yr duration. The most frequently reported autonomic symptoms were sweating, trembling, and warmness, and the most frequently reported neuroglycopenic symptoms were inability to concentrate, weakness, and drowsiness. Neuroglycopenic symptoms were reported more commonly at the onset of hypoglycemia, which was identified by the development of symptoms. Factor analysis grouped trembling, anxiety, sweating, warmness, and nausea together, and this grouping was labeled an autonomic factor. A second factor was identified that included dizziness, confusion, tiredness, difficulty in speaking, shivering, drowsiness, and inability to concentrate, which was labeled a neuroglycopenic factor.
This study demonstrated the high frequency with which neuroglycopenic symptoms occur at the onset of hypoglycemia and the symptoms that could be used by an individual patient as a warning of the development of acute hypoglycemia, although the rapid reduction of plasma glucose is faster than experienced by the ambulant diabetic patient. Factor analysis assisted with the allocation of symptoms to either the autonomic or neuroglycopenic groupings, but the allocation of some symptoms remained undefined, and care must be taken when assessing symptoms such as hunger, weakness, blurred vision, and drowsiness when comparing the frequency of autonomic versus neuroglycopenic symptoms. To reduce the confusion resulting from the use of different symptom questionnaires in studies of hypoglycemia, a sample questionnaire is presented, the development of which was assisted by our analysis.
We have measured the spatial density of cones and rods in eight whole-mounted human retinas, obtained from seven individuals between 27 and 44 years of age, and constructed maps of photoreceptor density and between-individual variability. The average human retina contains 4.6 million cones (4.08-5.29 million). Peak foveal cone density averages 199,000 cones/mm2 and is highly variable between individuals (100,000-324,000 cones/mm2). The point of highest density may be found in an area as large as 0.032 deg2. Cone density falls steeply with increasing eccentricity and is an order of magnitude lower 1 mm away from the foveal center. Superimposed on this gradient is a streak of high cone density along the horizontal meridian. At equivalent eccentricities, cone density is 40-45% higher in nasal compared to temporal retina and slightly higher in midperipheral inferior compared to superior retina. Cone density also increases slightly in far nasal retina. The average human retina contains 92 million rods (77.9-107.3 million). In the fovea, the average horizontal diameter of the rod-free zone is 0.350 mm (1.25 degrees). Foveal rod density increases most rapidly superiorly and least rapidly nasally. The highest rod densities are located along an elliptical ring at the eccentricity of the optic disk and extending into nasal retina with the point of highest density typically in superior retina (5/6 eyes). Rod densities decrease by 15-25% where the ring crosses the horizontal meridian. Rod density declines slowly from the rod ring to the far periphery and is highest in nasal and superior retina. Individual variability in photoreceptor density differs with retinal region and is similar for both cones and rods. Variability is highest near the fovea, reaches a minimum in the midperiphery, and then increases with eccentricity to the ora serrata. The total number of foveal cones is similar for eyes with widely varying peak cone density, consistent with the idea that the variability reflects differences in the lateral migration of photoreceptors during development. Two fellow eyes had cone and rod numbers within 8% and similar but not identical photoreceptor topography.
Measurements of lactate production and ATP concentration in superfused rat retinas were compared with extracellular photoreceptor potentials (Fast PIII). The effect of glucose concentration, oxygen tension, metabolic inhibition, and light were studied. Optimal conditions were achieved with 5-20 mM glucose and oxygen. The isolated retina had a high rate of lactate production and maintained the ATP content of a freshly excised retina, and Fast PIII potentials were similar to in vivo recordings. Small (less than 10%) decreases in aerobic and anaerobic lactate production were observed after illumination of dark-adapted retinas. There were no significant differences in ATP content in dark- and light-adapted retinas. In glucose-free medium, lactate production ceased, and the amplitude of Fast PIII and the level of ATP declined, but the rates of decline were slower in oxygen than in nitrogen. ATP levels were reduced and the amplitude of Fast PIII decreased when respiration was inhibited, and these changes were dependent on glucose concentration. Neither glycolysis alone nor Krebs cycle activity alone maintained the superfused rat retina at an optimal level. Retinal lactate production and utilization of ATP were inhibited by ouabain. Mannose but not galactose or fructose produced lactate and maintained ATP content and Fast PIII. Iodoacetate blocked lactate production and Fast PIII and depleted the retina of ATP. Pyruvate, lactate, and glutamine maintained ATP content and Fast PIII reasonably well (greater than 50%) in the absence of glucose, even in the presence of iodoacetate. addition of glucose, mannose, or 2-deoxyglucose to medium containing pyruvate and iodoacetate abolished Fast PIII and depleted the retina of its ATP. It is suggested that the deleterious effects of these three sugars depend upon their cellular uptake and phosphorylation during the blockade of glycolysis by iodoacetate.
Conventional electroretinographic techniques do not permit efficient mapping of retinal responsiveness for the detection of small dysfunctional areas. This study explores the application of a new technique that makes such mapping possible. It utilizes a multifocal electroretinogram technique based on binary m sequences that simultaneously tests a large number of small retinal areas by multiplexing their responses onto a single signal derived from the human cornea. The focal responses are subsequently extracted for the derivation of high-resolution maps that characterize retinal responsiveness. The required recording times are short enough to make such testing feasible in the clinic. In this study we demonstrate the high sensitivity of the technique by mapping a small area that has been partially bleached by a strobe flash in a normal retina and by mapping dysfunctional areas in three patients with different, well-documented retinal pathologies. The results suggest that the multifocal electroretinogram has the potential to become a valuable clinical tool.
Hypoglycaemia symptoms are of particular interest in view of the importance of hypoglycaemia unawareness. Visual symptoms arising during acute hypoglycaemia may be the result of metabolic disturbances in the visual pathways within the central nervous system or impairment of the refractive apparatus of the eye and binocular function. This study investigated the effect of hypoglycaemia upon visual acuity, binocular interaction and contrast sensitivity. Various aspects of visual function were examined in ten normal subjects before, during and after acute insulin-induced hypoglycaemia. A simultaneous study of hypoglycaemic symptoms enabled us to relate the objective findings to the symptoms as reported by the subjects. Snellen visual acuity, fusion and stereopsis were not affected by hypoglycaemia. Five subjects noted visual disturbance. Eight developed significant impairment of contrast sensitivity, which closely matched the lowered blood glucose concentration.
These observations suggest that hypoglycaemic visual symptoms are due to neuroglycopenia of central visual pathways rather than changes within the refractive apparatus or abnormality of binocular function. Although these symptoms are not a constant feature of the hypoglycaemic state, subtle impairment of visual function occurs in most cases. Contrast sensitivity testing can be useful for assessment of fine changes in visual function.
A general impairment of cognitive performance occurs during acute insulin-induced hypoglycaemia, but little objective evidence is available for disruption of more specific cognitive processes. The effect of controlled hypoglycaemia on the early stages of visual information processing and contrast sensitivity was examined in a homogeneous group of 20 nondiabetic human subjects. Hypoglycaemia caused a significant disruption in general cognitive performance as assessed by a digit symbol task (P < 0.001) and the trail making B task (P < 0.05). Hypoglycaemia also produced a highly significant deterioration in performance on all of the visual information processing tasks, namely inspection time (IT) (P = 0.01), visual change detection (VCD) (P < 0.005) and visual movement detection (VMD) (P < 0.005). A significant deterioration in contrast sensitivity was observed during hypoglycaemia (P < 0.005). In contrast, no significant effect of hypoglycaemia was demonstrated on standard clinical measures of visual acuity or stereoscopic vision. Thus, although hypoglycaemia caused no detectable deterioration in visual acuity as measured by Snellen-type tests, a marked deterioration occurred in the speed of visual information processing and in contrast sensitivity. As many decisions are made under conditions of limited perceptual time and low visual contrast (e.g. when driving), the disruptive effect of moderate insulin-induced hypoglycaemia on visual perception will have important practical implications in diabetic humans exposed to this metabolic stress. The present results are congruent with other evidence which shows that the early stages of visual information processing are susceptible to deterioration by general cerebral insults.
The multi-input technique of Sutter and Tran (1992) yields multiple focal ERGs. The purpose here was to compare the components of this multifocal ERG to the components of the standard, full-field ERG. To record multifocal ERGs, an array of 103 hexagons was displayed on a monitor. Full-field (Ganzfeld) ERGs were elicited by flashes presented upon steady background fields. The latencies of two prominent subcomponents of the full-field ERG were altered by varying the intensity of the incremental flash or the intensity of the background field. By showing that similar manipulations of the multi-input parameters produce similar changes in latency, we were able to relate the components of the multifocal ERG to the components of the full-field ERG. The biphasic responses of the multifocal ERG appear to be generated by the same cells generating the a-wave and positive peaks of the full-field cone ERG.
The glucose concentration (gl) in mammalian serum incorporates a normal range of variation of several millimoles. We studied the effects of such variations on light-evoked electrical signals in the in vitro arterially perfused cat eye, avoiding extraocular regulatory mechanisms that might confound data interpretation. Changes in gl from the nominal control value of 5 mmol/l were maintained for 5-40 min. Stimuli of near rod threshold intensity were presented in full dark adaptation, and stimuli of higher intensity were presented in the presence of a white background for cone responses. We recorded the dc-electroretinogram (ERG), the scotopic threshold response (STR), the optic nerve response (ONR), and the transretinal slow P-III and transepithelial retinal pigment epithelium c-wave from the subretinal space. The ocular standing potential changed by up to +/- 2 mV in parallel with an increase and decrease in gl, independent of the adaptation condition. Our results show that the rod-ERG, STR, and rod-driven optic nerve response (ONR) have a marked sensitivity to small changes in gl (+/- 1 to 3 mmol/l). The field potentials increased and decreased in parallel with changes in gl. The cone ERG and cone ONR, in contrast, failed to respond consistently to increases in gl and revealed decreases in amplitudes only with an extreme decrease in gl. Decrease in gl, down to 2 mmol/l and less, is known to induce drastic behavioral and electrophysiologic phenomena in the central nervous system. Our results imply that the "normal" glucose level, at least in the cat, could be marginal for rod-mediated retinal function. The results also suggest a marked difference in metabolic mechanisms for cone versus rod photoreceptors.
The purpose of this study was to evaluate the effectiveness of the warm-air box method on the arterialization of venous blood during euglycaemia and hypoglycaemia. Six healthy male volunteers were studied using an i.v. infusion of insulin (144 mU.kg-1.h-1). Arterial blood glucose was clamped at the baseline level for the first 30 min and subsequently reduced to 3.2 and to 2.5 mmol/lf or 20 min. At each stage, including prior to insulin infusion, arterial, arterialized venous (heating the hand in a warm-air box set to 55-60 degrees C), venous and capillary blood samples were taken simultaneously for analyses of blood glucose and oxygen saturation (not for capillary blood). The oxygen saturations in arterialized blood were approximately 3% below the arterial values. The arterial-arterialized difference of blood glucose was about 0.1 mmol/l (the 95% confidence interval: from -0.19 to 0.41 mmol/l), which tended to correlate with the difference in oxygen saturations between the arterial and arterialized blood samples (r = 0.25, p = 0.08). During the test the forearm venous blood oxygen saturation increased by 9% and the arteriovenous difference in blood glucose ranged from 0.2 to 0.5 mmol/l which correlated significantly with the difference in oxygen saturations (r = 0.48, p less than 0.001). Capillary glucose was similar to the arterialized value. Rectal temperature was stable during the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
A technique of multi-input systems analysis is used to explore the field topography of ERG responses to local luminance modulation. Variations in amplitude and wave form are studied within the central 23 degrees. Outside the fovea, the amplitude appears to follow a simple power law rx as a function of eccentricity r where x is approximately -2/3. The largest inter-subject variability is found in the fovea. Some nasal-temporal asymmetry is observed in all subjects with higher response densities in the temporal field outside the blind spot. The topography of the luminance response shares all these properties with the density of retinal cones.
Summary The aim of this study was to discover the frequency, severity and causes of hypoglycaemic reactions in Type 1 (insulin-dependent) diabetes. One hundred and seventy-two outpatients answered a questionnaire which also inquired about their feelings, opinions and fears with respect to insulin reactions. Hypoglycaemic reactions were common: a mild episode occurred at least once a month in 58% of patients, and at least one severe reaction (defined by the need of assistance) during the past year was described by 26%. Both were positively related to the duration of the disease. However, the occurrence of mild and severe attacks was not related. In addition, patients prone to mild hypoglycaemia seem to be somewhat different from patients prone to severe attacks in their attitudes towards the disease. For example, mild reactions are more frequent in patients devoted to perfect control, whereas severe episodes were observed more frequently in those who did not think that controlling diabetes is a difficult task. The social consequences of any reaction, even mild, were important in 30% of the patients. Twenty-one percent of the patients said that the short-term risks of a hypoglycaemic reaction, even if correctly treated, were high and 6% said that the fear of having a reaction was unbearable. In addition to rational explanations, emotional factors were given as a cause of hypoglycaemia (14%), but 11% of cases felt that attacks occured without any obvious reason in spite of correct management.
With the multifocal technique, as developed by Erich Sutter and colleagues, scores of focal electroretinogram (ERG) responses can be obtained in a matter of minutes. Although this technique is relatively new, it has already provided insights into the mechanisms of retinal disease. However, because it is new, there also remain questions about how it works and what it measures. This chapter considers some of these insights and some of these questions. The first part (Section 2) describes how the multifocal ERG (mERG) is recorded and considers its relationship to the full-field ERG. The mERG responses are shown to be from relatively local regions of the retina and are comprised of the same components as the full-field ERG. The diagnostic advantage of the mERG as compared to the full-field ERG is also illustrated. In Section 3, the effects of damage to different cell layers of the retina are shown to affect the mERG differently, and these changes are summarized within a conceptual framework. It is argued, for example, that when diseases of the receptor outer segment, like retinitis pigmentosa, result in small, depressed mERG responses, then the damage is, as expected, at the outer segment. However, when these diseases result in mERG responses that are reasonably large but very delayed, then the damage is beyond the outer segment, probably in the outer plexiform layer. The implicit time of the mERG, not amplitude, is the more sensitive measure of damage in degenerative diseases of the receptors. On the other hand, diseases, like glaucoma, which act on the ganglion axon, do not result in easily identified changes to the mERG unless inner retinal damage is involved as well. Inner retinal damage changes the waveform of the mERG and decreases the naso-temporal variation normally observed. Finally, diseases, like diabetes, that act on more than one layer of the retina can have a range of effects. In Section 4, recent work with the monkey mERG is reviewed, with emphasis on the relevance to human diseases. For example, blocking the sodium-based action potentials produced by ganglion and amacrine cells eliminates the naso-temporal variation in the monkey mERG and these altered mERG responses resemble those from some patients with diabetes or glaucoma. Finally, in Section 5 the second-order kernel is described. The presence of a second-order kernel has important implications for understanding the shape of the mERG response (first-order kernel). Full-field simulations of the mERG paradigm illustrate that the first-order kernel is comprised of responses with different waveforms. Further, it is argued that the nonlinear, adaptive mechanisms that produce the second-order kernel are involved in shaping the time course of the response. Patients with large, but abnormally delayed mERG responses (first-order kernel), do not have a detectable second-order kernel. It is speculated that a markedly diminished second-order kernel is diagnostic of outer plexiform layer damage, not inner plexiform layer damage as is commonly assumed.
Human and macaque retinae have similar retinal vascular anatomy. The general features of the retinal vascular anatomy of these two primates have much in common with more widely studied animal models such as rat and cat. However, primates are unique amongst mammals in having a region in temporal retina specialized for high visual acuity, which includes the fovea centralis (or ‘fovea’). Several features distinguish the fovea from other parts of the retina, including a very high local density of cone photoreceptors, a high density of inner retinal cells during development, and an absence of retinal blood vessels.
The retina is among the most metabolically active tissues in the body, requiring a constant supply of blood glucose to sustain function. We assessed the impact of low blood glucose on the vision of C57BL/6J mice rendered hypoglycemic by a null mutation of the glucagon receptor gene, Gcgr. Metabolic stress from moderate hypoglycemia led to late-onset loss of retinal function in Gcgr(-/-) mice, loss of visual acuity, and eventual death of retinal cells. Retinal function measured by the electroretinogram b-wave threshold declined >100-fold from age 9 to 13 months, whereas decreases in photoreceptor function measured by the ERG a-wave were delayed by 3 months. At 10 months of age Gcgr(-/-) mice began to lose visual acuity and exhibit changes in retinal anatomy, including an increase in cell death that was initially more pronounced in the inner retina. Decreases in retinal function and visual acuity correlated directly with the degree of hypoglycemia. This work demonstrates a metabolic-stress-induced loss of vision in mammals, which has not been described previously. Linkage between low blood glucose and loss of vision in mice may highlight the importance for glycemic control in diabetics and retinal diseases related to metabolic stress as macular degeneration.
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