Hypoglycemia leads to age-related loss of vision

Abstract

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.C57BL/6J mice ͉ cell death ͉ glucagon receptor gene ͉ retinal function ͉ visual acuity C hanges in metabolism can affect vision. Lowering blood glucose (BG) can decrease human visual sensitivity (1-3) as does reducing the partial pressure of inhaled oxygen (4). Natural nighttime decreases in glucose availability (5, 6) parallel a decline in visual sensitivity that can be restored by glucose ingestion (7). In the cat, acute decreases in glucose supply can transiently reduce retinal sensitivity (8) and exacerbate the effects of hypoxia on the retina (9). The effects of metabolite supply on vision are not surprising in view of the high energy consumption by the retina (10, 11). Although the retina's high metabolic activity has been known for Ͼ40 years (12), the consequences of an inadequate supply of metabolites are not completely understood.We report here that a chronic decrease in BG in mice decreases retinal function, leading to a loss of vision and eventual degeneration of the retina. We observed decreases in both electroretinogram (ERG) a-and b-waves, as well as a loss in visual acuity. Retinal cell death, assayed by TUNEL, was increased in Gcgr Ϫ/Ϫ mice, and decreases in cell number were detected. These data indicate that a chronic decrease in BG leads to loss of vision and cell death in mice and highlight the possibility that the human retina may likewise be susceptible to hypoglycemia. ResultsGlucagon Receptor and Changes in BG. Hypoglycemia was induced in C57BL/6J mice by a null mutation of the glucagon receptor gene, Gcgr (13). Among its actions, the glucagon receptor under control of glucagon regulates gluconeogenesis to increase BG levels. Liver and kidney abundantly express Gcgr, and PCR analysis reveals trace levels of receptor mRNA in the retina of wi...

Reentrant spiral waves of spreading depression cause macular degeneration in hypoglycemic chicken retina

“…Our results suggest that spontaneous and recurrent SD may be initiated in the macula during hypoglycemia and can lead to macular degeneration. Progressive expansion of retinal lesions in an aging mouse has been reported as a result of chronic hypoglycemia induced by disruption of the glucagon receptor gene, Gcgr (15), although the time course was vastly slower than that we observed with SD in the chicken retina. Blockade of SD may represent a useful therapeutic approach not only to prevent retinal degeneration resulting from fluctuations in glucose levels in diabetes but also in other conditions, including focal brain ischemia, where the number of episodes of SD correlates with the expansion of focal ischemic lesions (37)(38)(39), spiral propagation of SD results in an expanding cortical lesion (39), and repetitive SD waves may involve hypoglycemic regions in the penumbra.…”

“…Linkage between low glucose levels and loss of vision highlight the importance of glycemic control in diabetics to prevent retinal injury such as macular degeneration (15). Our results suggest that spontaneous and recurrent SD may be initiated in the macula during hypoglycemia and can lead to macular degeneration.…”

“…Recovery can occur in minutes, but repeated episodes of SD increase neuronal loss surrounding traumatic brain lesions, and have been implicated in other central nervous system (CNS) pathologies, including migraine (14). SD has been demonstrated in a number of taxa, including fishes, amphibians, reptiles, birds, and mammals (8, 9).The retina is an energy-demanding tissue and is very sensitive to interruption of its supply of oxygen and glucose in both avian and mammalian tissue (15,16). Hypoglycemia, a condition that facilitates the initiation of cerebral SD in rats (17), appears to lead to retinal cell death and gradual loss of visual acuity in aging mice (15).…”

“…Hypoglycemia, a condition that facilitates the initiation of cerebral SD in rats (17), appears to lead to retinal cell death and gradual loss of visual acuity in aging mice (15). Here we used the ex vivo chicken retina, an established system in which waves of SD can be visualized as areas of increased light scattering (8).…”

“…The retina is an energy-demanding tissue and is very sensitive to interruption of its supply of oxygen and glucose in both avian and mammalian tissue (15,16). Hypoglycemia, a condition that facilitates the initiation of cerebral SD in rats (17), appears to lead to retinal cell death and gradual loss of visual acuity in aging mice (15).…”