Abstract
ObjectiveGlucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. MethodsIn this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Müller cells to elucidate the underlying mechanisms of action in vitro. ResultsGlucosamine did not alter the blood glucose or HbA1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Müller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. ConclusionsIn conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care.
Highlights
The hexosamine biosynthesis pathway (HBP), a nutrient-sensing pathway, accounts for 2e5% of the total glucose flux under normal conditions [1] and combines elements of glucose, amino acid, fatty acid, and nucleotide metabolisms
It causes vascular damage in the retina, inducing pericyte loss and acellular capillary formation in non-diabetic retinas, which might be a result of interfering with endothelial survival signals
Our results are consistent with a study conducted by Chen et al, who demonstrated that glucosamine treatment protects the retina against neuronal injury in an ischemia/reperfusion-induced rat glaucoma model by hampering damage to retinal ganglion cells [15]
Summary
The hexosamine biosynthesis pathway (HBP), a nutrient-sensing pathway, accounts for 2e5% of the total glucose flux under normal conditions [1] and combines elements of glucose, amino acid, fatty acid, and nucleotide metabolisms. Activation of the HBP and protein O-GlcNAcylation are considered key mediators in the initiation and progression of diabetic complications such as diabetic retinopathy and diabetic nephropathy [2,3]. Diabetic retinopathy is characterized morphologically by the loss of pericytes and subsequent disappearance of endothelial cells from capillaries. This leads to the formation of acellular capillaries that consist of only the vascular basement membrane and do not support blood flow, resulting in the progression of the disease [4]. The pathology of diabetic retinopathy is exemplified by vascular damage, and neuronal damage. The hyperglycemia-induced vascular and neuronal damage in the retina is modulated by the interplay of oxidative stress, inflammation, and aberrant growth factor signaling via VEGF-A and Angiopoietin-2 (Ang2) [8e10]
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