The inhibitory effect of D-glucosamine on thymidine kinase in chick embryo retinas and HeLa cells

Tesoriere, Giovanni; Tesoriere, Luisa; Vento, Renza; Giuliano, Michela; Cantoro, Giulio

doi:10.1007/bf01949733

Cited by 1 publication

(1 citation statement)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specific alterations in glycosylation of N-linked glycoproteins such as IR and IGF-IR may, therefore, be endogenous signals for the induction of apoptosis in neuronal cells, because glucosamine also affected IR processing in L6 cells with no induction of apoptosis. On the other hand, previous papers (59,60) indicated that glucosamine as well as tunicamycin preferentially kill tumorigenic cells rather than nontumorigenic cells. Therefore, inhibition of N-glycosylation may have induced apoptosis in R28 cells in part because they are immortalized cells.…”

Section: Discussionmentioning

confidence: 93%

Excessive Hexosamines Block the Neuroprotective Effect of Insulin and Induce Apoptosis in Retinal Neurons

Nakamura¹,

Barber²,

Antonetti

et al. 2001

Journal of Biological Chemistry

163

101

View full text Add to dashboard Cite

In addition to microvascular abnormalities, neuronal apoptosis occurs early in diabetic retinopathy, but the mechanism is unknown. Insulin may act as a neurotrophic factor in the retina via the phosphoinositide 3-kinase/Akt pathway. Excessive glucose flux through the hexosamine biosynthetic pathway (HBP) is implicated in the development of insulin resistance in peripheral tissues and diabetic complications such as nephropathy. We tested whether increased glucose flux through the HBP perturbs insulin action and induces apoptosis in retinal neuronal cells. Exposure of R28 cells, a model of retinal neurons, to 20 mM glucose for 24 h attenuated the ability of 10 nM insulin to rescue them from serum deprivation-induced apoptosis and to phosphorylate Akt compared with 5 mM glucose. Glucosamine not only impaired the neuroprotective effect of insulin but also induced apoptosis in R28 cells in a dose-dependent fashion. UDP-N-acetylhexosamines (UDP-HexNAc), end products of the HBP, were increased ϳ2-and 15-fold after a 24-h incubation in 20 mM glucose and 1.5 mM glucosamine, respectively. Azaserine, a glutamine:fructose-6-phosphate amidotransferase inhibitor, reversed the effect of 20 mM glucose, but not that of 1.5 mM glucosamine, on attenuation of the ability of insulin to promote cell survival and phosphorylate Akt as well as accumulation of UDP-HexNAc. Glucosamine also impaired insulin receptor processing in a dose-dependent manner but did not decrease ATP content. By contrast, in L6 muscle cells, glucosamine impaired insulin receptor processing but did not induce apoptosis. These results suggest that the excessive glucose flux through the HBP may direct retinal neurons to undergo apoptosis in a bimodal fashion; i.e. via perturbation of the neuroprotective effect of insulin mediated by Akt and via induction of apoptosis possibly by altered glycosylation of proteins. The HBP may be involved in retinal neurodegeneration in diabetes. Diabetic retinopathy (DR)1 is usually considered a disease of the microvasculature, but significant involvement of neuronal components has been implicated as well. Previous studies by us and others (1, 2) indicate that neuronal cells in the retina, including ganglion cells, undergo apoptosis both in rats and humans with early diabetes. The pro-apoptotic BAX protein was also reported to be induced in neuronal as well as vascular components of the retina in patients with diabetes (3). However, the mechanism of the neurodegeneration in DR remains open to debate. Because insulin administration reduced the rate of apoptosis in streptozotocin-diabetic rats (2), systemic metabolic compromise such as hyperglycemia or defective insulin action, or both, adversely affects neuronal survival in the retina.Insulin is known to act as a neurotrophic factor in cultured neuronal cells including retinal ganglion cells (4, 5). Insulin exerts a broad array of biological responses by binding to its specific receptors and activating the intracellular signaling cascades such as the IRS-1/PI3K/Akt pathway. Our recen...

show abstract

Section: Discussionmentioning

confidence: 93%