In utero and milk-mediated effect of aldose reductase inhibitor on galactose cataracts

Unakar, Nalin J.; Tsui, Jane; Johnson, Margaret; Dang, Loan

doi:10.1016/0014-4835(91)90227-6

Cited by 6 publications

(3 citation statements)

References 17 publications

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“…Similar morphological disturbances as in the present study have been noted previously among offspring of diabetic rats (Giavini et al 1987;Giavini & Prati 1990), and in offspring of rats fed with extra galactose (Bannon et al 1945). Interestingly, the development of cataracts in offspring of galactose-fed rats can be inhibited by administration of an AR inhibitor to the pregnant rat mother (Unakar et al 1991). The combined set of 634 data, including the present findings, therefore suggest that the formation of the congenital cataract is associated with increased polyol pathway activity, in analogy with the pathogenesis of the adult sugar cataract.…”

Section: Discussionsupporting

confidence: 92%

“…In the latter condition large amounts of dulcitol accumulates in the fetal lens. Furthermore, administration of an aldose reductase inhibitor to the pregnant rat diminishes the formation of dulcitol as well as the incidence of cataract in the offspring (Unakar et al 1991), findings which suggest that accumulation of the polyols are involved in the development of cata-racts in these fetuses. The repeated findings of increased polyol content of several tissues affected by complication in diabetic animals with severe hyperglycemiai.e.…”

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confidence: 99%

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Increased lenticular aldose reductase activity and high incidence of congenital cataract in the offspring of diabetic rats

Naeser

Eriksson

1993

Acta Ophthalmologica

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In previous experimental studies we have found a 47% incidence of congenital cataracts among the fetuses of manifestly diabetic (MD) rats, and 4% of the offspring of normal (N) rats. The aim of the present study was to clarify the role of the sorbitol shunt in the pathogenesis of this congenital defect. Light microscopical evaluation of the fetal lenses revealed excessive formation of vacuoles in offspring of MD rats compared to N offspring. On gestational day 16 we found that aldose reductase (AR) activity was doubled in the lenses of fetuses of MD rats as compared to that of N fetuses. This difference as well as the net activity of AR declined in both groups during subsequent development. The sorbitol concentration was elevated more than ten-fold in the MD fetal lenses compared to N fetal lenses at all time points. The sorbitol concentration in both the MD and the N group decreased from day 16 to day 20 and increased again slightly on day 22. We conclude that the diabetic uterine milieu induces elevated AR activity and sorbitol formation in the fetal lens. This over-activity of the sorbitol shunt may produce metabolic and osmotic imbalances in the fetal lens, resulting in excessive vacuole formation and subsequent development of congenital cataract.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Increased lenticular aldose reductase activity and high incidence of congenital cataract in the offspring of diabetic rats

Naeser

Eriksson

1993

Acta Ophthalmologica

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“…This model is reminiscent of rodent models for human type 2 diabetes mellitus by stressing with excess glucose to examine the effect of exaggerated polyol pathway activity on the target tissues as an analogy for human, organ-specific complications [33, 173–180]. With normal insulin responses, these rodent models had little analogy to type 2 human diabetes [30, 181, 182].…”

Section: Animal Models For Galactosemia and Experimental Hypergalactomentioning

confidence: 99%

Galactose toxicity in animals

2009

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SummaryIn most organisms, productive utilization of galactose requires the highly conserved Leloir pathway of galactose metabolism. Yet, if this metabolic pathway is perturbed due to congenital deficiencies of the three associated enzymes, or an overwhelming presence of galactose, this monosaccharide which is abundantly present in milk and many non-dairy foodstuffs, will become highly toxic to humans and animals. Despite more than four decades of intense research, little is known about the molecular mechanisms of galactose toxicity in human patients and animal models. In this contemporary review, we take a unique approach to present an overview of galactose toxicity resulting from the three known congenital disorders of galactose metabolism and from experimental hypergalactosemia. Additionally, we update the reader about research progress on animal models, as well as advances in clinical management and therapies of these disorders.

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The role of polyols in the pathophysiology of hypergalactosemia

Berry

1995

Eur J Pediatr

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Cellular accumulation of galactitol has been suggested to cause the apparent dietary-independent, long-term complications in classic galactosemia. Experimental animals rendered hypergalactosemic by galactose feeding accumulate tissue galactitol, as well as millimolar quantities of galactose, and manifest biochemical, physiological and pathological abnormalities which are generally eliminated or curtailed by the concomitant administration of an aldose reductase inhibitor. This includes reduced cellular content of the cyclic polyol, myo-inositol, which like galactitol may function as an alternate intracellular osmolyte. However, the abnormalities detected in experimental galactosemic animals are more compatible with findings in experimental diabetes mellitus than in human galactosemia. Because patients with galactokinase deficiency fail to manifest the CNS and ovarian complications which characterize classic galactosemia, yet during long-term lactose restriction excrete comparable urinary quantities of galactitol, this polyol alone is not likely to play an important role during postnatal life in the pathogenesis of long-term complications. Notwithstanding, a role for either galactitol or myo-inositol in an intrauterine toxicity cannot be dismissed.

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In utero and milk-mediated effect of aldose reductase inhibitor on galactose cataracts

Cited by 6 publications

References 17 publications

Increased lenticular aldose reductase activity and high incidence of congenital cataract in the offspring of diabetic rats

Increased lenticular aldose reductase activity and high incidence of congenital cataract in the offspring of diabetic rats

Galactose toxicity in animals

The role of polyols in the pathophysiology of hypergalactosemia

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