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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biochemical and ultrastructural effects of the aldose reductase inhibitor sorbinil were examined in two experimental rat models of chronic diabetic neuropathy: rats with streptozocin-induced diabetes (STZ-D) and rats fed a galactose-enriched diet. The frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic ganglia of rats with untreated 8-mo STZ-D increased sevenfold compared with that in age-matched controls. Animals chronically maintained on a diet containing 50% galactose, however, did not develop neuroaxonal dystrophy in excess of that found in untreated age-matched control rats. Institution of sorbinil therapy at the time of induction of STZ-D decreased, but did not completely normalize, the frequency of neuroaxonal dystrophy without altering the severity of diabetes; this finding is based on measurements of plasma glucose, body weight, food consumption, 24-h urine volume, and levels of glycosylated hemoglobin. Sorbitol levels in the superior cervical sympathetic ganglia (SCG) of untreated 8-mo-diabetic animals increased three- to fourfold compared with levels in controls. The increase in sorbitol content of diabetic SCG was completely prevented by early institution of dietary sorbinil therapy. The myo-inositol content of 8-mo-diabetic SCG was modestly decreased compared with controls. Sorbinil administration improved but did not completely normalize diabetic SCG myo-inositol. The sorbitol content of the SCG, superior mesenteric and celiac sympathetic ganglia, and a major trunk of the superior mesenteric nerve of short-term (2.5-mo)-diabetic rats increased comparably, but only the diabetic SCG showed a decrease in myo-inositol.
Diabetes 1989 May
PMID:Effects of aldose reductase inhibitor sorbinil on neuroaxonal dystrophy and levels of myo-inositol and sorbitol in sympathetic autonomic ganglia of streptozocin-induced diabetic rats. 249 38

Sorbitol levels were determined in lens of genetically obese (ob/ob) and diabetic (db/db) mice, as well as in lean mice (+/db, +/ob) made diabetic by administration of streptozotocin (STZ). Treatment of lean mice with STZ resulted in hypoinsulinemia, whereas the ob/ob and db/db mice were hyperinsulinemic. Hyperglycemia was present in STZ-treated +/db and +/ob mice and in db/db mice, whereas relative euglycemia was observed in ob/ob mice and untreated +/db and +/ob mice. Sorbitol levels were elevated in lens tissue of db/db mice and STZ-treated +/db. In contrast, no changes in sorbitol content were observed in ob/ob mice and +/ob mice treated with STZ, suggesting that aldose reductase activity in lens of this animal model is considerably less than that present in db/db mice. Oral treatment of db/db mice and STZ-treated +/db mice with Ponalrestat reduced hyperglycemia-induced sorbitol accumulation significantly in lens, indicating that aldose reductase inhibitors may ameliorate long-term complications associated with sorbitol accumulation in diabetes.
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PMID:The effect of ponalrestat on sorbitol levels in the lens of obese and diabetic mice. 251 Jul 26

Intracellular accumulation of sorbitol, generated from D-glucose via the aldose reductase pathway, is thought to play an important role in diabetic complications such as lens cataracts and neuropathy. In order to elucidate the effect of diabetes on the renal inner medulla, another sorbitol-rich tissue, male Wistar rats were treated with a single dose of streptozotocin (60 mg/kg body weight, i.p.). Six weeks later total inner medullary tissue (IM) or isolated inner medullary collecting duct (IMCD) cells were prepared. In diabetic IM tissue, sorbitol content was 1.8-fold higher than in control IM tissue (134 +/- 17 vs. 74 +/- 22 mumol/g tissue protein). Sorbitol production in both normal and diabetic IMCD cells was strongly dependent on extracellular D-glucose concentration. In normal cells, for example, sorbitol production was 90 +/- 9 mumol sorbitol/g protein x h at 45 mM D-glucose compared to 13 +/- 1 mumol/g protein x h at 5 mM. At identical D-glucose concentrations sorbitol synthesis in diabetic IMCD cells was, however, always significantly higher than in control cells (122% of control at 15 mM and 126% of control at 45 mM). In addition, aldose reductase activity in diabetic IM was found to be augmented. The maximal velocity was 4.2 times higher (97 +/- 22 U/g protein vs. 23 +/- 7 U/g protein) while the Km of the enzyme remained unchanged. Membrane permeability for sorbitol or the response to changes in extracellular osmolarity was not significantly different in diabetic IMCD cells and normal cells with correspondingly high intracellular sorbitol concentrations. Similarly the kinetic parameters of D-glucose uptake were not altered by streptozotocin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sorbitol metabolism in inner medullary collecting duct cells of diabetic rats. 252 20

Renal inner medullary cells accumulate high concentrations of organic solutes. Sorbitol and glycerophosphorylcholine accumulation (concentration) increase progressively from the outer medulla to the papillary tip. Inositol accumulation is the reverse; its concentration decreases from the outer medulla to the papillary tip. Diabetes mellitus (1 week) increases sorbitol at all levels of the inner medulla, decreases glycerophosphorylcholine and has little effect on inositol. Thin slices of the inner medulla incubated in vitro concentrate inositol and choline from the medium. Although the inner medullary cells are permeable to sorbitol, membrane transport appears to play no role in its accumulation.
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PMID:Organic solute profiles and transport in the rat renal medulla. 280 1

Sorbitol accumulation, myo-inositol depletion, and reduced Na+-K+-ATPase activity have been identified in experimental diabetes in several tissues in which diabetic complications occur. However, a reduction in renal Na+-K+-ATPase activity has not been universally reported, prompting us to examine the influence of diabetes duration on the activity of this enzyme complex in isolated glomeruli. Additionally, we examined the ability of the aldose reductase inhibitor sorbinil to directly stimulate glomerular Na+-K+-ATPase activity in vitro, an area of interest in view of the central position that the ability of sorbinil to restore Na+-K+-ATPase activity in vivo occupies in the interpretive scheme that links associated changes in sorbitol, myo-inositol, and Na+-K+-ATPase to enhanced polyol-pathway activity. Glomerular Na+-K+-ATPase activity was significantly decreased in rats with acute (less than 18 days) streptozocin-induced diabetes but was significantly greater than control values in rats with more chronic (greater than 32 days) diabetes. In vitro addition of sorbinil (1 x 10(-7) M) directly stimulated Na+-K+-ATPase in control (0.627 +/- 0.090 vs. 0.843 +/- 0.098 mumol P1.mg-1.min-1) but not diabetic glomeruli. These results indicate that the time of examination after induction of diabetes critically influences glomerular Na+-K+-ATPase activity and suggest that sorbinil, at least in normal glomerular tissue, has a membrane-associated effect that may be independent of its aldose reductase-inhibiting property.
Diabetes 1988 May
PMID:Glomerular Na+-K+-ATPase activity in acute and chronic diabetes and with aldose reductase inhibition. 283 50

Recent clinical data strongly suggest that elevated urinary albumin excretion (UAE) identifies diabetic subjects at risk of developing nephropathy. Elevated UAE is attributed to increased transglomerular pressure, which is associated with poor metabolic control in rats. Because excess glucose in diabetes is metabolized via the polyol pathway, we were interested in whether the diabetes-induced elevation in UAE in rats could be prevented by inhibiting aldose reductase (AR), the first enzyme in the polyol pathway, with the AR inhibitor tolrestat. In fact, in rats made diabetic with streptozocin (35 mg/kg IV), treatment for 6 months with tolrestat (25 mg/kg/day in the diet) prevented both sorbitol accumulation in the kidney and the increase in UAE. Sorbitol accumulation and the increased UAE were not associated with statistically significant mesangial expansion, and the thickening of glomerular basement membranes was not affected by tolrestat treatment. The authors conclude that the 4.7-fold elevation in UAE in chronically diabetic rats is linked to the increased flux of glucose through the polyol pathway since it was prevented by inhibiting aldose reductase with tolrestat.
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PMID:Prevention of urinary albumin excretion in 6 month streptozocin-diabetic rats with the aldose reductase inhibitor tolrestat. 296 49

Sugar cataract formation has been demonstrated to result from lenticular sorbitol accumulation. In the lens, the activity of aldose reductase has been observed to increase with the onset of diabetes, while the activity of sorbitol dehydrogenase decreases. This shift in activities of these two Sorbitol Pathway enzymes favors the increased accumulation of sorbitol. Immunohistochemical studies with antibodies prepared against purified rat lens aldose reductase reveal a striking increase in immunoreactive positive staining for aldose reductase in lenses from diabetic rats. Two weeks after the onset of diabetes, increased immunohistochemical staining for aldose reductase appears beneath the epithelial region where water cleft formation occurs, and the intensity of this staining increases with the formation of vacuoles. By 6-8 weeks, the presence of large vacuoles and areas of liquifaction containing dense immunoreactive stain can be observed. Examination of human cataractous lenses with antibodies prepared against purified human placenta aldose reductase suggest similar increases in immunoreactive staining in the human diabetic lens. Cataractous lenses from diabetic patients revealed increased immunoreactive staining for aldose reductase, which was associated with the presence of vacuoles in both the anterior or posterior superficial cortical layers. Examination of similar vacuole containing regions from non-diabetic cataractous lenses revealed no increase in immunoreactive staining for aldose reductase. These results suggest that the enhanced activity of aldose reductase observed in diabetes is due to an increased amount of enzyme, rather than enzyme activation.
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PMID:Immunohistochemical localization for aldose reductase in diabetic lenses. 310 Apr 73

Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus. Spiro hydantoins derived from five- and six-membered ketones fused to an aromatic ring or ring system inhibit aldose reductase isolated from calf lens. In vivo these compounds are potent inhibitors of sorbitol formation in sciatic nerves of streptozotocinized rats. Optimum in vivo activity is reached in spiro hydantoins derived from 6-halogenated 2,3-dihydro-4H-1-benzopyran-4-ones (4-chromanones). In 2,4-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione, the activity resides exclusively in the 4S isomer, compound 115 (CP-45,634, USAN: sorbinil). This compound is currently being used to test, in humans, the value of aldose reductase inhibitors in the therapy of diabetic complications.
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PMID:Spiro hydantoin aldose reductase inhibitors. 312 57

Sorbitol concentration has been measured in retina, optic, and sural nerve of normal, diabetic, and aldose reductase inhibitor-treated diabetic rats. The sural nerve displayed significantly higher sorbitol content than the retina and the optic nerve both in control animals and in diabetic animals. In the sural nerve the response to treatment with an aldose reductase inhibitor was more marked than in the two other tissues. The activities of aldose reductase and sorbitol dehydrogenase were not influenced by diabetes. It is suggested that aldose reductase inhibition may be of greater use for alleviating peripheral nervous system accumulation of sorbitol than for hindering CNS accumulation of the polyol.
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PMID:Sorbitol metabolism in the retina, optic nerve, and sural nerve of diabetic rats treated with an aldose reductase inhibitor. 314 49

Sorbitol metabolism of the endothelial cells of the aorta has been studied in normal and alloxan diabetic rats by the aid of a new time- and gradient governed elution method. In the normal rats the amount of sorbitol was small whereas in the diabetic animals the content was significantly increased (p less than 0.001). The activity of sorbitol-dehydrogenase was not changed. It is possible that a metabolic injury of endothelial cells induced by a glucose overload may be mediated by formation of sorbitol.
Diabetes Res 1988 Jun
PMID:Sorbitol in aortic endothelium of diabetic rats. 322 72


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