Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wide-field specular microscopy was used to examine the central corneal endothelium of age- and sex-matched beagle dogs fed for up to 32 months either normal control diets containing 30% nonnutrient filler (13 dogs) or diets containing 30% galactose with (13 dogs) or without (12 dogs) concomitant treatment with the aldose reductase inhibitor, sorbinil. Computerized morphometric analysis of the endothelial cells indicated that a significant decrease in cell density and increase in mean cell area occurred in untreated galactose-fed dogs after 32 months of feeding compared with the normal controls. However, no significant difference could be observed in similar galactose-fed dogs treated with sorbinil. No significant difference in the coefficient of variation of the area, or percent hexagonality of the endothelial cells, or the corneal thickness could be observed in any group. These findings demonstrated that endothelial abnormalities were present in the cornea of the galactose-fed dogs which were similar to those reported for diabetic dogs, rats, and patients and that these changes can be prevented by the concomitant administration of an aldose reductase inhibitor. These findings suggest a role for aldose reductase in the abnormalities noted in the corneal endothelium in diabetes and galactosemia.
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PMID:The effects of sorbinil, an aldose reductase inhibitor, on the corneal endothelium in galactosemic dogs. 212 61

We measured motor nerve conduction velocity (MNCV), Na(+)-K(+)-ATPase activity, polyol-pathway metabolites, and myo-inositol in sciatic nerves from control mice, galactose-fed (20% wt/wt diet) mice, and galactose-fed mice given the aldose reductase inhibitor ponalrestat (300-mg/kg diet). Treatments were maintained for 4 wk. Galactose feeding was associated with a 21.5% reduction in MNCV (P less than 0.001), which was almost completely prevented by ponalrestat. Galactose-fed mice showed an 81% increase in Na(+)-K(+)-ATPase (P less than 0.01), an effect completely prevented by aldose reductase inhibition. Treatment of a separate galactose-fed group with sorbinil (300 mg/kg diet) also attenuated the MNCV deficit and prevented the increased Na(+)-K(+)-ATPase activity associated with galactosemia. Accumulation of galactitol in the nerves of galactose-fed mice was prevented by aldose reductase inhibition, but there were no alterations in myo-inositol levels in the sciatic nerves of any group. These data show that exaggerated flux through the polyol pathway can cause an MNCV deficit that is unrelated to either myo-inositol levels or NA(+)-K(+)-ATPase activity.
Diabetes 1990 Jun
PMID:Coexistence of nerve conduction deficit with increased Na(+)-K(+)-ATPase activity in galactose-fed mice. Implications for polyol pathway and diabetic neuropathy. 216 66

This study showed that steady-state kinetics of ATP hydrolysis by Na(+)-K(+)-ATPase are altered in the BB Wistar diabetic rat and experimental galactosemia. Four days after onset, this change was not evident if NaCNBH3 was omitted during enzyme preparations (indicating reversibility). Ninety days after onset, NaCNBH3 reduction was not necessary to see the change in ATP hydrolysis kinetics (indicating nonreversibility). The change in steady-state ATP hydrolysis was similar to that reported earlier for Na(+)-K(+)-ATPase of the lens epithelium and kidney medulla of diabetic individuals and for two in vitro glycosylation models. Our study also showed that the affinities of Na(+)-K(+)-ATPase for K+ are altered, and Na(+)-K(+)-ATPase-dependent K+ occlusion is inhibited in diabetic and galactosemic animals. Because K+ occlusion is required for efficient K+ transport, this finding supports previous in vitro studies that indicated that glycosylation inhibits pump-dependent K+ transport. Furthermore, our study suggested an irreversible impairment of Na(+)-K(+)-ATPase function in the diabetic BB Wistar rat as early as 15 days after onset, even when blood glucose was maintained at 6.7 mM by daily insulin injection.
Diabetes 1990 Dec
PMID:Na(+)-K(+)-ATPase and changes in ATP hydrolysis, monovalent cation affinity, and K+ occlusion in diabetic and galactosemic rats. 217 7

To evaluate the role of hyperglycemia and excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes, motor nerve conduction velocity (MNCV) was measured in dogs alloxan diabetic or experimentally galactosemic for 5 years. Diabetic dogs in poor glycemic control showed a progressive decline of MNCV from baseline values. Diabetic dogs that had been randomly assigned to good glycemic control retained normal MNCV. Nondiabetic dogs made galactosemic by a 30% galactose diet developed erythrocyte polyol concentrations many-fold greater than in diabetic animals, but the MNCV remained unchanged and comparable to that of normal dogs. Nerve polyol levels, when compared in short-term diabetic dogs or dogs galactose-fed 2 to 4 months, were elevated at least as much by the galactose-rich diet as by diabetes. Thus, in dogs, excessive tissue polyol accumulation is associated with subnormal MNCV in diabetes, but not in experimental galactosemia.
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PMID:Nerve conduction velocity in dogs is reduced by diabetes and not by galactosemia. 235 80

Experimental dietary galactosemia is known to result in accumulation of the polyol, galactitol, via the aldose reductase metabolic pathway in a variety of tissues, including renal glomeruli. Because increased polyol accumulation also occurs in insulin-dependent diabetes mellitus (IDDM), in which marked renal glomerular hyperperfusion occurs, we have studied glomerular hemodynamics in rats with experimental galactosemia. Insulin deficiency and its accompanying metabolic disorders are not present in this experimental model. In additional groups of animals, aldose reductase inhibitors, either sorbinil or tolrestat, were added to the galactose diet. In all, five groups of rats were studied: regular diet, 50% galactose diet, regular diet plus sorbinil, 50% galactose diet plus sorbinil, and 50% galactose plus tolrestat. The diets were comparable in protein and salt, and the rats were pair fed. Micropuncture and whole kidney clearance measurements were carried out after 10-14 days on these diets. Compared with rats fed the regular diet, those fed with 50% galactose diet had significantly higher glomerular filtration rates, renal plasma flow, single-nephron glomerular filtration rates, and plasma flow (QA), whereas afferent vascular resistance (RA) was decreased. Addition of sorbinil or tolrestat to the high-galactose diet not only prevented renal hyperperfusion but RA and single-nephron filtration fraction (SNFF) were higher than in normal rats, and QA was lower. In addition, sorbinil administration to rats on the control diet caused significant decreases in single-nephron blood flow and the ultrafiltration coefficient and a rise in SNFF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Galactose feeding causes glomerular hyperperfusion: prevention by aldose reductase inhibition. 250 30

Blood viscosity was investigated in alloxan-diabetic dogs and in dogs made experimentally hyperglycemic by a galactose-rich diet. The diabetics were prospectively assigned to levels of glycemic control ranging from poor to good. After up to 5 years of study, the blood viscosity of hyperglycemic diabetic animals was significantly greater than normal at both high (100 sec-1) and low (0.1 sec-1) shear rates. Blood viscosity at the low shear rate correlated closely with fibrinogen concentration, (r = 0.75; p less than 0.02) but not with HbA1 concentration (r = 0.14) in the diabetics. Galactosemic animals likewise had elevated blood viscosity at the low shear rate, but the correlation of viscosity with fibrinogen concentration in those animals was not statistically significant (r = 0.42). Plasma viscosity tended to be elevated in both diabetes and galactosemia, but not to a statistically significant degree.
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PMID:Elevated blood viscosity in alloxan diabetic dogs and experimentally galactosemic dogs. 252 59

Diabetic retinopathy involves anatomic changes in retinal vessels and neuroglia. The pathogenetic mechanism responsible for retinopathy is imperfectly understood, but much of the mechanism is apparently reproduced by experimental diabetes in animals and by chronic elevation of blood galactose in nondiabetic animals. The evidence that retinopathy is a consequence of excessive blood sugars and their sequelae is consistent with a demonstrated inhibition of retinopathy by strict glycemic control in diabetic dogs. However, retinopathy in the dog model has shown a tendency to resist intervention by strict control. Biochemical and pathophysiological sequelae of hyperglycemia possibly critical to the development of retinopathy in humans and animal models are being studied in many laboratories. Retinopathy occurs in experimental galactosemia in the absence of the renal hypertrophy, mesangial expansion, and glomerular obliteration typical of diabetes in humans and dogs, implying that retinopathy and nephropathy differ appreciably in pathogenesis.
Diabetes 1989 Oct
PMID:Pathogenesis of diabetic retinopathy. 267 55

Dogs were randomly assigned to experimental galactosemia or diabetes, or to a normal untreated group, and diabetic animals were then randomly assigned to either poor or good glycemic control. At five years duration, kidneys from the animals were compared by quantitative stereology. Glomerulopathy appeared in the poor control diabetes group, and the thickness of glomerular capillary basement membrane, the glomerular tuft volume, and the fraction of glomerulus occupied by mesangium were each significantly greater than normal. The capillary filtering surface area per glomerulus was supranormal also, but nonetheless was subnormal relative to glomerular volume. The development of glomerulopathy was significantly inhibited in dogs assigned to good glycemic control. In galactosemic animals, the basement membrane thickness was greater than normal, but the glomerular volume, fractional and absolute volumes of mesangium, and capillary filtering surface area remained normal. The polyol concentration in renal cortex seemed elevated by galactosemia no less than by diabetes, and was highest in galactosemia. The galactosemic animals are known to have developed a retinopathy morphologically comparable to that of diabetic patients and diabetic dogs. Thus, sequelae of hyperglycemia sufficient to produce glomerular basement membrane thickening and retinopathy proved not necessarily sufficient to produce the mesangial expansion and glomerular hypertrophy typical of diabetes.
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PMID:Hyperglycemia and development of glomerular pathology: diabetes compared with galactosemia. 281 Oct 56

Cataracts associated with diabetes and galactosemia are characterized by their rapid onset and bilateral appearance. These cataracts display similar morphology and histology and have common biochemical mechanisms initiating the cataractous processes. An understanding of these biochemical mechanisms have been aided both by the ability to reproduce these cataracts in various animal models and by the development of potent inhibitors of aldose reductase. This is a US government work. There are no restrictions on its use.
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PMID:The effect of aldose reductase and its inhibition on sugar cataract formation. 308 4

Diabetes mellitus is marked by hyperglycemia and a variety of other metabolic disorders. The significance of hyperglycemia in the pathogenesis of diabetic retinopathy has proven difficult to evaluate in patients. Diabetic dogs are known to develop retinal lesions morphologically identical to those typical of diabetes in man, provided hyperglycemia in the animal is allowed to persist at least for many months and usually for 3 to 5 years. The development of retinopathy in this animal model can be inhibited by careful improvement of diabetic (glycemic) control. Comparable retinopathy has recently been found to develop in nondiabetic dogs as a result of experimental galactosemia of several years' duration. Included in this retinopathy and in the retinopathy of diabetic patients and dogs as well are saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, varicose vessels, and loss of capillary pericytes. Retinal capillary basement membrane has been measured (to date) in two dogs that had been galactosemic for 5 years, and it was found to be significantly thicker than in normal dogs (P less than 0.01). Many metabolic abnormalities typical of diabetes are absent from galactosemic dogs. Unlike diabetic dogs, the blood levels of glucose, nonesterified fatty acids, branched-chain amino acids, and fibrinogen are not elevated in the galactosemic dogs, and their serum insulin concentration seems normal. Excessive blood hexose itself appears to be an important determinant of retinopathy. One possible mechanism by which excessive blood hexose might produce retinopathy involves the polyol pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperglycemia as a cause of diabetic retinopathy. 308 5


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