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PubMed2005

Spray-drying of proteins: effects of sorbitol and trehalose on aggregation and FT-IR amide I spectrum of an immunoglobulin G.

An immunoglobulin G (IgG) was spray-dried on a Buchi 190 laboratory spray-dryer at inlet and outlet air temperatures of 130 and 190 degrees C, respectively. The IgG solution contains initially 115 mg/ml IgG plus 50 mg/ml sorbitol. After dialysis, at least 80% of low molecular weight component was removed. After spray-drying the dialyzed IgG and immediate redissolution of the powder, an increase in aggregates from 1 to 17% occurred. A major shift towards increase beta-sheet structure was detected in the spray-dried solid, which, however, reverted to native structure on redissolution of the powder. A correlation between aggregation determined by size exclusion chromatography and alterations in secondary structure determined by Fourier transformation infra-red spectroscopy could not therefore be established. On spray-drying a non-dialyzed, sorbitol-containing IgG only some 0.7% aggregates were formed. The sorbitol is therefore evidently able to stabilize partially the IgG during the process of spray-drying. Addition of trehalose to the liquid feed produced quantitatively the same stabilizing action on the IgG during spray-drying as did the sorbitol. This finding again points towards a water replacement stabilization mechanism. The IgG spray-dried powder prepared from the dialyzed liquid feed showed continued substantial aggregation on dry storage at 25 degrees C. This was substantially less in the non-dialyzed, sorbitol-containing spray-dried powder. Addition of trehalose to both dialyzed and non-dialyzed system produced substantial improvement in storage stability and reduction in aggregate formation in storage. The quantitative stabilizing effect of the trehalose was only slightly higher than that of the sorbitol. Taken together, these results indicate that both the sorbitol and trehalose stabilize the IgG primarily by a water replacement mechanism rather than by glassy immobilization. The relevance of this work is its questioning of the importance of the usually considered dominance of glassy stabilization of protein in dried systems of high glass transition temperature, such as trehalose. The low glass transition temperature sorbitol produces almost equal process and storage stability in this case.

Humans↗
PubMed2003

Dissolution of sucrose crystals in the anhydrous sorbitol melt.

The dissolution of a sugar (sucrose as a model) with higher melting point was studied in a molten food polyol (sorbitol as a model) with lower melting point, both in anhydrous state. A DSC and optical examination revealed the dissolution of anhydrous sucrose crystals (mp 192 degrees C) in anhydrous sorbitol (mp 99 degrees C) liquid melt. The sucrose-sorbitol crystal mixtures at the proportions of 10, 30, 60, 100 and 150 g of sucrose per 100 g of sorbitol were heat scanned in a DSC to above melting endotherm of sorbitol but well below the onset temperature of melting of sucrose at three different temperatures 110, 130 and 150 degrees C. The heat scanning modes used were with or without isothermal holding. The dissolution of sucrose in the sorbitol liquid melt was manifested by an increase in the glass transition temperature of the melt and corresponding decrease in endothermic melting enthalpy of sucrose. At given experimental conditions, as high as 25 and 85% of sucrose dissolved in the sorbitol melt during 1 h of isothermal holding at 110 and 150 degrees C, respectively. Optical microscopic observation also clearly showed the reduction in the size of sucrose crystals in sorbitol melt during the isothermal holding at those temperatures.

Calorimetry, Differential Scanning↗
PubMed1998

Improved fluorometric enzymatic sorbitol assay in human blood.

Samples for use in the fluorometric enzymatic assay of sorbitol in erythrocytes are normally prepared using HClO4 and K2CO3. We have replaced these reagents with NaOH and ZnSO4. Human whole blood, erythrocyte and plasma samples prepared with NaOH and ZnSO4 are colorless and clear, while erythrocyte samples prepared with HClO4 and K2CO3 are a pale yellow-brown color. The sorbitol dehydrogenase reaction in the supernatant of the mixture of NaOH and ZnSO4 is inhibited, but ethylenediaminetetraacetate completely eliminates this effect. The sorbitol assay in erythrocytes prepared with NaOH and ZnSO4 shows higher sensitivity and reproducibility than did that with HClO4 and K2CO3. Recovery of sorbitol added to erythrocytes is similar in both assay methods. Concentrations of whole blood and erythrocyte sorbitol assayed by the present method are significantly higher in diabetics than in normals. Poorly controlled diabetics had higher whole blood and erythrocyte sorbitol than well-controlled diabetics. Whole blood sorbitol concentrations differed more between diabetic and normal subjects than did erythrocyte sorbitol concentrations.

Adult↗
PubMed2002

Sorbitol activates atypical protein kinase C and GLUT4 glucose transporter translocation/glucose transport through proline-rich tyrosine kinase-2, the extracellular signal-regulated kinase pathway and phospholipase D.

Sorbitol, "osmotic stress", stimulates GLUT4 glucose transporter translocation to the plasma membrane and glucose transport by a phosphatidylinositol (PI) 3-kinase-independent mechanism that reportedly involves non-receptor proline-rich tyrosine kinase-2 (PYK2) but subsequent events are obscure. In the present study, we found that extracellular signal-regulated kinase (ERK) pathway components, growth-factor-receptor-bound-2 protein, son of sevenless (SOS), RAS, RAF and mitogen-activated protein (MAP) kinase/ERK kinase, MEK(-1), operating downstream of PYK2, were required for sorbitol-stimulated GLUT4 translocation/glucose transport in rat adipocytes, L6 myotubes and 3T3/L1 adipocytes. Furthermore, sorbitol activated atypical protein kinase C (aPKC) through a similar mechanism depending on the PYK2/ERK pathway, independent of PI 3-kinase and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Like PYK2/ERK pathway components, aPKCs were required for sorbitol-stimulated GLUT4 translocation/glucose transport. Interestingly, sorbitol stimulated increases in phospholipase D (PLD) activity and generation of phosphatidic acid (PA), which directly activated aPKCs. As with aPKCs and glucose transport, sorbitol-stimulated PLD activity was dependent on the ERK pathway. Moreover, PLD-generated PA was required for sorbitol-induced activation of aPKCs and GLUT4 translocation/glucose transport. Our findings suggest that sorbitol sequentially activates PYK2, the ERK pathway and PLD, thereby increasing PA, which activates aPKCs and GLUT4 translocation. This mechanism contrasts with that of insulin, which primarily uses PI 3-kinase, D3-PO(4) polyphosphoinositides and PDK-1 to activate aPKCs.

3T3 Cells↗
PubMed2006

Silencing leaf sorbitol synthesis alters long-distance partitioning and apple fruit quality.

Sorbitol and sucrose are major products of photosynthesis distributed in apple trees (Malus domestica Borkh. cv. "Greensleeves") that affect quality in fruit. Transgenic apple plants were silenced or up-regulated for sorbitol-6-phosphate dehydrogenase by using the CaMV35S promoter to define the role of sorbitol distribution in fruit development. Transgenic plants with suppressed sorbitol-6-phosphate dehydrogenase compensated by accumulating sucrose and starch in leaves, and morning and midday net carbon assimilation rates were significantly lower. The sorbitol to sucrose ratio in leaves was reduced by approximately 90% and in phloem exudates by approximately 75%. The fruit accumulated more glucose and less fructose, starch, and malic acid, with no overall differences in weight and firmness. Sorbitol dehydrogenase activity was reduced in silenced fruit, but activities of neutral invertase, vacuolar invertase, cell wall-bound invertase, fructose kinase, and hexokinase were unaffected. Analyses of transcript levels and activity of enzymes involved in carbohydrate metabolism throughout fruit development revealed significant differences in pathways related to sorbitol transport and breakdown. Together, these results suggest that sorbitol distribution plays a key role in fruit carbon metabolism and affects quality attributes such as sugar-acid balance and starch accumulation.

Fruit↗
PubMed1994

Vitamin C: an aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus.

OBJECTIVE: Diabetic hyperglycemia promotes sorbitol production from glucose via aldose reductase. Since the intracellular accumulation of sorbitol, or its sequelae, are postulated to contribute to the progression of chronic diabetic complications, aldose reductase inhibitors (ARI) offer therapeutic promise. Others have shown that vitamin C at pharmacologic doses decreases erythrocyte (RBC) sorbitol. We examined whether smaller, physiologic doses of vitamin C were also effective in individuals with insulin-dependent diabetes mellitus (IDDM) and whether vitamin C was an ARI in vitro. METHODS: Vitamin C supplements (100 or 600 mg) were taken daily for 58 days by young adults with IDDM and nondiabetic adults in an otherwise free-living design. Diabetic control was monitored by fasting plasma glucose, glycosylated hemoglobin, and glycosuria and was moderate to poor throughout the study. RBC sorbitol was measured at baseline and again at 30 and 58 days. Three-day dietary records and 24-hour urine collections were performed for each sampling day. RESULTS: RBC sorbitol levels were significantly elevated in IDDMs, on average doubled, despite their more than adequate dietary intakes of vitamin C and normal plasma concentrations. Vitamin C supplementation at either dose normalized the RBC sorbitol in IDDMs within 30 days. This correction of sorbitol accumulation was independent of changes in diabetic control. Furthermore, our in vitro studies show that ascorbic acid inhibited aldose reductase activity. CONCLUSIONS: Vitamin C supplementation is effective in reducing sorbitol accumulation in the erythrocytes of diabetics. Given its tissue distribution and low toxicity, we suggest a superiority for vitamin C over pharmaceutic ARIs.

Adult↗
PubMed1994

Initial catabolism of sorbitol in Actinomyces naeslundii and Actinomyces viscosus.

The initial steps of sorbitol catabolism were studied in 4 strains of Actinomyces naeslundii and Actinomyces viscosus that had been isolated from human dental plaque. Cell-free extracts were prepared from cells grown in the presence of either sorbitol, xylitol or glucose. The extracts from all strains grown on sorbitol had nicotinamide adenine dinucleotide-linked dehydrogenase activities for sorbitol and xylitol and reduced nicotinamide adenine dinucleotide-linked reductase activities for fructose and xylulose. Two of the strains also exhibited these activities when grown in the presence of xylitol, and all glucose-grown cells lacked them. The results indicate that sorbitol metabolism in oral actinomyces involve oxidation of sorbitol to fructose by an inducible enzyme, nicotinamide adenine dinucleotide-linked sorbitol dehydrogenase. This step is followed by the phosphorylation of fructose with guanosine triphosphate as a main phosphoryl donor. Thus, the initial catabolic pathway of sorbitol in A. naeslundii and A. viscosus is different from those described for other oral bacteria.

Actinomyces↗
PubMed1996

Reversible inhibition of sheep liver sorbitol dehydrogenase by thiol compounds.

Reversible inhibition of sheep liver sorbitol dehydrogenase by various thiol compounds has been studied. Most species inhibit the enzyme-catalyzed reaction competitively with respect to sorbitol, due to the formation of ternary enzyme-NAD-thiol complexes. The primary interaction of thiol inhibitors with the enzyme active site involves the catalytic zinc atom, and a bidentate mode of binding to the active site metal is indicated for some bifunctional thiols in their ternary complexes. Enzyme-bound thiolate facilitates NAD binding to the enzyme and vice versa, mainly due to mutual electrostatic stabilization. The aromatic thiols 1-thio-1-phenylmethane and 1-thio-2-phenylethane are especially potent inhibitors with an inhibition constant of 0.30 microM at pH 9.9. The inhibitory effect of aliphatic thiols, which is positively correlated with alkyl chain length, parallels that observed previously with the related enzyme horse liver alcohol dehydrogenase and indicates that interaction with an enzymic hydrophobic site is important for inhibitor binding. Several reversible inhibitors afford competitive protection against affinity labelling of the enzyme by 2-bromo-3-(5-imidazolyl) propionic acid due to the formation of binary enzyme-thiol complexes. The present study establishes thionucleosides as a novel class of potent sorbitol dehydrogenase inhibitors. The thionucleosides 6-thioguanosine and 6-thioinosine gave mixed inhibition with respect to sorbitol, due to the formation of enzyme-NAD-inhibitor and enzyme-NADH-inhibitor complexes. In order to enable a correlation of the substrate and inhibitor specificities of the enzyme, the kinetic constants for several sorbitol dehydrogenase substrates were determined. L-threitol and DL-1-phenyl-1,2-ethanediol are good substrates with, at high pH, kinetic constants similar to those of sorbitol. The potent inhibition by dithiothreitol and the aromatic thiols thus parallels the substrate specificity of the enzyme. The sorbitol competitive inhibitor 1-thiosorbitol is also a substrate with, at pH 7.4, a maximum velocity of 0.17 s-1 and a Michaelis constant of 8.6 mM. Dithiothreitol forms a tight ternary complex with the enzyme-NAD complex with a molar absorbance of 16.4 x 10(3) M-1 . cm-1 at 311 nm. A spectrophotometric titration of the enzyme with NAD in the presence of dithiothreitol is described, which enables an accurate determination of the concentration of sorbitol dehydrogenase active sites and confirms the activity assay of the enzyme.

Affinity Labels↗
PubMed1994

Red blood cell sorbitol in diabetic children.

When red blood cells (RBC) were incubated with various concentrations of glucose, the RBC sorbitol level increased in a concentration-dependent manner. The elevated RBC sorbitol level was not reduced by further incubation in a glucose-free medium. In both diabetic and non-diabetic children, an increase of RBC sorbitol levels occurred in the oral glucose tolerance test and the return to baseline was delayed in diabetics compared with non-diabetics. In the majority of diabetics (87%), RBC sorbitol levels exceeded the upper limit of the normal range, which was arbitrarily determined as the mean + 2 s.d., in healthy non-diabetic children and adults. A good correlation was observed between RBC sorbitol levels and plasma glucose levels (r = 0.644). In both diabetics and non-diabetics, no correlation was observed between RBC sorbitol levels and age, and in diabetics the RBC sorbitol level was not related to the duration of disease. A good correlation was observed between RBC sorbitol levels, and hemoglobin Alc (HbAlc) or fructosamine levels in diabetic children.

Adolescent↗
PubMed1993

Adaptation of dental plaque to sorbitol after 3 months' exposure to chewing gum.

Five subjects used sorbitol-containing chewing gum for a period of 12 wk. Plaque was collected before and after the sorbitol exposure and also 12 wk after the termination of the exposure. The individual plaque samples were incubated with 14C-labeled sorbitol, and the medium was examined by HPLC. It was found that plaque samples from all subjects catabolized more sorbitol after the exposure. The flora adapted to sorbitol was persistent, and all the subjects had a higher capacity for metabolizing sorbitol even 12 wk after the end of the sorbitol exposure than before it. Formate, acetate, ethanol, and lactate were the major catabolites of sorbitol. Small amounts of succinate and propionate were found in some samples.

Acetates↗
PubMed2005

An optimized enumeration method for sorbitol-fermenting Bifidobacteria in water samples.

With increased focus on watershed protection under the Surface Water Treatment Rule, indicators that discriminate among sources of microbial inputs (microbial source tracking) are needed to supplement the quantitative information provided by total and fecal coliform measurements for drinking water monitoring. Bifidobacteria are found in the digestive tract and feces of humans and other animals, and also in sewage. Sorbitol is a food additive used exclusively in food intended for human consumption. Therefore, the presence of sorbitol-fermenting Bifidobacteria in environmental waters can be indicative of sources of human fecal contamination. A series of media were evaluated using ATCC cultures of B. breve and B. adolescentis, feces from different animals, and domestic wastewater samples. The media evaluated were Human Bifid Sorbitol agar (HBSA), modified Human Bifid Sorbitol agar, Beerens Medium, modified Beerens Medium, Reinforced Clostridial agar, BIM-25 Medium, and modified BIM-25 Medium. Variables such as sample preservation, incubation time, different pH indicators, plating technique, and discontinuous exposure to sorbitol were also evaluated. A series of biochemical tests were used to confirm positive colonies enumerated on the various media. Membrane filtration and enumeration of sodium sulfite preserved samples on HBSA containing bromocresol purple using loose lidded plates for 48 h provided the best recoveries for presumptive positive colonies. A number of sorbitol-fermenters that were not Bifidobacteria were able to grow on all media tested, resulting in false-positives. Therefore, plating on HBSA should be followed by a confirmation step when monitoring for sorbitol-fermenting Bifidobacteria in environmental waters. A year-long sampling survey of a managed reservoir in Massachusetts provided field validation of the proposed methodology for sorbitol-fermenting Bifidobacteria as a human-related source tracking indicator tool.

Bifidobacterium↗
PubMed1991

Sorbitol permease: an apical membrane transporter in cultured renal papillary epithelial cells.

The efflux of sorbitol from the rabbit papillary epithelial cell line PAP-HT25 occurs through a specific transport pathway, which we denote the "sorbitol permease." The permease was studied by measuring cell volume changes that accompanied osmotic swelling and by determination of the sorbitol efflux from plasma membrane vesicles. The cell volume studies showed that sorbitol efflux in response to hypotonicity occurred only across the apical membrane of the cells and that loss of sorbitol was the primary mechanism for regulatory volume decrease (RVD) by these cells. Quinidine, a permeant inhibitor of the sorbitol permease, was shown to prevent RVD when added to either apical or basolateral bathing solution. Cell volume experiments also showed that the permease was present only on the apical membrane of cells that had been grown in isotonic medium and did not accumulate sorbitol. The permease could be demonstrated in membrane vesicles obtained from cells exposed to a hypotonic environment before being homogenized. Quinidine blocked the sorbitol efflux from vesicles indicating that it either directly inhibited the permease or a membrane-associated activation step.

Animals↗
PubMed1986

The effect of oxidation on sorbitol pathway kinetics.

The rapid conversion of glucose to sorbitol by aldose reductase and the consequent hyperosmolarity of the cytoplasm has been shown to be the primary cause of the so-called "sugar" or "osmotic" cataract in many animal lenses. It is not as clear, however, that hyperosmolarity is the principal factor in the etiology of cataracts in human diabetic subjects. In fact, the comparatively low activity of aldose reductase in the human lens as compared with several animal lenses, and the osmotically insignificant levels of sorbitol pathway products (sorbitol and fructose), suggest that hyperosmolarity, per se, may not be as important a factor in human cataract formation as it is in animals. We present evidence that the flux of glucose and sorbitol through the rat lens is markedly reduced by oxidative stress (0.1 mM H2O2). Sorbitol accumulation is reduced by 114%, sorbitol turnover is reduced by 78%, sorbitol production is reduced by 90%, fructose accumulation is reduced by 60%, and fructose turnover is reduced by 76% in the presence of 36 mM glucose. H2O2 does not affect glucose turnover, the glucose rate constant, or the ATP level significantly at 36 mM glucose, but at 5.5 mM glucose, 0.2 mM H2O2 leads to a rapid loss of ATP that can be prevented by 0.04 mM sorbinil, an aldose reductase inhibitor. These results suggest that inhibition of aldose reductase by sorbinil renders rat lenses better able to cope with oxidative stress. In the absence of an aldose reductase inhibitor, elevating ambient glucose may render a lens less able to scavenge oxidants by diverting NADPH into sorbitol production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1998

Effects of sorbitol dehydrogenase deficiency on nerve conduction in experimental diabetic mice.

In this report, we made use of sorbitol dehydrogenase (SDH)-deficient mutant mice (C57BL/LiA) to test whether there is a close correlation between the level of polyol accumulation and the degree of reduction in motor nerve conduction velocity (MNCV) associated with diabetes. The C57BL/LiA mouse has SDH deficiency due to a G-to-A mutation at the +1 position of intron 8, thus producing only aberrant SDH transcripts. These C57BL/LiA mice should have higher levels of polyol accumulation in the peripheral nerve because of the inability to further metabolize sorbitol to fructose. Here, we confirm by Western blot analysis and high-performance liquid chromatography that these mice lack SDH in the sciatic nerve and other various tissues, whereas normal mice possess SDH. These C57BL/LiA mice do not display any obvious phenotype that includes peripheral neuropathy in the normal laboratory environment and breed normally as described previously, although the tissues that normally contain SDH accumulate more sorbitol. This finding suggested that C57BL/LiA mouse strain is a valid model for studying the role in diabetic neuropathy of the polyol pathway, which consists of two enzymes-aldose reductase for converting glucose to sorbitol and SDH for converting sorbitol to fructose. Sorbitol levels in the sciatic nerve of diabetic C57BL/10N, nondiabetic, and diabetic C57BL/LiA mice were increased 4.3-, 16.6-, and 38.1-fold, respectively, above that of nondiabetic C57BL/10N. The fructose level in the sciatic nerve was increased 2.4-fold in diabetic C57BL/10N mice compared with that of nondiabetic and diabetic C57BL/LiA mice. Diabetic SDH-deficient mice showed an MNCV reduction similar in magnitude to that of diabetic C57BL/10N mice, despite greater nerve sorbitol accumulation and the lack of fructose in the former. The present data suggest that the levels of sorbitol and fructose in the sciatic nerve of mice do not correlate with the severity of MNCV deficit associated with diabetes.

Animals↗
PubMed1990

Isolation of acid producing sorbitol-adapted bacteria from dental plaque using selective agar media.

Acidogenic bacteria metabolizing sorbitol were isolated and identified from dental plaque of twenty nine volunteers, claiming to be users (sixteen) and non-users (thirteen) of sorbitol-containing chewing gum and candy. Sixty bacterial strains were isolated, using improved selective agar media. The taxonomy of twenty strains, all Gram-positive cocci, was determined employing a customized BBL MinitekR system and other biochemical reactions. The majority of these strains represented Streptococcus sanguis and Streptococcus acidominimus. Although sorbitol-metabolizing bacteria were found in plaque specimens of most persons tested, a larger number of acidogenic sorbitol degrading bacteria was detected in the plaque of the volunteer group claiming to use sorbitol-containing sweets. Bacteriological results indicate that frequent consumption of sorbitol-containing products will lead to a shift in oral ecology, numerically favouring sorbitol-metabolizing bacteria. These sorbitol adapted bacteria appear to be as acidogenic as Streptococcus mutans in the presence of ordinary sugars.

Adult↗
PubMed1995

Sorbitol absorption in the healthy human small intestine is increased by the concomitant ingestion of glucose or lipids.

OBJECTIVE: To test the effect of the concomitant ingestion of glucose or lipids on sorbitol absorption in the human small intestine using the hydrogen breath test. METHOD: After an overnight fast, on four occasions separated by at least 1 week 14 healthy volunteers randomly ingested 20 g sorbitol alone, 20 g sorbitol and 20 g glucose, 20 g sorbitol and 9 g lipids, and 10 g lactulose. Hydrogen concentration was measured in end-expiratory samples every 10 min for 3 h, and then every 30 min for 5 h. Sorbitol malabsorption was calculated from the ratio of the areas under the curve. RESULTS: The estimated rate of sorbitol malabsorption was 98 +/- 14% (mean +/- SEM) when sorbitol was ingested alone, and was significantly lower when ingested with glucose or lipids (68 +/- 10 and 70 +/- 7%, respectively; P < 0.05). Orocaecal transit times did not differ significantly between the different time periods. CONCLUSION: Sorbitol absorption in the human small intestine is increased by the concomitant ingestion of glucose or lipids.

Adult↗
PubMed1994

[Reduction of erythrocyte sorbitol by ascorbic acid in patients with diabetes mellitus].

The content of erythrocyte sorbitol could be reduced by ascorbic acid (AA). To confirm the effect of AA on human erythrocyte sorbitol accumulation and explore its mechanism of the action, we studied in vitro the effects of ascorbic acid on the contents of both sorbitol and glucose in human erythrocytes. The effect of AA on the ratio of sorbitol to glucose in erythrocyte (S/EG) which was referred to as a marker of aldose reductase (AR) activity was observed. Both the accumulation of erythrocyte sorbitol and S/EG were reduced by the addition of ascorbic acid (AA) during in vitro incubations. The sorbitol content in the erythrocyte and S/EG were reduced by a maximum of 87.3%, 83.4% and 93.8%, 63.9% when the medium's AA concentration was at its peak in the 5.6 mmol/L and 28 mmol/L glucose concentration of medium respectively. These suggested that the activity of polyol pathway could be inhibited effectively by AA which might directly act on the activity of AR. The results of a double-blind cross-over trial using AA tablets or inert inositol tablets in 8 diabetic patients showed that the supplementation of 1,000 mg AA/day continued for 2 weeks resulted in reductions of 12.2% and 21.8% in both erythrocyte sorbitol and red cell sorbitol: plasma glucose (S/PG) ratio, respectively (P < 0.05). The fasting plasma glucose levels measured coincidently revealed no changes (P > 0.05). This suggests that the supplementation of moderate AA (1,000 mg/day) might provide a simple, safe and effective means of preventing and ameliorating chronic complications of diabetes.

Adolescent↗
PubMed1999

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study.

AIMS/HYPOTHESIS: Studies of the role of sorbitol dehydrogenase in nerve functional deficits induced by diabetes reported contradictory results. We evaluated whether sorbitol dehydrogenase inhibition reduces metabolic abnormalities and enhances oxidative stress characteristic of experimental diabetic neuropathy. METHODS: Control and streptozotocin-diabetic rats were treated with or without sorbitol dehydrogenase inhibitor (SDI)-157 (100 mg x kg(-1) x day(-1), in the drinking water, for 3 weeks). Sciatic nerve free mitochondrial (cristae and matrix) and cytosolic NAD(+): NADH ratios were calculated from the beta-hydroxybutyrate, glutamate and lactate dehydrogenase systems. Concentrations of metabolites, e. g. sorbitol pathway intermediates and variables of energy state were measured in individual nerves spectrofluorometrically by enzymatic procedures. RESULTS: The flux through sorbitol dehydrogenase (manifested by nerve fructose concentrations) was inhibited by 53 % and 74 % in control and diabetic rats treated with SDI compared with untreated control and diabetic groups. Free NAD(+):NADH ratios in mitochondrial cristae, matrix and cytosol were decreased in diabetic rats compared with controls and reduction in either of the three variables was not prevented by sorbitol dehydrogenase inhibitor. Phosphocreatine concentrations and phosphocreatine:creatine ratios were decreased in diabetic rats compared with controls and were further reduced by the inhibitor. Malondialdehyde plus 4-hydroxyalkenals concentration was increased and reduced gluthathione concentration was reduced in diabetic rats compared with the control group, and changes in both variables were further exacerbated by sorbitol dehydrogenase inhibitor. Neither NAD-redox and energy states nor lipid aldehyde and reduced gluthathione concentrations were affected by treatment with the inhibitor in control rats. CONCLUSION/INTERPRETATION: Inhibition of sorbitol dehydrogenase does not offer an effective approach for prevention of oxidation and metabolic imbalances in the peripheral nerve that is induced by diabetes and is adverse rather than beneficial. [Diabetologia (1999) 42: 1187-1194]

Animals↗