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PubMed1980

Red cell sorbitol: an indicator of diabetic control.

Intact human erythrocytes accumulate intracellular sorbitol in response to the medium's glucose concentration during in vitro incubations. Sorbitol was identified and measured both enzymatically and by gas-liquid chromatography. The sorbitol produced is most likely a result of the activity of aldose reductase, since (1) a low glucose concentration in the medium elicits this response, and (2) this activity is completely blocked by tetramethylene glutaric acid, a specific inhibitor of aldose reductase. Erythrocyte sorbitol levels in insulin-dependent diabetics are clearly above those of nondiabetics after an 8 h fast. A good correlation exists between red cell sorbitol content and coincident plasma glucose concentrations. Individual exceptions to this rule exist, however, and suggest that red cell sorbitol levels may provide information about in vivo polyol pathway activity that may be important in the pathogenesis of diabetes-associated complications.

Blood Glucose↗
PubMed1984

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Administration, Oral↗
PubMed1986

Increased accumulation of sorbitol in offspring of manifest diabetic rats.

The effects of maternal diabetes on somatic development and activity of the polyol pathway were investigated during early and late gestation in a rat model for diabetic pregnancy. We studied embryo-fetal growth, mortality, and malformation rate in the offspring of nondiabetic rats and in the offspring of diabetic rats either treated with an aldose reductase inhibitor during gestation or left untreated. The numbers of embryo-fetal resorptions and malformations were significantly increased in the diabetic groups compared with the controls despite maternal treatment with the aldose reductase inhibitor. The sorbitol content of embryos and membranes from the diabetic rats in early gestation was increased 3-5 times over the control values. Similarly, elevated sorbitol levels were observed in the fetal livers and placentas of the diabetic rats in late gestation. Administration of the aldose reductase inhibitor to the pregnant diabetic rats normalized the sorbitol levels in the embryos and their membranes, whereas the sorbitol contents of the fetal livers and placentas were significantly lowered but not completely corrected. Furthermore, in the diabetic groups, no differences in sorbitol levels could be demonstrated between malformed and nonmalformed offspring. The results of this study suggest that enhanced polyol metabolism leading to increased sorbitol accumulation is present in the embryos of diabetic mothers as early as organogenesis. This accumulation is apparently not a major factor in the early developmental disturbances (e.g., growth perturbations and congenital malformations) of diabetic pregnancy.

Animals↗
PubMed1992

Variation in sorbitol accumulation and polyol-pathway activity in cultured human proximal tubule cells.

The polyol pathway is present in tissues of several organs where its activation may participate in the development of diabetic complications. We measured the accumulation of polyol-pathway intermediates in HPT cells isolated from 21 different human kidneys from nondiabetic individuals. When exposed to 27.5 mM glucose in the growth media, cells isolated from approximately 75% of individuals (accumulators) accumulated sorbitol within 1-4 days, whereas 25% (nonaccumulators) accumulated only negligible amounts, even when the period of exposure was extended to 2 wk. Surprisingly, measurement of the activities of the polyol-pathway enzymes showed no difference in the levels of either AR or SDH between accumulators and nonaccumulators, even when the conversion of galactose to galactitol was used to measure AR activity in intact cells independently of SDH. Measurement of sorbitol in the growth media indicated that nonaccumulators were not releasing sorbitol into the growth media. Fructose levels in the conditioned growth media were 4 times higher in the sorbitol-accumulating cells. Together, these results indicate that the tendency of cells from an individual to accumulate significant amounts of sorbitol may reflect the cells' ability to metabolize sorbitol in steps subsequent to the polyol pathway.

Aldehyde Reductase↗
PubMed1990

Clinical significance of erythrocyte sorbitol-blood glucose ratios in type II diabetes mellitus.

The polyol pathway has been implicated in the pathogenesis of diabetic complications. To determine the activity of the polyol pathway, the ratio of erythrocyte sorbitol to blood glucose, which reflects aldose reductase activity, was evaluated in 329 patients with type II (non-insulin-dependent) diabetes mellitus and in 100 nondiabetic age-matched control subjects. Although erythrocyte sorbitol levels were markedly elevated, sorbitol-glucose ratios were significantly lower in diabetic patients than in nondiabetic subjects. Sorbitol-glucose ratios in diabetic patients decreased progressively as blood glucose and hemoglobin A1c (HbA1c) levels increased. Sorbitol-glucose ratios were also studied during a 75-g oral glucose tolerance test. Ratios were again lower in diabetic patients than those in nondiabetic subjects and significantly decreased 120 min after glucose loading. The ratio in diabetic patients also fell with increasing age of the patients. In diabetic patients with neuropathy, retinopathy, or nephropathy, however, sorbitol-glucose ratios were significantly higher than in those without these complications; ratios increased further as complications became more severe. Our findings suggest that the affinity of aldose reductase for glucose in patients with diabetic complications may be increased and that the polyol pathway is implicated in the pathogenesis of diabetic complications.

Biomarkers↗
PubMed1990

Effect of culture medium on acid production from sorbitol by oral bacteria.

The fermentation of sorbitol or glucose and the acid production by strains belonging to the genera Actinomyces, Lactobacillus, and Streptococcus isolated from the predominant sorbitol-fermenting human dental plaque flora were studied in cultures in complex or defined bacteriologic broths and in saliva-based broth. The growth yields of Lactobacillus and Streptococcus in the saliva-based media and of Actinomyces in the defined broth were poor. Addition of fermentable carbohydrate to the saliva-based broth favored the growth of Streptococcus and Lactobacillus but not that of Actinomyces. The results showed obvious differences in the capacity of oral bacteria to ferment sorbitol between cultures in saliva-based and bacteriologic broths. Lactobacillus failed to utilize sorbitol when saliva was the only source of nutrients. Lower proportions of lactic and formic acids were formed from sorbitol by Actinomyces and Lactobacillus in the saliva-based than in the bacteriologic media. The findings illustrate some mechanisms possibly involved in the interactions between sorbitol and dental plaque flora.

Actinomyces↗
PubMed1983

Pulmonary hydrogen and methane and plasma ammonia after the administration of lactulose or sorbitol.

The gut microfloral metabolism of sorbitol and lactulose was investigated in 10 healthy control subjects and 10 patients with cirrhosis of the liver, by measuring the pulmonary excretion of the fermentational gases hydrogen and methane during 3 h. A possible acute effect on venous plasma ammonia after a single dose of sorbitol or lactulose was also investigated. No significant difference in fermentation gas excretion was found after ingestion of sorbitol compared with lactulose in healthy controls or cirrhotic patients (p greater than 0.05). Neither sorbitol nor lactulose had significant effect on plasma ammonia concentrations during the first 3 h after ingestion. These findings indicate that both sorbitol and lactulose are extensively fermented by the colonic flora and that the possibility of replacing lactulose with the much cheaper sorbitol in the treatment of portal-systemic encephalopathy ought to be investigated. The suggested acute gut-ammonia trapping effect of lactulose caused by acidification of the gut lumen from fermentative end-products was not supported by the present findings.

Adult↗
PubMed1992

Symptom provocation in irritable bowel syndrome. Effects of differing doses of fructose-sorbitol.

The role of fructose and sorbitol, when ingested together, in the aetiology of irritable bowel syndrome (IBS) is controversial. The aims of this study in IBS patients, therefore, were to compare differences in symptom provocation with various doses of fructose-sorbitol and to relate differences in the extent of colonic hydrogen production after each dose to such symptom provocation. Two different mixtures of fructose and sorbitol--20 g fructose plus 3.5 g sorbitol ('lower' dose) and 25 g fructose plus 5 g sorbitol ('higher' dose)--were administered to 15 patients with IBS and to 24 healthy controls. Breath hydrogen concentrations were determined at 10-min intervals for 3 h after ingestion of each mixture, and the presence and severity of a range of gastrointestinal symptoms were recorded on a standard form before, during, and after the study. Total symptom score in IBS patients, but not controls, was greater (p < 0.05) after the higher than after the lower dose of fructose-sorbitol mixture, and, for the higher dose, symptoms were significantly greater in IBS patients than in controls (p < 0.05). Moreover, the increase in total symptom score between the higher and lower dose mixtures was of a greater magnitude (p = 0.01) in IBS patients than in controls. No significant correlation was observed between the increase in symptom score and the increase in peak hydrogen concentration or the increase in integrated hydrogen response between lower and higher dose mixtures, although these latter increases were at times substantial.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions.

Two hypotonic but non-haemolysing irrigating solutions, sorbitol-mannitol (2% + 1%) and glycine (1.5%), were compared in 40 TURP cases using a continuous resection technique. Ethanol (1%) was added to the irrigating fluid as a marker to make possible early detection of fluid absorption by breath analysis. Mannitol and sorbitol were determined in plasma and urine; glycine and ethanol were determined in plasma. Apparent absorbed fluid volumes were calculated from the immediate postoperative plasma concentrations of ethanol, mannitol, sorbitol and glycine and from the elimination of mannitol in urine during 24 hours following the operation. The use of a continuous operating technique with a suprapubic trocar resulted in very small absorptions (less than 1 l) in this series. The concentrations of the two solutes in the sorbitol-mannitol irrigating fluid were balanced so that the plasma concentrations immediately postoperatively were of the same order when absorption occurred. The sorbitol concentration declined more rapidly than the mannitol concentration in conformity with previous findings. In most cases the peak plasma level was observed immediately postoperatively but in some cases at a later time (during the interval 0-2 hours), indicating absorption from a depot of fluid accumulated extravesically in addition to direct intravenous absorption. The best estimate of fluid absorption seems to be obtained from the urinary elimination of mannitol, followed by estimates based on the plasma mannitol concentration immediately postoperatively. The plasma ethanol level determined at the same time gave an estimate of the same order, whereas plasma sorbitol and glycine levels gave lower estimates (owing to rapid redistribution and metabolism).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1997

Effect of sorbitol on the phosphate adsorptive capacity of ferrihydrite suspensions.

The purpose of this study was to stabilize the phosphate adsorptive capacity of aqueous suspensions of ferrihydrite, a potential phosphate binder. Ferrihydrite was precipitated by the addition of 1 N NaOH to 1 M FeCl3 until pH 8.0 was reached. The ferrihydrite suspension was divided into three portions and an amount of sorbitol was added to produce sorbitol concentrations of 0, 1, or 5% w/v, respectively. The phosphate adsorptive capacity and X-ray diffraction pattern were periodically determined during aging at room temperature. The phosphate adsorptive capacity of the ferrihydrite suspension containing 0% sorbitol decreased steadily from 0.012 mgP/mg to 0.007 mgP/mg during the 1-year aging period. In contrast, suspensions containing 1 or 5% sorbitol exhibited constant phosphate adsorptive capacities during this period. X-ray diffraction patterns revealed that ferrihydrite transformed to hematite and goethite during aging of the control suspension. The presence of 1 or 5% sorbitol prevented the transformation of ferrihydrite to more crystalline iron oxides. This study suggests that the phosphate adsorptive capacity of ferrihydrite suspensions can be stabilized by the incorporation of small amounts of sorbitol into the formulation.

Adsorption↗
PubMed1989

Inhibition of sorbitol formation in human erythrocytes by calcium dobesilate.

The effects of calcium dobesilate (Doxium, a drug already known to prevent or reverse the retinal microvascular lesions of diabetes mellitus) on sorbitol formation in human erythrocytes was studied, and compared with the effects of tetramethylene glutaric acid (TMGA), a specific aldose reductase inhibitor. Both compounds inhibited sorbitol formation. In a 29 mmol/l glucose medium, calcium dobesilate in concentrations of 2 and 10 mmol/l caused, 50 and 100% inhibition of sorbitol formation, respectively, whereas TMGA completely inhibited sorbitol formation at a concentration of 0.1 mmol/l. These results suggest that calcium dobesilate may exert, at least in part, its beneficial effect on diabetic microangiopathy by inhibiting the formation of sorbitol. The inhibition of sorbitol synthesis may be mediated by an inhibitory action of calcium dobesilate on aldose reductase.

Aldehyde Reductase↗
PubMed1987

Erythrocyte sorbitol content in diabetic patients: relation to metabolic control.

Since intracellular sorbitol is considered a factor perhaps involved in the pathogenesis of some diabetic complications, erythrocyte sorbitol content was measured in diabetics (IDDM and NIDDM) and in a control group and its relation with metabolic control was investigated. The erythrocyte sorbitol content was significantly increased in diabetic population (p less than 0.001) as compared to the controls. In newly diagnosed IDDMs the erythrocyte sorbitol content changed in parallel with the blood sugar level indicating that the accumulation can be reversed in erythrocytes. In a cross-sectional study a significant positive correlation existed in IDDMs between the concentration of red cell sorbitol and the plasma glucose concentration (r = 0.45; p less than 0.001). Also the HbA1 values correlated (r = 0.44; p less than 0.001) with the erythrocyte sorbitol content. In NIDDMs no correlation with metabolic control could be demonstrated.

Adult↗
PubMed1980

[A comparison of the blood glucose increase and insulin requirement after oral sucrose, fructose and sorbitol alone or in combination (author's transl)].

The artificial pancreas allows a new means of quantification of the behaviour of blood glucose (BG) and insulin requirement after the administration of nutrient sweeteners such as fructose and sorbitol as compared to sucrose. The purpose of the present study was to compare the effects of these substances, plus a combination of fructose and sorbitol (70:30) in a group of maturity-onset diabetics. Sucrose produced the steepest BG increase and the greatest insulin requirement in order to return to baseline BG levels. Sorbitol at a dosage of 20 g did not act as a laxative, produced the smallest BG increase, and required the least amount of insulin to return to baseline. The combination of 70% fructose and 30% sorbitol achieved similar results to those of sorbitol alone, regarding both BG increase and amount of insulin required to return to baseline. Since this mixture has the same sweetening ability as sucrose, and shows no laxative effect, it was concluded that it is superior to fructose or sorbitol alone.

Aged↗
PubMed1994

Membrane traffic and sorbitol release during osmo- and volume regulation in isolated rat renal inner medullary collecting duct cells.

In response to hypotonic stress, cells of the inner medullary collecting duct (IMCD) undergo swelling followed by a regulatory volume decrease (RVD) and a transient release of organic osmolytes such as sorbitol. In this study, we tested the hypothesis whether membrane recycling is involved in the latter process. Therefore, the state of submembranal actin and the cellular uptake or release of the fluid-phase marker fluorescein isothiocyanate (FITC)-dextran (FD) were investigated as related to changes in membrane permeability for sorbitol. After exposure to hypotonic medium the submembranal actin web rapidly disaggregated but it started to reorganize after 5 min of incubation. The basal-lateral pole of IMCD cells showed a significant uptake of extracellular FD after 100 sec. After 5 min, part of this fluorescence intensity had moved towards the cell center but the main part remained submembranal. Disintegration of the actin network by cytochalasin D diminished the uptake of FD during hypotonicity as did a permanent increase in intracellular calcium induced by ionomycin treatment. During a second osmotic stimulation of IMCD cells preloaded with FD, FD was released in a linear time course reaching a plateau after 1 min. Isotonic ionomycin treatment of preloaded cells also generated a rapid FD release during the first minute but induced a further 2-fold increase during the next 4 min. Under both conditions initial FD release was highly correlated with the simultaneously determined increase in sorbitol permeability. A similar strong correlation was found when different incubation temperatures were used (0 degree C, 15 degrees C, 37 degrees C). These results suggest that during exposure of IMCD cells to hypotonicity the submembranal actin web rapidly disintegrates, and "reserve" vesicles, probably containing sorbitol transporter, move to and fuse with the basal-lateral plasma membrane. The fusion causes a rapid increase in sorbitol permeability. These membrane areas are recovered by internalization, and the transport systems for sorbitol are concomitantly retrieved. In parallel to this internalization the submembranal actin filament network is rearranged. This process seems to be regulated by changes in intracellular calcium.

Actins↗
PubMed1995

Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism. Implications for diabetic retinopathy.

PURPOSE: To assess effects of elevated glucose levels on retinal glycolysis and sorbitol pathway metabolism. METHODS: Freshly isolated retinas from normal male Sprague-Dawley rats were incubated for 2 hours at 37 degrees C, pH 7.45, in Krebs bicarbonate-Hepes buffer containing 5, 10, 20, or 30 mM glucose. Glycolytic metabolites, sorbitol, and fructose were measured in extracts of retina and medium. RESULTS: Elevated glucose levels increased retinal levels of sorbitol and triose phosphates, decreased sn-glycerol-3-phosphate levels, increased lactate and fructose production, and increased the retinal lactate-pyruvate ratio (indicative of an increased cytosolic ratio of free NADH-NAD+ like that induced by hypoxia). An inhibitor of aldose reductase (AL 4114) normalized sorbitol, fructose, triose phosphates, and the lactate-pyruvate ratio without affecting lactate production or sn-glycerol 3-phosphate levels. CONCLUSIONS: Elevation of retinal glucose levels causes a hypoxia-like redox imbalance "pseudohypoxia" that results from increased oxidation of sorbitol to fructose in the second step of the sorbitol pathway. This redox imbalance provides a plausible explanation for impaired regulation of retinal blood flow (in the absence of vascular structural changes) in humans with diabetes and in nondiabetic acutely hyperglycemic animals. These findings, together with other observations, suggest that this redox imbalance precedes, and may contribute to, hypoxic and ischemic retinopathy associated with diabetes.

Aldehyde Reductase↗
PubMed1994

Three clinical trials comparing xylitol- and sorbitol-containing chewing gums for their effect on supragingival plaque accumulation.

Studies have evaluated the effects of xylitol when administered in chewing gum, as a dietary substitute for sugar, in dentifrice and in mouthrinse. Three clinical trials were conducted to further investigate chewing gums containing xylitol or xylitol/sorbitol mixtures for their ability to reduce plaque accumulation when compared to a sorbitol containing gum. These studies all had two phases; supragingival prophylaxis with an assessment of plaque accumulation to be used for balanced assignment for the second phase, which assessed plaque regrowth following a second supragingival prophylaxis and various chewing gum regimens. In the first trial of xylitol/sorbitol versus sorbitol gum only, the combination gum had a significantly greater reduction in plaque growth. In the second trial, different regimens of chewing gums with xylitol/sorbitol and sorbitol alone were compared. The combined average of the plaque regrowth scores for the subjects chewing the xylitol/sorbitol gum was significantly better than that for the sorbitol gum alone. The final trial evaluated two regimens in two forms (stick and pellet) of a xylitol gum versus a sorbitol gum. Both xylitol-containing gum forms were statistically superior to the sorbitol gum in retarding plaque regrowth.

Adolescent↗
PubMed1998

Effect of sorbitol dehydrogenase inhibition on sugar cataract formation in galactose-fed and diabetic rats.

Several recent studies with the sorbitol dehydrogenase inhibitors 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine, SDH-1, and its active metabolite 4-[4-(N, N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine , SDH-2, suggest that inhibition of sorbitol dehydrogenase may be beneficial in delaying the onset of diabetic complications due to their ability to ameliorate redox changes associated with polyol metabolism. To compare the relative importance of sorbitol dehydrogenase versus aldose reductase inhibition on sugar cataract formation, cataract formation was monitored in 50% galactose-fed and diabetic rats treated with/without the sorbitol dehydrogenase inhibitors SDH-1 or SDH-2 or the aldose reductase inhibitors AL 1576 or Ponalrestat. For these studies, diabetes was induced in young 50 g rats with streptozotocin while galactosemia was produced by feeding a diet containing 50% galactose. Inhibitors were administered in the diet with the diet containing 0.06% (w/w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0.0125% (w/w) of AL 1576. Cataract formation was monitored by hand-held slit lamp and polyol levels were measured by gas chromatography. Sugar cataract formation was accelerated in diabetic rats treated with sorbitol dehydrogenase inhibitors while no difference in cataract formation was observed in galactose-fed rats treated with/without SDH inhibitors. Cataract formation was inhibited in both diabetic and galactosemic rats by either Ponalrestat or AL 1576. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalysed intracellular accumulation of polyols and that these sugar cataracts can be prevented through inhibition of aldose reductase.

Aldehyde Reductase↗
PubMed1984

Sorbitol dehydrogenase deficiency in several pig tissues: potential implications for studies of experimental diabetes.

Screening for red blood cell sorbitol dehydrogenase deficiency in 12 different mammalian species was performed. A wide inter-species variability in red cell sorbitol dehydrogenase with a virtually complete deficiency in pigs was observed. Aldose reductase and sorbitol dehydrogenase activities in 12 different pig tissues also were measured. Aldose reductase activity was present in all the tissues studied, whereas organ specificity for sorbitol dehydrogenase was observed. Sorbitol dehydrogenase activity was not detectable in lenses, among other tissues, making the pig a potential model for studies in experimental diabetes, particularly for the investigation of sorbitol dehydrogenase deficiency as a risk factor in the development of cataracts.

Aldehyde Reductase↗