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Aim: Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). It directs glucose to sorbitol and fructose in polyol pathway (PP). To pursue contribution of PP in hepatocarcinogenesis., Methods: We utilized ascorbic acid (AA) and diallyl sulfide (DAS) in experimental DM and HCC against control. HCC was induced by diethyl nitrosamine (DENA, one intraperitoneal (IP) dose 125 mg/kg), DM, by streptozotocin (STZ, IP dose 65 mg/kg). AA was given as 7.4 g/kg/d, I.P., DAS 200mg/kg/d, orally. All animals were killed after 10 weeks., Results: DENA elevated serum AFP, erythrocyte sorbitol (ES), neoplastic changes in liver, lowered blood glucose, increased hepatocyte aldose reductase (AR) and sorbitol dehydrogenase (SDH), significantly alleviated by DAS/AA combination. DM elevated ES activating AR, inhibiting SDH, improved by DAS and AA., Conclusion: Co-induction of DM and HCC increased liver tissue lesion, serum AFP, ES, liver AR and SDH. Co-administration of DAS/AA reduced ES, AR without changing SDH. DAS/AA co-therapy lowered ES by depressing AR without affecting SDH, meaning that AR is activated by cancer and DM in different ways. PP is early marker for HCC detection and response to chemoprevention. DAS/AA combination is promising cost effective chemopreventive and anti-diabetic combination., (Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.)

In order to investigate the underlying mechanism of alterations in bone mineral metabolism in patients with type 2 diabetes, we determined circulating levels of bone functional markers along with urinary excretion of sorbitol (SOR) and bone mineral density (BMD), and also examined their mutual interrelationship. A total of 151 male type 2 diabetic patients were examined in this study. Forty-eight age-matched male healthy subjects were also studied as the controls. A significant reduction of serum intact osteocalcin (i-OC) was found in the diabetic groups (p<0.01). On the other hand, circulating levels of tartrate resistant acid phosphatase (TRAP) in the diabetic patients were significantly higher than those in the controls (p<0.01). Interestingly, a significantly negative relationship was observed between BMD and serum TRAP (p<0.01), although no significant relationship was noted between BMD and serum i-OC in diabetic patients. Urinary excretion of SOR was significantly elevated in the diabetic patients when compared with the controls (p<0.01). In addition, a significantly positive correlation was observed between serum TRAP and urinary SOR (p<0.01), but not between serum i-OC and urinary SOR. Elevated serum TRAP in diabetes was reduced after the administration of aldose reductase inhibitor (p<0.05). It seems most likely that the increase in osteoclastic function probably due to accelerated polyol pathway plays a crucial role in the pathogenesis of decreased bone mineral content in male patients with type 2 diabetes.

Introduction: Decreased myo-inositol levels and increased activity of the polyol pathway have been proposed to play a role in causing diabetic microvascular complications. There are few clinical methods for examining the activity of the polyol pathway in diabetic patients. We assessed the effect of changes in glycemic control on polyol pathway activity by measuring urinary polyol excretion., Materials and Methods: Gas-chromatography/mass-spectrometry (GC/MS) was used to assess the urinary excretion of glucose and polyols (myo-inositol, sorbitol, and fructose) in 50 patients who had type 2 diabetes without nephropathy and 20 healthy subjects., Results: In the diabetic patients with poor glycemic control, urinary sorbitol levels were significantly increased and urinary myo-inositol excretion was approximately 6.5-fold higher than in healthy controls (33.0+/-6.5 vs 221.7+/-45.9 mg/day, mean+/-SE, P<0.01). During strict glycemic control, some patients (Group A) showed simultaneous disappearance of glucosuria and normalization of the urinary excretion of myo-inositol (<50 mg/day) and, while others (Group B) showed delayed normalization of urinary myo-inositol excretion. Group B showed significantly higher urinary myo-inositol, sorbitol, and fructose excretion than Group A at the time of disappearance of glucosuria. These findings suggest that patients in Group B may have increased polyol pathway activity., Conclusion: Even though short-term strict glycemic regulations were established in long-standing hyperglycemic diabetic patients, to normalize the once-exaggerated polyol pathway activities, it was essential to maintain glucosuria-free conditions for some period. Quantitation of urinary polyols using GC/MS appears to be a clinically useful method for assessing polyol pathway activity.

The level of erythrocyte aldose reductase protein (AR-p) was determined in diabetic patients as well as in 76 healthy controls by a two-site enzyme-linked immunosorbent assay. No significant difference in the mean AR-p level was demonstrated between the healthy and diabetic individuals. Based on the results of seven nerve function tests, 95 non-insulin-dependent diabetes mellitus (NIDDM) patients were classified into two groups: Group I, without demonstrable neuropathy ( < or = 1 abnormal test results); Group II, overt neuropathy ( > or = 2 abnormal results). The AR-p level was significantly higher in Group II than that in Group I. Multivariate logistic regression analysis identified two independent risk factors for overt neuropathy: longer duration of diabetes after clinical diagnosis (odds ratio, 1.15 per year; 95% confidence interval, 1.05-1.25) and a higher level of AR-p (odds ratio, 1.92 per 1 ng mgHb(-1); 95% confidence interval, 1.39-2.65). On 31 patients the AR-p level was re-assessed after a 12-month follow-up period. Irrespective of improved or stable HbA(1c) levels during the follow-up period, no apparent alteration in the level of AR-p was demonstrated. These results suggest that erythrocyte AR-p level may affect the susceptibility or development of diabetic neuropathy in NIDDM patients.

The present study was conducted in order to determine whether an aldose reductase inhibitor (ARI), epalrestat, prevents the progression of diabetic nephropathy in rats. Rats were made diabetic by intravenous injection of streptozotocin (STZ 50 mg/kg) and epalrestat (100 mg/kg) was administered orally through a gastric tube once daily for 4 weeks. Examination by electron microscope revealed that the number of anionic sites (AS) in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased in diabetic rats compared to control values (17.6 + or - 0.4 vs. 21.9 + or -0.4, P < 0.01), whereas, significant recovery (20.3 + or - 0.7, P < 0.05) was observed after 4 weeks of epalrestat treatment. Urinary albumin excretion (UAE) rate was markedly increased in diabetic rats and the treatment resulted in its significant suppression from diabetic rats. In conclusion, administration of epalrestat to diabetic rats is capable of preventing a reduction in the number of AS in GBM which would ameliorate an increased permeability of the basement membrane leading to albuminuria.

In order to confirm the effect of ascorbic acid (AA) on human erythrocyte sorbitol accumulation and explore its mechanism of action, the effects of ascorbic acid in vitro on the sorbitol (S) and glucose (EG) content of human erythrocytes and in particular on the S/EG ratio as a marker of aldose reductase (AR) activity were carefully observed. The results showed that both the accumulation of erythrocyte sorbitol and the S/EG ratio were strongly reduced by the addition of AA. The sorbitol content in the erythrocyte and the S/EG ratio were reduced by a maximum of 87.3% and 83.4% and 93.8% and 63.9% when the medium's AA concentration was at its peak with 5.6 mmol/l and 28 mmol/l glucose in the medium, respectively. The contents of erythrocyte glucose measured coincidentally revealed a positive correlation with the ascorbic acid concentration in the medium during incubation in 5.6 mmol/l glucose while at a higher glucose level (28 mmol/l) in the medium the correlation became negative. These results suggested that the polyol pathway could be inhibited effectively by AA through its direct action on AR. The results of a double-blind cross-over trial using AA tablets or inositol tablets in eight diabetic patients showed that the supplementation of 1000 mg AA/day for 2 weeks resulted in reductions of 12.2% and 21.8% in erythrocyte sorbitol and red cell sorbitol/plasma glucose (S/PG) ratio, respectively (P < 0.05), whereas the fasting plasma glucose levels measured coincidentally revealed no changes (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

(5-(3-Thienyl)tetrazol-1-yl)acetic acid (TAT), a novel potent aldose reductase inhibitor, was administered for 4 weeks to rats with streptozotocin-induced diabetes. Physiological and biochemical studies were subsequently conducted on rat nerve tissue and erythrocyte sorbitol content was estimated. Sciatic nerve blood flow (SNBF) was markedly lower (about 43.4%) in untreated diabetic (DC) rats than in non-diabetic controls (NC). A significant delay in caudal motor nerve conduction velocity (MNCV) and significantly higher glucose, sorbitol and fructose values were observed in the sciatic nerve, accompanied by a markedly higher sorbitol concentration in erythrocytes. In contrast, TAT-treated diabetic groups (DT-10, DT-40 and DT-200) had significantly higher SNBF, MNCV and sciatic nerve myo-inositol values and lower sciatic nerve sorbitol and fructose levels and erythrocyte sorbitol concentration than the DC group. There were good correlations between SNBF and MNCV (r = 0.672, P < 0.001) and between SNBF and erythrocyte sorbitol (r = 0.455, P < 0.003). These findings suggest that both vascular and metabolic factors play an important role in diabetic neuropathy and the effect of aldose reductase inhibitors on diabetic neuropathy may be mediated by at least these two factors.

The effects of a high-glucose medium, insulin, and an aldose reductase inhibitor (ONO-2235) on sorbitol accumulation were compared in the human erythrocyte and the rabbit retina, while the effects of epinephrine on in vitro sorbitol accumulation were investigated in the human and rabbit retina. In both erythrocytes and the retina, linear increments of sorbitol accumulation were observed in a dose-dependent manner with 5 to 50 mM glucose. These increments were markedly inhibited by 100 microM ONO-2235 but not by insulin (400 microU/ml). In the presence of 5 mM glucose, a dose-dependent increase of the sorbitol content of the rabbit retina was seen following epinephrine stimulation (0.4-4.0 microM and this was markedly reduced by 100 microM ONO-2235. Moreover, both 50 mM glucose and 4.0 microM epinephrine increased the sorbitol content of the retina from a diabetic patient, and the glucose-induced increment in sorbitol was significantly reduced by 100 microM ONO-2235. Our data suggested that aldose reductase inhibitors might be useful for the treatment of diabetic retinopathy, since the polyol pathway appears to be an important factor in its pathogenesis, and that catecholamines might have some role in the activation of the retinal polyol pathway.

To determine whether erythrocyte sorbitol content could become an indicator of diabetic microangiopathy, we studied the relationship between the changes in erythrocyte sorbitol content in response to diet loading and diabetic microangiopathy in patients with non-insulin-dependent diabetes mellitus. The increase of change in erythrocyte sorbitol content (delta Sor) after diet loading (420 kcal) significantly correlated with that of plasma glucose levels (delta BS). The patients with less than or equal to 40 m/s of motor or sensory nerve conduction velocity (MCV and SCV) had significantly higher delta Sor and delta Sor/delta BS values than those with greater than 40 m/s of MCV and SCV; nevertheless, there were no significant differences in delta BS between the two groups. Furthermore there was a significant negative correlation between nerve conduction velocity and delta Sor and Delta Sor/delta BS values. On the other hand, the patients with nephropathy or retinopathy showed no significant increase in delta Sor or delta Sor/delta BS compared with patients without these complications. The results demonstrated that delta Sor and delta Sor/delta BS could become indicators of the presence or severity of diabetic neuropathy. Furthermore the more significant participation of alteration in the polyol pathway in the pathogenesis of neuropathy than of the other microangiopathies was suggested.