Biomedical subjects

F Sakakibara

Publications and source records attributed to F Sakakibara.

At least 19 recordsLinked to original sources

PubMed2001

Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats.

To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.

2,3-Diphosphoglycerate↗

PubMed2001

Cloning, expression, and characterization of a family 52 beta-xylosidase gene (xysB) of a multiple-xylanase-producing bacterium, Aeromonas caviae ME-1.

A lambda phage genomic library of Aeromonas caviae ME-1, a multiple-xylanase-producing bacterium, was screened for xylan degradation activities. We isolated one clone, B65, which had weak xylanase activity, by the DNS method, but gave no visible bands on zymogram assay using SDS-xylan-PAGE. Based on TLC analyses of enzymatic products and some glycosidase assays using p-nitrophenyl substrates, we established that pB65 encodes a beta-xylosidase gene. In the nucleotide sequence analysis, we found a 2190-bp open reading frame (ORF) named xysB. XysB protein is similar to some beta-xylosidases, which are categorized in the glycosyl hydrolase family 52. Another ORF (xyg), that showed similarity to the family 67 alpha-glucuronidase, was also found downstream of the xysB gene. The xysB ORF and its promoter region were cloned into the pT7-Blue vector and the transformant cells had beta-xylosidase activity. The relative molecular mass were estimated to be 75 kDa by SDS-PAGE and 159 kDa by gel filtration. These data showed that XysB has a dimeric structure of 80,697 Da subunits. This enzyme showed optimal activity at 50 degrees C and pH 6.0. It was stable below 40 degrees C and pH 5-8. The Km and Vmax were calculated to be 0.34 mM and 33 nmol x min(-1) x microg(-1), respectively. This enzyme also showed transglycosylation activity against X3 and produced X4 and X5.

Aeromonas↗

PubMed2000

The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet.

AIMS/HYPOTHESIS: Fat balance is critical in the aetiology of obesity and related diseases. Lipoprotein lipase is of major importance in lipid metabolism. The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet. METHODS: Male, Sprague-Dawley rats were fed for 10 weeks on a chow diet or a high-fat diet with, or without, NO-1886 (50 mg x kg(-1) x day(-1)). Weight gain, fat accumulation and both hormone-sensitive and lipoprotein, lipase activities were measured. Insulin action was assessed by the euglycaemic hyperinsulinaemic clamp and metabolic rate/substrate utilisation by open-circuit respirometry. RESULTS: Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 +/- 3, high-fat, 222 +/- 9; high-fat + NO-1886, 109 +/- 6, all groups differed p < 0.001]. A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 +/- 3.2; high-fat, 81.9 +/- 6.6; high-fat + NO-1886, 52.3 +/- 4.7, p < 0.01 high-fat vs the other groups]. A high-fat diet induced wholebody insulin resistance (clamp glucose infusion rate: 4.8 +/- 1.3 mg x kg(-1) x min(-1) vs 10.6 +/- 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 +/- 0.5, p < 0.05 vs high-fat). The 24-h respiratory quotient was lower in the high-fat + NO-1886 group (0.825 +/- 0.010) compared with high-fat alone (0.849 +/- 0.004, p < 0.05). A high-fat diet increased lipoprotein and hormone-sensitive, lipase activities in epididymal fat, an effect not altered by NO-1886. In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886. CONCLUSION/INTERPRETATION: Lipoprotein lipase activators could have potential benefits for the treatment of obesity by increasing fat utilisation.

Adipose Tissue↗

PubMed1999

Effect of vitamin E and allylamine on the proliferation of cultured aortic smooth muscle cells from streptozotocin-induced diabetic rats.

To investigate the effect of vitamin E on the proliferation activity of vascular smooth muscle cells (SMCs) in diabetes mellitus, [3H]-thymidine incorporation was measured in cultured SMCs isolated from normal and streptozotocin-induced diabetic rats treated with or without vitamin E and/or allylamine. Untreated diabetic rats demonstrated significantly elevated concentrations of serum total cholesterol, triglycerides and malondialdehyde (MDA). Allylamine caused a further increase in serum MDA. Treatment with vitamin E decreased the serum concentrations of triglycerides and MDA in both allylamine-treated and -untreated diabetic rats. [3H]-Thymidine incorporation in cultured SMCs from diabetic rats was significantly increased compared with that from normal rats. SMCs from allylamine-treated diabetic rats showed an enhanced increase in thymidine incorporation compared with that from untreated diabetic rats. The increase in thymidine incorporation in SMCs from untreated and allylamine-treated diabetic rats was significantly reduced by the treatment with vitamin E. These observations suggest that vitamin E has a preventive effect on the proliferation of vascular SMCs in diabetes, and that this effect may be mediated through an enhancement of free radical scavenging.

Allylamine↗

PubMed1999

Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.

AIM: To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils. METHODS: We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor. The sorbitol and myo-inositol contents, and myo-inositol uptake were measured by high performance liquid chromatography and radio isotope technique with 2-[3H]-myo-inositol. RESULTS: After 2 h incubation, the sorbitol content increased with rising extracellular glucose concentrations, while the myo-inositol content decreased. Both AR inhibitors reduced the sorbitol content in neutrophils exposed to 40 mmol/l glucose medium. A 70% fall in the myo-inositol content in neutrophils exposed to 40mmol/glucose medium was attenuated approximately 40% by the addition of AR inhibitors. myo-Inositol uptake into neutrophils was inhibited by high glucose. AR inhibitors significantly ameliorated the decrease in myo-inositol uptake, but did not completely normalize it. CONCLUSIONS: Our present in vitro studies showed that the glucose-induced metabolic alterations in human neutrophils were similar to those in tissues prone to diabetic complications, and that AR inhibitors effectively corrected glucose-induced imbalances of the polyol pathway and myo-inositol uptake in neutrophils. In addition, our study suggests that glucose-induced metabolic alterations may result in the neutrophil dysfunction and that an AR inhibitor may be capable ameliorating it.

Adult↗

PubMed1999

A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.

Aldehyde Reductase↗

PubMed1998

Influence of interindividual variability of aldose reductase protein content on polyol-pathway metabolites and redox state in erythrocytes in diabetic patients.

OBJECTIVE: To clarify the influence of interindividual difference in the level of aldose reductase on the polyol pathway-related metabolism in diabetic patients. RESEARCH DESIGN AND METHODS: The enzyme protein content was determined by a two-site enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies to recombinant human aldose reductase in erythrocytes from 35 diabetic patients and 11 healthy volunteers. Patients were stratified into two groups by the median of aldose reductase content, and the erythrocyte sorbitol level, the fructose level, and the lactate-to-pyruvate ratio were compared between the two groups. We also examined the correlation of the enzyme content with these metabolic parameters. RESULTS: The group of patients whose enzyme content was above the median showed a significant increase in the levels of sorbitol (34.7 +/- 4.9 vs. 20.4 +/- 2.0 nmol/g Hb, P < 0.05) and fructose (99.8 +/- 17.2 vs. 45.9 +/- 4.6 nmol/g Hb, P < 0.05), along with an elevated lactate-to-pyruvate ratio (28.6 +/- 6.1 vs. 11.7 +/- 1.2, P < 0.05), compared with patients with low enzyme levels. The aldose reductase content in erythrocytes was well correlated with its activity, and there was a significant correlation between the enzyme content and the erythrocyte sorbitol (r = 0.58, P < 0.001) or fructose (r = 0.57, P < 0.001) levels as well as between the enzyme level and the lactate-to-pyruvate ratio (r = 0.38, P < 0.05). CONCLUSIONS: These results suggest that the interindividual variability of aldose reductase content may contribute tangibly to the polyol-pathway flux and cytoplasmic redox alteration in diabetic patients.

Aldehyde Reductase↗

PubMed1998

Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.

To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.

Acetylcarnitine↗

PubMed1997

Effect of an aldose reductase inhibitor on abnormalities of electroretinogram and vascular factors in diabetic rats.

The effect of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), on the electroretinogram was determined in rats with streptozotocin-induced diabetes. Laboratory chow containing 0.05% TAT was given to rats for 2 months, while other diabetic rats were untreated. Groups of TAT-treated and untreated normal rats were also studied. Treatment with TAT produced significant improvement of the electroretinogram. TAT shortened the peak latencies of the b-wave oscillatory potentials, which were significantly prolonged in untreated diabetic rats (P < 0.0001 vs. untreated normal rats). This was accompanied by a significant decrease in the retinal sorbitol and fructose concentrations (by 46.5% and 25.7%, respectively). TAT treatment of diabetic rats also markedly reduced ADP-induced platelet aggregation and significantly increased the red blood cell 2,3-diphosphoglycerate level, accompanied by a marked reduction in sorbitol and fructose concentrations of platelet and red blood cells. There were significant correlations between the summed b-wave peak latencies and platelet aggregation or the 2,3-diphosphoglycerate level in diabetic rats. These findings suggest that an aldose reductase inhibitor, TAT, has therapeutic value for diabetic retinopathy.

2,3-Diphosphoglycerate↗

PubMed1997

Diabetic neuropathy in sucrose-fed Otsuka Long-Evans Tokushima fatty rats: effect of an aldose reductase inhibitor, TAT.

In an animal model of human non-insulin dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima Fatty (OLETF) rats were fed with sucrose for 8 weeks to obtain severe hyperglycemia. The effects of sucrose administration on peripheral nerve functions, motor nerve conduction velocity (MNCV) and coefficient of variance of R-R interval (CVR-R), were investigated with concomitant measuring of sciatic nerve blood flow (SNBF), ADP-induced platelet aggregation and polyol content in the sciatic nerves. The effects of an aldose reductase inhibitor, TAT, on these parameters were also studied. Administration of sucrose to OLETF rats caused significant body weight reduction and remarkable hyperglycemia. Sucrose-fed OLETF rats demonstrated significantly delayed MNCV, decreased CVR-R, reduced SNBF and increased platelet aggregation activity to ADP. Sorbitol and fructose accumulation, and myo-inositol depletion in sciatic nerves were observed only in sucrose-fed OLETF rats. These abnormalities were all ameliorated by the treatment with TAT. These observations suggest that the sucrose-fed OLETF rat is a useful animal model for studying the pathogenesis of diabetic neuropathy in human NIDDM, and that an aldose reductase inhibitor is a useful therapeutic agent for the treatment of diabetic neuropathy.

Aldehyde Reductase↗

PubMed1997

Electroretinogram in sucrose-fed diabetic rats treated with an aldose reductase inhibitor or an anticoagulant.

To investigate the role of increased polyol pathway activity and hemodynamic deficits in the pathogenesis of diabetic retinopathy in non-insulin-dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human NIDDM, were given water with or without 30% sucrose and some of them were fed laboratory chow containing 0.03% cilostazol, an anticoagulant, or 0.05% [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT), an aldose reductase inhibitor, for 8 wk. Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic controls. The peak latencies of oscillatory potentials of the electroretinogram in sucrose-fed OLETF rats were significantly prolonged compared with those in OLETF rats without sucrose feeding and LETO rats. There was a marked increase in platelet aggregability and a significant decrease in erythrocyte 2,3-diphosphoglycerate in sucrose-fed OLETF rats. Cilostazol significantly improved these parameters without changes in retinal levels of sorbitol and fructose. TAT, however, ameliorated all of these parameters. These findings confirm that the sucrose-fed OLETF rat is a useful animal model of retinopathy in human NIDDM and suggest that cilostazol improved diabetic retinopathy by modifying vascular factors, not by altering polyol pathway activity.

2,3-Diphosphoglycerate↗

PubMed1997

Increased alanine uptake and lipid synthesis from alanine in isolated hepatocytes of Wistar-Kyoto fatty rats: an inhibitory effect of biguanides.

To examine the pathophysiological characteristics of non-insulin-dependent diabetes mellitus, alanine metabolism in isolated hepatocytes of male Wistar-Kyoto (WKY) fatty rats (genetically obese and hyperglycemic) and their lean littermates was investigated. The effects of glucagon and the biguanides, metformin and buformin, on alanine metabolism were also studied by measuring alanine uptake and lipid synthesis from alanine. WKY fatty rats showed higher plasma insulin and lipid concentrations than lean rats at 5 as well as at 12 weeks of age. Alanine uptake into hepatocytes was increased in fatty rats only at 12 weeks of age compared with lean rats. Lipid synthesis from alanine in hepatocytes was increased in fatty rats at 5 and 12 weeks of age compared with lean rats. Glucagon increased alanine uptake into hepatocytes but did not affect lipid synthesis from alanine in both fatty and lean rats. Low concentrations (0.1 mM) of biguanides decreased lipid synthesis from alanine only in fatty rats without inhibiting alanine uptake into hepatocytes. These observations suggest that lipid synthesis from alanine in hepatocytes of WKY fatty rats is accelerated prior to the onset of diabetes mellitus, which might be associated with the development of diabetes, and that an inhibitory effect on increased lipid synthesis is one of the pharmacodynamic actions of biguanides.

Aging↗

PubMed1996

Nerve function and blood flow in Otsuka Long-Evans Tokushima Fatty rats with sucrose feeding: effect of an anticoagulant.

To investigate the pathogenesis of diabetic neuropathy in non-insulin-dependent diabetes mellitus, Otsuka Long-Evans Tokushima Fatty rats, an animal model of non-insulin-dependent diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka rats were fed with or without sucrose and/or cilostazol, an anticoagulant, for 8 weeks. Sucrose-fed diabetic rats showed a delayed motor nerve conduction velocity, decreased R-R interval variability of electrocardiogram, reduced sciatic nerve blood flow, increased platelet aggregability and a decreased erythrocyte 2,3-diphosphoglycerate concentration compared with non-sucrose-fed diabetic rats and non-diabetic rats. These abnormalities were significantly prevented by treatment with cilostazol without changes in the nerve tissue levels of polyols. These findings indicate that sucrose-fed Otsuka Long-Evans Tokushima Fatty rats may be a useful animal model of neuropathy in non-insulin-dependent diabetes mellitus, and that cilostazol may prevent the development of diabetic neuropathy by modifying vascular factors.

2,3-Diphosphoglycerate↗

PubMed1996

Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats.

The effect of propionyl-L-carnitine, an analogue of L-carnitine, and insulin on the oscillatory potentials of the electroretinogram was determined in rats with streptozotocin-induced diabetes. Propionyl-L-carnitine was administered at a daily dose of 0.5 g/kg by gavage for 4 weeks, while other rats were treated with subcutaneous injections of insulin (8-10 U/day). Both treatments shortened the peak latencies of the oscillatory potentials in the electroretinogram, which were significantly prolonged in untreated diabetic rats (O1, O2 and O3, and sigma (O1 + O2 + O3)) (P < 0.0001 vs. untreated normal rats). A significant decrease in the erythrocyte free carnitine level in diabetic rats was prevented by both treatments. Insulin produced a significant reduction of retinal glucose, sorbitol and fructose levels in diabetic rats, while propionyl-L-carnitine failed to do so. However, both treatments markedly reduced serum lipids levels in the diabetic rats. These findings provide information on the pathogenesis of diabetic retinopathy as well as suggesting the potential therapeutic value of propionyl-L-carnitine for retinopathy.

Analysis of Variance↗

PubMed1996

Effects of propionyl-L-carnitine and insulin on the electroretinogram, nerve conduction and nerve blood flow in rats with streptozotocin-induced diabetes.

The effect of an analogue of L-carnitine, propionyl-L-carnitine, on the electroretinogram, motor nerve conduction velocity and nerve blood flow was determined in rats with streptozotocin-induced diabetes, and was compared with the effects of insulin alone or combined therapy. Oral administration of propionyl-L-carnitine (3 g/kg daily for 4 weeks) significantly increased caudal nerve motor conduction velocity and sciatic nerve blood flow in diabetic rats. There were no differences in the effects of insulin (8-10 U daily for 4 weeks), propionyl-L-carnitine and combined therapy. Although propionyl-L-carnitine significantly shortened the peak latency of the electroretinogram b-wave in diabetic rats, its effect was far weaker than that of insulin or combined therapy, with combined therapy producing the greatest improvement. These effects of propionyl-L-carnitine were accompanied by a decrease of serum lipid levels, an increase of the sciatic nerve carnitine content, and no changes of the tissue (nerve and retinal) sorbitol and myo-inositol concentrations. In contrast, insulin significantly reduced the tissue sorbitol content and markedly increased myo-inositol. These findings suggest that propionyl-L-carnitine may improve diabetic neuropathy and retinopathy without influencing the polyol pathway, and that this beneficial effect may be mediated through the amelioration of microcirculation and tissue carnitine content, thus probably increasing fatty acid oxidation.

Animals↗

PubMed1996

Enhancement and inhibition of mitogenic action of insulin-like growth factor I by high glucose in cultured bovine retinal pericytes.

To explore the possible relationship between insulin-like growth factor I(IGF-I) and diabetic retinopathy, we examined the effects of glucose on IGF-I stimulated thymidine incorporation into DNA and IGF-I binding in cultured bovine retinal pericytes. IGF-I significantly increased thymidine incorporation, and its effect was completely inhibited by IGF-I receptor antibody. The exposure to high glucose for 8 h significantly enhanced the IGF-I induced increase in thymidine incorporation as compared with those to normal glucose and to high osmolarity. In contrast, the incubation with high glucose for 24 h decreased thymidine incorporation in response to IGF-I. Specific binding of IGF-I to pericytes was increased by the incubation with high glucose for both 8 and 24 h. These results suggest that glucose may play an important role in the regulation of mitogenic action of IGF-I in retinal pericytes.

Animals↗

PubMed1996

Effect of acarbose on blood glucose profiles and plasma 1,5-anhydro-d-glucitol in type 2 diabetes poorly controlled by sulfonylurea therapy.

Sixteen patients with type 2 diabetes poorly controlled by glibenclamide (7.5-10.0 mg/day) were treated with acarbose (100 mg tds) for one week and the effect on the blood glucose profile, 24-hour urinary glucose excretion, plasma fructosamine, and plasma 1,5-anhydro-D-glucitol (1,5-AG) level was determined. The blood glucose profile was more stable and levels were lower during acarbose administration. In some patients, this improvement was maintained after discontinuing acarbose. The M-value, an indicator of blood glucose fluctuations, decreased significantly from 33.2 +/- 3.0 (mean +/- SEM) in the run-in period to 13.4 +/- 2.4 during acarbose therapy (P < 0.001), and rose again to 26.5 +/- 4.4 (P < 0.001) in the follow-up period. The 24-hour urinary glucose excretion and plasma fructosamine decreased similarly (P < 0.001 and P < 0.01, respectively) during and after acarbose therapy. Plasma 1,5-AG levels did not change significantly during acarbose therapy, but increased markedly afterwards (from 19.3 +/- 3.1 mumol 1(-1) to 25.0) +/- 3.1 mumol l-1, P < 0.001). Plasma 1,5-AG levels were significantly correlated with urinary glucose excretion one week earlier (r = 0.513, P < 0.006). These findings suggest that acarbose may improve glycemic control in type 2 diabetic patients poorly controlled by sulfonylurea therapy and that plasma 1,5-AG might be used as a marker of glycemic control cooperating with other markers such as fructosamine and urinary glucose determination for monitoring the short-term response to antidiabetic therapy.

Acarbose↗

PubMed1996

Effect of a novel hypoglycemic agent, KAD-1229 on glucose metabolism and fructose-2,6-bisphosphate content in isolated hepatocytes of normal rats.

The effects of a novel hypoglycemic agent, calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229), which is a benzyl succinate derivative, on liver metabolism were investigated using isolated hepatocytes from normal rats. In the presence of 10 mM glucose, KAD-1229 increased the L-lactate production (41.1 +/- 0.9 versus 60.9 +/- 2.6 mumol of lactate/g of cells/30 min; P < 0.05) and inhibited gluconeogenesis in hepatocytes (0.94 +/- 0.02 versus 0.70 +/- 0.03 mumol of [2-14C]-pyruvate converted to glucose/g of cells/20 min; P < 0.05). These effects by KAD-1229 were accompanied by an increase in the cellular content of fructose-2,6-bisphosphate (F-2,6-P2), which is one of the important regulators of hepatic glucose metabolism, in a dose-dependent manner (0.05-2.5 mM). KAD-1229 also stimulated the oxidation of [2-14C]-pyruvate and [6-14C]-glucose in the tricarboxylic acid cycle (+18 and +31%, respectively), indicating that stimulation of tricarboxylic acid cycle activity and/or enhancement of the glycolytic flux rate had occurred. Moreover, KAD-1229 did not modify the activities of 6-phosphofructo 2-kinase or fructose-2,6-bisphosphatase, but increased significantly the accumulation of fructose 6-phosphate in hepatocytes. These results suggest that KAD-1229 has extrapancreatic effects on hepatic glucose metabolism, that its actions are mediated through the inhibition of fructose-1,6-bisphosphatase and stimulation of both the 6-phosphofructo 1-kinase reaction and tricarboxylic acid cycle activity by increasing the F-2,6-P2 content in hepatocytes, and that these multiple effects may account in part for the ability of KAD-1229 to reduce blood glucose levels in vivo.

Analysis of Variance↗