[Early diagnosis and therapy of diabetic nephropathy].
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Albuminuria↗
Biomedical subjects
Y Shigeta
Publications and source records attributed to Y Shigeta.
Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone.
The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21-81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol I-1) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA(1c) decreased significantly after the treatment (before vs after, FPG: 10.8 +/- 2.0 mmol I(-1) vs 9.2 +/- 2.5 mmol I(-1), p< 0.001; HbA(1c): 9.2 +/- 1.4% vs 8.5 +/- 1.5%, p< 0.001). FPG and HbA(1c) did not change after the treatment in the placebo group (before vs after, FPG: 10.5 +/- 1.7 mmol I(-1) vs 10.7 +/- 2.2 mmol I(-1); HbA(1c): 9.0 +/- 1.5% vs 9.2 +/- 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day(-1) had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.
Administration, Oral↗
Lysophosphatidylcholine stimulates the expression and production of MCP-1 by human vascular endothelial cells.
Lysophosphatidylcholine (LPC increased monocyte chemoattractant protein-1 (MCP-1) messenger RNA concentrations in human umbilical vein endothelial cells (HUVECs). A time-course study showed that the increase in MCP-1 mRNA levels peaked at 6 hours after treatment with LPC. The effect of LPC on the accumulation of MCP-I mRNA levels in HUVECs depended on LPC concentration, and the maximal effect was obtained at 50 micromol / L LPC, which induced a sixfold increase in MCP-1 mRNA levels. The amount of MCP-1 released from HUVECs measured using an enzyme-linked immunosorbent assay (ELISA) showed a 38% increase in the presence of 50 micromol/L LPC, but not in the presence of phosphatidylcholine or lysophosphatidylethanolamine. Coincubation with staurosporine, a potent inhibitor of protein kinase C (PKC) activity, attenuated the LPC-induced increase in MCP-1 mRNA levels by 53%. These results indicate that LPC can induce an increase in MCP-1 mRNA concentrations and stimulate the release of MCP-1 protein from HUVECs, and that the effect of LPC on the MCP-1 gene may be mediated through activation of the PKC pathway.
Base Sequence↗
Tolrestat improves nerve regeneration after crush injury in streptozocin-induced diabetic rats.
To delineate the ability of diabetic nerves to regenerate and to determine the effect of aldose reductase (AR) inhibitors (ARIs) on nerve regeneration in diabetic neuropathy, we evaluated nerve regeneration electrophysiologically and morphologically after sciatic nerve crush injury in three groups of male Sprague-Dawley rats: untreated diabetic (streptozocin [STZ]-induced, n = 16), tolrestat-treated diabetic (n = 16), and age-matched controls (n = 16). Compound muscle action potentials (CMAPs) appeared 4 weeks after crush injury in the control group and 5 weeks after injury in both diabetic groups. Motor nerve conduction velocity (MNCV) in the crushed nerves was decreased in both diabetic groups compared with the control group throughout the experiment. However, this decrease was significantly prevented at 24 weeks with tolrestat treatment. Morphologically, the density of myelinated nerve fibers (MNFs) and the number of MNFs per fascicle were significantly decreased in untreated diabetic rats, but tolrestat significantly prevented the former decrease at 5 weeks and the latter at 24 weeks. The mean diameter of large MNFs (>4 microm) was smaller in the untreated diabetic group than in the control group, but this decrease also was significantly prevented with tolrestat treatment. These results suggest that nerve regeneration is impaired in diabetic neuropathy and that tolrestat can prevent this impairment.
Animals↗
Glycation, oxidative stress, and scavenger activity: glucose metabolism and radical scavenger dysfunction in endothelial cells.
It has been reported that oxidative stress is increased in vivo in the diabetic state. Increased oxidative stress is caused not only by accelerated production of oxygen-free radicals but also by decreased scavenging of those molecules. Endothelial cells are extremely sensitive to oxidative stress, resulting in impairments of various endothelial cell function. In this report, we studied the association of intracellular glucose metabolism and oxygen radical scavenging function via the glutathione redox (GR) cycle in cells exposed to high-glucose conditions using cultured human umbilical vein endothelial cells. Glutathione-dependent H2O2 degradation in cells exposed to 33 mmol/l glucose (HG) for 5-7 days was reduced by 48% vs. 5.5 mmol/l glucose (NG). This impairment under the oxidative stress was D-glucose-specific and concentration-dependent and was also associated with a 42% decrease in intracellular NADPH content. Exposure of cells to 200 micromol/l H2O2 stimulated the GR cycle and the pentose phosphate pathway (PPP) at the same time. In the HG condition, activation of PPP was reduced by 50%, which was consistent with a decrease in NADPH content. Inhibition of glycolysis by H2O2 was less marked in HG cells versus NG cells. Activation of polyol pathway in HG cells is not responsible for the decrease in intracellular NADPH content. These results indicate that activation of the PPP and NADPH supply to the GR cycle is impaired in HG cells exposed to H2O2, which may result in increased oxidative stress to endothelial cells.
Cells, Cultured↗
Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy.
OBJECTIVE: To investigate the clinical efficacy of troglitazone, a newly developed oral hypoglycemic agent, in patients with NIDDM. RESEARCH DESIGN AND METHODS: There were 284 NIDDM patients (20-82 years of age) whose glycemic control while on a diet was judged stable but was judged unsatisfactory (fasting plasma glucose [FPG] > or = 8.3 mmol/l) when entered into a multicenter and double-blind study with parallel groups study. They were randomly allocated into two groups, the troglitazone group (the T group: 400 mg/day p.o.) and the placebo group (the P group), and were treated with test drugs for 12 weeks. RESULTS: We evaluated efficacy in 136 patients of the T group and 126 patients of the P group. There was no significant difference in any of baseline characteristics between the T and P groups. In the T group, FPG and HbA1c decreased significantly after treatment (before versus after, FPG 10.1 +/- 1.6 vs. 8.8 +/- 1.9 mmol/l, P < 0.001; HbA1c: 8.6 +/- 1.5 vs 8.1 +/- 1.7%, P < 0.001). FPG and HbA1c did not change after treatment in the P group (before versus after, FPG 10.1 +/- 1.8 vs. 9.9 +/- 2.1 mmol/l; HbA1c 8.5 +/- 1.5 vs. 8.6 +/- 1.6%). Of 136 patients in the T group, 62 (45.6%) were classified as responders. Serum triglyceride level also decreased in the T group but not in the P group. Body weight increased slightly only in the T group. There were no differences in changes in blood pressure between the two groups. No serious adverse events occurred in either group. CONCLUSIONS: Troglitazone at 400 mg/day decreased FPG and HbA1c significantly in NIDDM patients who had failed to respond to diet therapy. Troglitazone, developed as a drug to enhance insulin action, can be a useful hypoglycemic agent for the treatment of NIDDM.
Adult↗
Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities.
The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the effect of high glucose concentration (HG) and its modulation by thiazolidine derivatives, on insulin signaling using Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubating HIRc cells in 27 mM D-glucose for 4 days impaired the insulin-stimulated phosphorylation of pp185 and receptor beta-subunits. Both protein kinase C activities and phorbol dibutyrate binding to intact cells were unchanged; however, cytosolic protein-tyrosine phosphatase (PTPase) activity increased within 1 h prior to the impairment of insulin receptor kinase in HG cells (Maegawa, H., Tachikawa-Ide, R., Ugi, S., Iwanishi, M., Egawa, K., Kikkawa, R., Shigeta, Y., and Kashiwagi, A. (1993) Biochem. Biophys. Res. Commun. 197, 1078-1082). Increased PTPase activity was consistent with a 2-fold increase in the amount of PTP1B, and anti-PTP1B antibody inhibited this increment of cytosolic PTPase activity in HG cells. Co-incubating cells with pioglitazone prevented these abnormalities in cytosolic PTPase, the PTP1B content and the impaired phosphorylation of pp185 and receptor beta subunits in HG cells. Finally, HG cells had impaired insulin-stimulated alpha-amino-isobutyric acid uptake, which was ameliorated by exposure to thiazolidine derivatives. In conclusion, exposing cells to high glucose levels desensitizes insulin receptor function, and thiazolidine derivatives can reverse the process via the normalization of cytosolic PTPase, but not of protein kinase C.
Aminoisobutyric Acids↗
[Obesity as a risk factor for developing non-insulin dependent diabetes mellitus--obesity and insulin resistance].
Obesity is considered to be one of the major risk factors for developing non-insulin dependent diabetes mellitus (NIDDM). Our cohort study for NIDDM in Aito, Shiga 1980-1990 confirmed that aging, higher body mass index (obesity) and high blood pressure were independent risk factors for developing NIDDM in Japan. In Pima Indians, decreased glucose disposal rate (GDR) is significantly related to percentage of body fat (%fat). Insulin signaling for glycogen synthesis in the skeletal muscles is impaired in the early stages of obesity. Although the molecular mechanism for insulin resistance in obesity is still unknown, hyperinsulinemia induces insulin receptor loss by means of the down regulation mechanism, and prolonged hyperglycemia may induce the impairment of insulin receptor kinase in the skeletal muscles in obese subjects. These dysfunctions in insulin signaling may cause the deterioration of insulin sensitivity, resulting in worsening glycemic control. Thus dysfunction of insulin receptor signaling in skeletal muscles may be a target for preventing diabetes in obese subjects.
Animals↗
Scanning-tunneling-microscopy study of surface morphology at the initial growth stage of Si on a 7 x 7 superlattice surface of Si(111).
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Journal Article↗
Antibodies against GM1 ganglioside affect K+ and Na+ currents in isolated rat myelinated nerve fibers.
High titers of anti-GM1 ganglioside antibodies (anti-GM1 antibodies) may be implicated in lower motor neuron disease. We studied the pathogenic role of anti-GM1 antibody using the petroleum jelly-gap voltage clamp technique on isolated single myelinated rat nerve fibers. Anti-GM1 antisera were obtained from rabbits immunized with GM1 ganglioside. Extracellularly applied anti-GM1 antisera without complement activity increased both the rate of rise and the amplitude of the K+ current elicited by step depolarization, with little effect on Na+ current. In the presence of active complement, however, anti-GM1 antibodies decreased the Na+ current, and caused a progressive increase of nonspecific leakage current. Neither complement alone nor complement-supplemented antisera from which anti-GM1 antibodies were depleted by affinity chromatography had any effect on ionic current. These observations indicate that anti-GM1 antibodies themselves can uncover K+ channels in the paranodal region, while anti-GM1 antibodies bound to the nodal membrane in the presence of complement may form antibody-complement complexes that block Na+ channels and disrupt the membrane at the node of Ranvier.
Action Potentials↗
Prevention of glomerular hyperfiltration in rats with streptozotocin-induced diabetes by an atrial natriuretic peptide receptor antagonist.
The contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration in diabetes was investigated by examining the effects of HS-142-1, a non-peptide antagonist of biological receptors for ANP, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in rats with streptozotocin-induced diabetes. Three to four weeks after streptozotocin injection, the plasma concentration of ANP, urinary cyclic GMP excretion rate, GFR, and RPF were significantly higher in diabetic rats than in control rats. The increase in GFR and RPF in diabetic rats was significantly reduced, in a dose-dependent manner, by a single intravenous injection of HS-142-1; the maximal effect was apparent at a dose of 10 mg per kg of body weight. Continuous subcutaneous administration of HS-142-1 with an osmotic minipump for 3 to 4 weeks, beginning 2 days after streptozotocin injection, prevented the increases in urinary cyclic GMP excretion rate, GFR, and RPF observed in untreated diabetic rats. These results highlight the importance of ANP in the development of diabetic glomerular hyperfiltration and indicate that this condition can be prevented by continuous inhibition of the action of ANP.
Animals↗
Insulin-specific activation of S6 kinase and its desensitization in cultured rat vascular smooth muscle cells.
To elucidate the role of hyperinsulinemia in the development of atherosclerosis, we evaluated insulin-specific signaling in cultured vascular smooth muscle cells (SMCs) and its desensitization by continuous exposure to insulin. The concentration of unlabeled insulin that inhibited specific [A14-125I]-insulin binding by 50% (IC50) was 0.33 +/- 0.02 nM, which was 100 times less than the IC50 of unlabeled IGF-I. For [125I]-IGF-I binding, the IC50 of unlabeled IGF-I was found to be 6.6 +/- 0.88 nM, which was 100 times less than the IC50 of unlabeled insulin. The binding capacities for insulin and IGF-I were found to be 1.28 +/- 0.86 and 1200 +/- 170 fmol/0.5 mg protein, respectively. Autophosphorylation of the beta-subunit of the insulin receptor was stimulated at above 0.17 nM (24 microU/ml) insulin. Insulin concentrations exceeding 1 nM significantly activated the S6 kinase in a dose-dependent manner. In contrast, 10 nM insulin did not activate MAP kinase nor [3H]thymidine incorporation into DNA, while both were activated by 38% and 44% with 1 microM insulin and by 52% and 67% with 10 nM IGF-I, respectively. By pre-exposing cells to 10 nM insulin for 12 h, the binding capacity for insulin decreased by 34% (P < 0.05), and activation of S6 kinase by insulin almost disappeared, while both IGF-I binding and the activation of S6 kinase by IGF-I were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Increase of voltage-sensitive calcium channels and calcium accumulation in skeletal muscles of streptozocin-induced diabetic rats.
The number of voltage-sensitive calcium channels (VOCC) in triceps surae muscle membrane fractions isolated from control and streptozocin (STZ)-induced diabetic rats was determined using [3H]PN200-110, a dihydropyridine derivative, as a ligand. Furthermore, quantitative analysis of calcium in soleus muscle fibers was performed by the calcium oxalate-pyroantimonate method and x-ray microanalysis. The maximum binding (Bmax) of [3H]PN200-110 in skeletal muscle membrane isolated from 10-week diabetic rats (1,091 +/- 77 fmol/mg protein) was increased significantly by 91% as compared with the control value (572 +/- 32 fmol/mg protein), without a significant change in Kd. The increase in Bmax of [3H]PN200-110 was dependent on the duration of diabetes, and was not found until 6 weeks after STZ injection. Insulin treatment for 8 weeks after induction of diabetes normalized Bmax to the control level (583 +/- 53 fmol/mg protein). Precipitates of calcium antimonate, identified by x-ray microanalysis, were observed much more frequently in specimens from 10-week diabetic rats versus controls. The increase in the incidence of precipitates was not observed in 3-week diabetic rats and was suppressed by 8 weeks' insulin treatment. These results indicate that the number of VOCC in chronically diabetic rats was increased in the sarcolemmal membrane of skeletal muscle and that calcium was accumulated inside skeletal muscle fibers.
Analysis of Variance↗
Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study.
The clinical efficacy of epalrestat (150 mg/day, 50 mg tid, po; A group), an aldose reductase inhibitor, was evaluated in 196 patients with diabetic neuropathy by a double-blind study using placebo (9 mg/day, 3 mg tid, po; P group) as a control for 12 weeks. The disappearance rates of upper limb spontaneous pain were 42.9% and 12.0% in the A and P groups, respectively, and those of lower limb spontaneous pain 48.6% and 22.6%, thus being significantly higher in the A group (p < 0.05, logrank-test). The motor nerve conduction velocity of the peroneal nerve significantly increased only in the A group (delta 1.6 +/- 0.6 m/sec, p < 0.01, paired t-test), and the extent of increase in that of the median nerve was significantly greater in the A group than in the P group (p < 0.05). Thresholds of vibratory sensation and autonomic nerve function were also significantly improved in the A group (p < 0.05). The data were reanalyzed by dividing patients into two groups according to their HbA1c values. The improvement ratings of subjective symptoms and of nerve function tests for cases with HbA1c > or = 7.5% were both significantly different between the A and P groups, with the improvement rate being higher in the A group, and also higher as compared to the analysis for cases with HbA1c < 7.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
C-cell distribution in ovine thyroid gland.
The number and percentage of C-cells per unit area were investigated in 2-3-year-old sheep by an immunoperoxidase technique, using a digital-image analysis. C-cells were distributed throughout the thyroid lobes but were not present in either the isthmus or the superior and inferior poles of the thyroid. C-cells were more concentrated in the deep central region of the lobes and decreased gradually toward the periphery. There was a high correlation between the number and the percentage of C-cells per unit area of thyroid gland in sheep. Significant differences were not present between male and female sheep of 2-3 years of age.
Animals↗
High glucose condition desensitizes insulin action at the levels of receptor kinase.
The mechanisms for the insulin resistance induced by hyperglycemia were investigated by studying the in vitro effects of a high glucose concentration on insulin signaling with Rat 1 fibroblasts expressing human insulin receptors (HIRc). Incubation of HIRc cells for 4 days in 27 mM D-glucose led to impaired insulin-stimulation of both alpha-aminoisobutyric acid uptake (AIB) and phosphorylation of pp185 and receptor beta-subunits in vivo. In vitro autophosphorylation and tyrosine kinase activities toward poly Glu80 Tyr20 of insulin receptors from cells exposed to high glucose media (HG) were also impaired (46-48% of control), although the binding of insulin to HG cells was unchanged. One possible explanation for these high glucose effects is that they are mediated by the activation of protein kinase C (PKC). However, a 4-day-high glucose culture had no effect on cytosolic and membrane PKC activities or on phorbol dibutyrate binding to whole cells. This is in accordance with the orthophosphate labeling study, in which basal autophosphorylation activity in HG cells did not increase, suggesting that phosphorylation of serine and threonine residues in the basal state might not increase in HG cells. These results indicate that in cells exposed to high glucose, desensitization of insulin receptors was induced via several intracellular events, but might not be due to persistent activation of PKC in HIRc cells.
Animals↗
Endothelin-1 stimulates tyrosine phosphorylation of p125 focal adhesion kinase in mesangial cells.
Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. Because ET-1 was found to stimulate the tyrosine phosphorylation of unidentified cellular proteins in cultured mesangial cells, protein tyrosine kinase might serve as one of the important signals leading to various functions of ET-1. Focal adhesion kinase (p125FAK) is a newly identified cytoplasmic protein tyrosine kinase that is activated by the phosphorylation of its own tyrosine residue. Because p125FAK was found to play a role in the signal transduction of not only integrins but also various neurotransmitters, including bombesin, endothelin, and vasopressin in Swiss 3T3 cells and Rat-1 fibroblasts, whether ET-1 could stimulate the tyrosine phosphorylation of p125FAK in glomerular mesangial cells was examined. ET-1 stimulated the tyrosine phosphorylation of p125FAK by threefold to fourfold in cultured mesangial cells. This effect of ET-1 was detected at 1 min and reached a maximum within 5 min and was blocked by BQ-123, an antagonist for ETA receptor. A23187, a calcium ionophore, failed to stimulate the tyrosine phosphorylation of p125FAK, and ET-1 was able to stimulate the tyrosine phosphorylation of p125FAK, even in a calcium-free medium. The activation of protein kinase C (PKC) by phorbol 12, 13-dibutyrate resulted in a stimulation of the tyrosine phosphorylation of p125FAK, and an inhibition of PKC by calphostin C or staurosporine significantly reduced the effect of ET-1. Furthermore, prolonged treatment of the cells with phorbol 12, 13-dibutyrate markedly inhibited the ET-1-induced tyrosine phosphorylation of p125FAK. These results indicate that p125FAK might play a role in a signal transduction system of ET-1 in glomerular mesangial cells and that the ET-1-induced tyrosine phosphorylation of p125FAK is largely dependent on the PKC pathway.
Animals↗
Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H2O2 in high-glucose medium.
The effects of glucose concentration on D-glucose oxidation and reduced nicotinamide adenine dinucleotide phosphate (NADPH) supply were studied during exposure of cultured human umbilical vein endothelial cells to hydrogen peroxide (H2O2). The activation of glucose oxidation via the pentose phosphate pathway (PPP), induced by exposure of cells to 200 mumol/l H2O2 for 1 h, was reduced by 50% (P < 0.01) in cells cultured for 5-7 days in 33 mmol/l D-glucose (HG) versus those cultured in 5.5 mmol/l D-glucose without (NG) or with (HR) 27.5 mmol/l D-raffinose. The intracellular NADPH content in HG cells, but not in NG or HR cells, was decreased by 42% (P < 0.01) by exposing cells to 200 mumol/l H2O2. The decrease in NADPH was dependent on D-glucose concentration in the medium and was prevented in glutathione (GSH)-depleted cells. The latter observation suggests that the decrease in NADPH is associated with activation of the GSH redox cycle. In the presence of 200 mumol/l H2O2, lactate release into the medium, NADH/NAD ratio, and phosphofructokinase activity in HG cells were 56, 53, and 68% greater, respectively, than in the NG group, which indicates that inhibition of glycolysis by H2O2 is less marked in the HG group compared with NG group. These results indicate that activation of the PPP was impaired in endothelial cells cultured under conditions of high-glucose and oxidative stress, resulting in a decreased supply of NADPH to various NADPH-dependent pathways, including the GSH redox cycle.
Adenosine Triphosphate↗