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Biomedical subjects

Y Shigeta

Publications and source records attributed to Y Shigeta.

At least 91 records · Page 5Linked to original sources
PubMed1992

A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats.

In view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.

Aldehyde Reductase↗
PubMed1992

Suppressive effect of vasopressin on ketosis in diabetic rats.

In order to clarify if vasopressin (VP) plays a role in the pathophysiology of hyperosmolar nonketotic diabetic coma (HNDC), VP has been infused to diabetic rats and plasma levels of glucose (PG), ketone bodies, FFA and glucagon were determined. High-dose VP infusion (1.2 U/kg/h) caused gradual elevation of PG (60%) and glucagon levels (600%), while ketone bodies showed transient decrease (20%) at 30 min. Under the suppression of endogenous glucagon secretion by constant infusion of somatostatin (100 micrograms/kg/h), high dose VP showed 25% increase in PG levels and 30% reduction of ketone body levels for the subsequent VP infusion for 1.5 hour. Low-dose VP infusion (0.06 U/kg/h) had no hyperglycemic effect, but suppressed ketosis (20%) in the same condition. There were no changes in plasma FFA concentrations, indicating no significant effect of VP on lipolysis. The results indicate that VP often elevated in HNDC may play an important role for the pathophysiology of HNDC through suppression of hepatic ketogenesis.

Animals↗
PubMed1992

Increased ketogenesis related to insulin deficiency in isolated hepatocytes from NIDDM model rats.

To investigate the hepatic ketone body metabolism in NIDDM, we studied the ketone body production rates in hepatocytes from newly developed non-obese NIDDM model rats. NIDDM model rats were prepared by intraperitoneal injection of streptozotocin at 2 or 5 days of age (STZ2, STZ5 respectively). After 10-15 weeks, ketone body production rates in hepatocytes isolated from these rats were compared with those from control rats as well as ketotic rats made by intravenous injection of streptozotocin into adult rats. Basal ketone body production rates from 0.3 mM [U-14C] palmitate in hepatocytes from control, STZ 2, STZ 5 and ketotic rats were 11.7 +/- 0.98, 14.9 +/- 0.72, 16.0 +/- 0.45, 22.8 +/- 2.32 nmole.palmitate/mg.prot/hr, respectively. These rates were stimulated by 1 microgram/ml of glucagon in control, STZ 2 and STZ 5 rats (14.1 +/- 0.99, 18.6 +/- 1.36, 18.7 +/- 0.69 nmole.palmitate/mg.prot/hr, respectively), but not in ketotic rats (22.8 +/- 2.07 nmole.palmitate/mg.prot/hr). The similar effects were observed by 1 microgram/ml of epinephrine. The basal ketone body production rates were negatively correlated to both hepatic glycogen contents and plasma IRI levels. Considering these parameters together, the extent of metabolic derangement in STZ 2 and STZ 5 rats was between that in control and ketotic rats. These results indicate that the derangements of hepatic ketone body production are related to the severity of insulin deficiency and suggest that the enhanced hepatic ketogenesis contributes in part to the elevated plasma ketone body levels in non-obese NIDDM.

Animals↗
PubMed1992

Abnormalities in cardiac alpha 1-adrenoceptor and its signal transduction in streptozocin-induced diabetic rats.

To investigate a mechanism of diabetic cardiomyopathy, we examined an alteration of cardiac alpha 1-adrenoceptor (alpha 1-AR) signaling in streptozotocin-induced diabetic rats. In diabetes, the cell surface alpha 1-AR concentration on isolated cardiac myocytes decreased by 45% without any change in the dissociation constant, and, moreover, norepinephrine (NE)-stimulated ventricular inositol 1,4,5-trisphosphate (IP3) production was also decreased by 34%. In contrast, basal ventricular protein kinase C (PKC) activity was elevated in both cytosolic (by 98%) and membrane (by 41%) fractions in diabetes. All of these abnormalities seen in diabetes were reversed by chronic insulin treatment. Rapid activation of PKC by phorbol ester in the normal rat heart revealed decreases in both receptor number (by 19%) and NE-stimulated IP3 production (by 21%). These results indicate that the impairment of cardiac alpha 1-AR signaling is closely associated with the diabetic state and may be linked, at least in part, with the abnormal activation of cardiac PKC.

Animals↗
PubMed1992

Hypertension and the development of complications in patients with non-insulin dependent diabetes mellitus in Japan.

Hypertension is a very frequent condition in individuals with non-insulin dependent diabetes mellitus (NIDDM) in Japan and has affected the occurrence of late diabetic complications, especially stroke and nephropathy. Despite similar characteristics of hypertension among Japanese and white patients, the effect of hypertension on the development of coronary artery disease (CAD) in these two populations is strikingly different. In white NIDDM patients, hypertension is one of the major risk factors for the development of CAD. However, CAD is an infrequent complication in NIDDM patients in Japan, even though they have hypertension, lipid abnormalities, and renal complications.

Adult↗
PubMed1992

Familial spinal xanthomatosis with sitosterolemia.

A family with multiple spinal xanthomas and sitosterolemia is described. A 48-year-old woman presented with paraplegia due to multiple intradural extramedullary tumors. The patient also showed marked tendon xanthomas and analysis of sterol composition in both plasma and the xanthoma established the diagnosis of the rare inherited metabolic disease, sitosterolemia and xanthomatosis. Two other siblings in the family presented with marked tendon xanthomas and coronary atherosclerosis, but did not show any neurological signs or symptoms. Magnetic resonance imaging (MRI) study revealed multiple intradural extramedullary tumors in spinal canals of the proband and her sister, but not in the other affected sibling (brother). This is the first report of familial occurrence of multiple extramedullary spinal tumors due to the inherited metabolic abnormality.

Cholesterol↗
PubMed1992

Pioglitazone increases insulin sensitivity by activating insulin receptor kinase.

A new oral agent, 5-[4-(2-(5-ethyl 12-pyridyl)ethoxy]- benzoyl]-2,4-thiazolidinedione (pioglitazone), has been developed for treatment of non-insulin-dependent diabetes mellitus (NIDDM). This agent increases insulin sensitivity in vivo in genetically obese Wistar fatty rats. Administration of the agent (3 mg/kg/day) for 10 days to the rats ameliorated hyperglycemia and hyperinsulinemia, indicating that it decreased insulin resistance. To clarify the mechanism of the drug to increase insulin sensitivity, we examined insulin binding and kinase activity of insulin receptors from muscles of both untreated and treated rats. Pioglitazone treatment did not change insulin binding in Wistar fatty rats but increased insulin-stimulated autophosphorylation of insulin receptors to 78% over the level in the control but not the basal state. Kinase activity toward exogenous substrate, poly Glu4Tyr1, was also increased to 87% over the level of untreated control obese rats. In contrast, in lean rats, pioglitazone treatment did not increase autophosphorylation and kinase activity toward exogenous substrates. To further elucidate the mechanism, we incubated insulin receptors with the agent and measured kinase activity. Incubation of solubilized receptors with the agent did not increase kinase activity. However, the receptors from IM-9 cells, which were incubated with 10(-8) M pioglitazone for 7 days, showed a 46% increase over the control in insulin-stimulated autophosphorylation and kinase activity. These results suggested that pioglitazone increased insulin sensitivity in part by activating kinase of the receptors through indirect effect on insulin receptors and that the drug may have useful benefits in insulin resistance of NIDDM.

Administration, Oral↗
PubMed1992

Identification and characterization of aldose reductase in cultured rat mesangial cells.

Although the enhanced activity of the polyol pathway has been detected in diabetic glomeruli, the intraglomerular localization of this pathway has not yet been well defined. In this study, we attempted to identify aldose reductase, a key enzyme of the polyol pathway, in cultured rat mesangial cells and to characterize the properties of this enzyme using enzymological and immunological methods. When the aldose reductase (DL-glyceraldehyde-reducing) activity was analyzed in mesangial cell extract, the Lineweaver-Burk plot showed concave downward curvature, and the Michaelis constant was 0.83 mM DL-glyceraldehyde, and this activity was noncompetitively inhibited by an aldose reductase inhibitor, ICI-128,436. The enzyme activity was enhanced by the addition of sulfate ion and partially suppressed by barbital. The enzyme cross-reacted with the antisera against rat lens and testis aldose reductases on Ouchterlony plate, and migrated to the region of molecular weight of about 36,500 Da on Western blotting. The presence of aldose reductase mRNA was also confirmed by Northern analysis using cDNA for rat aldose reductase, 10Q. From these results, it was concluded that the aldose reductase may exist in rat glomerular mesangial cells and may play a role in the development of diabetic glomerulopathy, though the coexistence of aldehyde reductase(s) may not be fully ruled out.

Aldehyde Reductase↗
PubMed1992

[A study of the measurement of p-aminohippurate in diabetic subjects].

Glomerular filtration rate has been found to be elevated in the early stage of insulin-dependent diabetes mellitus and has been proposed to play a pathogenetic role in the development of diabetic nephropathy. However, the reports about the change in renal plasma flow (RPF) among diabetic subjects were inconsistent, suggesting that the presence of hyperglycemia may in some way interfere the procedures of RPF measurement. Recently, it has been reported that the glucose in the urine may react with p-aminohippurate (PAH), a widely used marker for RPF measurement, and influence the chemical measurement of PAH, misleading the result of RPF value. In fact, we obtained the decrease of PAH value in urine samples obtained from diabetic subjects during the storage for one week in frozen condition. In order to clarify the factors which may influence the glucose-PAH reaction, we have conducted various in vitro studies. The decrease of PAH values was dose-dependent to urine glucose. The pH of the test solution or urine was also found to greatly influence the result of PAH measurement when glucose was present. The analysis of glucose-PAH reactants by HPLC suggested that the amino residue of PAH might be reacted with glucose, producing the glycation product (Schiff base). The rate of glycation of PAH was time- and pH-dependent. However, when the reaction time was prolonged at the last step of PAH measurement after the addition of the acid solution, the decrease of PAH value was gradually corrected reaching to the theoretical value in 7 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed1992

[Measurement of renal plasma flow and glomerular filtration rates in diabetic subjects].

To clarify the problem in the measurement of renal plasma flow and glomerular filtration rates in diabetes, the effect of glucose on the determination of para-aminohippuric acid (PAH) and inulin was examined. The concentration of urinary PAH in glucosuric diabetic subjects decreased after the storage of urine samples because of the glycation of PAH. Therefore, glucose must be removed by the acid treatment before the determination of the concentrations of urinary PAH. Since glucose can interfere with the assay of inulin, the sample must be treated with NaOH prior to the determination of the inulin concentration. GFR of the subjects with type 2 diabetes was next examined. GFR in the subjects with a duration of diabetes less than 10 years was significantly higher than that in the subjects with a duration of diabetes more than 10 years. Thus, the subjects with short-term type 2 diabetes may present with hyperfiltration similar to the subjects with short-term type 1 diabetes.

Diabetes Mellitus, Type 2↗
PubMed1991

Effect of verapamil on cardiac protein kinase C activity in diabetic rats.

We examined the effect of verapamil treatment on cardiac protein kinase C (PKC) activity in streptozocin-induced diabetic rats. Basal cardiac PKC activity in diabetes increased in both cytosolic (by 94%, P less than 0.01) and membrane (by 41%, P less than 0.05) fractions as compared with that in controls. Subcutaneous administration of 8 mg/kg verapamil twice a day for 8 weeks induced a significant decrease in both cytosolic (by 59%, P less than 0.01) and membrane (by 50%, P less than 0.01) PKC activity in diabetes as compared with the activity in the non-treated diabetic groups. In contrast, cardiac cytosolic PKC activity in control rats was significantly (P less than 0.01) decreased by 41% as compared with that of the non-treated control group without there being any change in membrane PKC activity. Our data demonstrate that verapamil treatment may ameliorate the abnormal activation of cardiac PKC in diabetes.

Animals↗
PubMed1991

Glucose enhances type IV collagen production in cultured rat glomerular mesangial cells.

Type IV collagen production by cultured glomerular mesangial cells and the effect of glucose on it were evaluated in order to explore the possible contribution of mesangial cells to the accumulation of type IV collagen in mesangial matrix typically seen in diabetes. Type IV collagen was measured quantitatively by enzyme-linked immuno-sorbent assay. The majority of type IV collagen was secreted into culture media and secreted-type IV collagen increased with cell growth in early log phase and decreased in late log phase and after confluency. By exposing the cells to high concentrations of glucose (27.8 mmol/l), both secreted- and cell-associated-type IV collagens increased significantly compared with the cells cultured under normal glucose concentrations (5.6 mmol/l) or under equivalent concentrations of mannitol, resulting in a significant increase in total type IV collagen accumulation from 32.1 +/- 6.4 (under 5.6 mmol/l glucose) to 51.0 +/- 4.6 micrograms/dish (mean +/- SD, n = 4) on day 4, from 113.6 +/- 6.6 to 156.8 +/- 7.1 on day 6, from 248.5 +/- 15.2 to 310.0 +/- 12.6 on day 8 and from 372.4 +/- 14.8 to 507.9 +/- 17.2 on day 12. These results indicate the importance of glucose-induced alteration of mesangial cell function in the development of diabetic mesangial expansion.

Animals↗
PubMed1991

Metabolic actions of insulin-like growth factor I in cultured glomerular mesangial cells.

Glomerular mesangial cells in culture have been reported to possess a considerable number of receptors specific to insulin-like growth factor I (IGF-I), with very small number of receptors specific to insulin. To explore acute metabolic effects of IGF-I on mesangial cells, uptake of glucose and amino acid was measured in the presence of IGF-I or insulin. IGF-I stimulated D-[U-14C]glucose incorporation, 2-deoxy[1-3H]glucose uptake and alpha-[methyl-3H]aminoisobutyric acid (AIB) uptake into cultured mesangial cells by 139.8% +/- 2.1%, 116.6% +/- 1.7%, and 214.9% +/- 12.8% (percent of basal), respectively. Similar maximal stimulation was also induced by insulin, while the ED50 of IGF-I to stimulate these uptake systems (9.98 +/- 2.36, 3.45 +/- 1.86, and 3.35 +/- 0.40 ng/mL, respectively) was significantly lower than that of insulin (120.8 +/- 28.5, 61.8 +/- 7.7, and 76.3 +/- 17.5, respectively). These results indicate that, in cultured glomerular mesangial cells, IGF-I induces acute metabolic effects, possibly through its own receptors.

Amino Acids↗
PubMed1991

In vitro stimulation of glucose utilization by insulin in primary cultures of rat hepatocytes.

The effect of glucose concentration and insulin on glucose incorporation was studied in primary cultures of rat hepatocytes. The rate of glucose incorporation into hepatocytes was proportional to the medium glucose concentration from 100 to 800 mg/dl. At 800 mg/dl glucose the rate reached a plateau. Of the glucose taken up by hepatocytes, 16 and 18% was incorporated into glycogen and lipid, respectively, and 58% into the nucleotide fraction after incubation for 4 h. In the medium, lactate was the major product found. Insulin stimulates glucose incorporation by 20-112% into all the above pathways at glucose concentrations between 100 and 800 mg/dl. The insulin effect was noted as early as 2-4 h (early effect) and up to 24 h (delayed effect). This effect of insulin was observed to be dose dependent from 5 to 200 ng/ml insulin. While the delayed insulin effect was abolished by cycloheximide, the early effect of insulin was not affected. With respect to the key enzyme activities of glucose utilization, activation of glycogen synthase (increase of I-activity/total activity) and pyruvate kinase (activation at 0.2 mM phosphoenolpyruvate) was noted 4 h after insulin addition, and these effects were not abolished by cycloheximide. These two enzymes increased in total activity after 24 h. Both glucokinase and glucose-6-phosphate dehydrogenase activities increased by 30-35% and 65-93% at 4 and 24 h, respectively. The results indicate that hepatocytes directly utilize glucose in a dose-dependent manner with respect to glucose and insulin. A major early and delayed effect of insulin appeared due to the activation and induction of the key hepatic enzymes of glucose utilization, respectively.

Animals↗
PubMed1991

A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus.

CS-045, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramkethylchroman-2- ylmethoxy)benzyl]-2,4-thiazolidinedione, lowers plasma glucose in several animal models of non-insulin dependent diabetes mellitus (NIDDM) presumably by increasing insulin sensitivity. Little adverse effect was found in a phase 1 study on healthy male subjects. In order to test its efficacy in lowering plasma glucose in NIDDM in man, a pilot multi-center clinical trial of CS-045 was carried out in 146 patients with NIDDM whose glycemic control was inadequate (FPG greater than 140 mg/dl) on diet and/or other oral hypoglycemic agents. CS-045 was given orally in a daily dose of 200 mg or 400 mg for 12 weeks in addition to the previous treatment. The mean fasting plasma glucose (FPG) and fructosamine began to decrease within 2 weeks and the mean HbA1c within 8 weeks. After 12 weeks, the FPG fell from 192 +/- 41 to 155 +/- 45 mg/dl (P less than 0.01), fructosamine from 3.7 +/- 0.6 to 3.3 +/- 0.6 (P less than 0.01), and HbA1c from 8.9 +/- 1.5 to 8.1 +/- 1.5% (P less than 0.01). The drug was effective in 39% of patients in that FPG fell by more than 20% of the initial value. This rate of efficacy was the same when CS-045 was given alone or together with other oral hypoglycemic agents. The drug was more effective in a dosage of 400 mg than with 200 mg (the rate of efficacy 46% vs 25%) and more effective in obese patients than in lean patients (46% vs 25%).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1991

Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation.

To evaluate an interaction between vasoconstrictive (Ang II) and vasodilating (ANP) peptides, we examined the effect of Ang II on ANP-induced accumulation of cGMP in cultured glomerular mesangial cells. ANP rapidly increased intracellular cGMP levels, with a peak stimulation at one minute in the absence of IBMX and at ten minutes in the presence of IBMX. The ANP-induced cGMP accumulation was significantly inhibited when the cells were treated with Ang II simultaneously with ANP for one minute in the absence of IBMX. This inhibitory effect of Ang II was completely abolished by IBMX and significantly reduced in calcium-free media or by W7, but not affected by H7. Similar inhibitory effect was observed when cells were treated with A23187 but not with TPA for one minute. In the presence of IBMX, Ang II inhibited ANP-induced cGMP accumulation when cells were treated with Ang II for 15 minutes prior to the stimulation by ANP. This inhibition by Ang II was blocked by H7. ANP-induced increase in particulate guanylate cyclase activity was significantly reduced in the cells treated with Ang II or TPA. This reduction of enzyme activity was also prevented by H7. These results indicate that Ang II inhibits ANP-induced cGMP accumulation in cultured glomerular mesangial cells through at least two mechanisms; one is the activation of calcium-dependent, calmodulin-stimulated cyclic nucleotide phosphodiesterase in the initial phase, and the other is the inhibition of guanylate cyclase resulting from protein kinase C activation in the maintenance phase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Amelioration of nerve Na(+)-K(+)-ATPase activity independently of myo-inositol level by PGE1 analogue OP-1206.alpha-CD in streptozocin-induced diabetic rats.

An oral prostaglandin E1 (PGE1) analogue, OP-1206.alpha-CD, was given to rats with streptozocin (STZ)-induced diabetes to examine the therapeutic effects of OP-1206 on short-term and long-term diabetic neuropathy and its action mechanism with special reference to nerve Na(+)-K(+)-ATPase activity. In the short-term experiment, OP-1206 was administered daily to diabetic rats in 3- and 30-mg/kg doses for 4 wk from the day of STZ injection. In the long-term study, 10 micrograms/kg OP-1206 was also given daily for 8 wk from 7 mo after induction of diabetes. The compound improved decreased sciatic motor nerve conduction velocity in both short-term and long-term diabetic rats. The nerve Na(+)-K(+)-ATPase activity of diabetic rats, reduced by 40% compared with controls, was reversed to the level of controls in both experiments, whereas weight loss and hyperglycemia were unchanged, and neither nerve sorbitol accumulation nor myo-inositol depletion was corrected. In a morphometric analysis of myelinated nerve fibers (MNFs) in long-term diabetes, the mean diameter of the largest 10% of MNFs was significantly reduced in untreated diabetic compared with control rats, but OP-1206 completely reversed this reduction. The results suggest that OP-1206 ameliorates a decrease in nerve Na(+)-K(+)-ATPase activity without any effect on nerve myo-inositol level and that the compound may be not only a potent therapeutic agent for the treatment of diabetic neuropathy but also a useful research tool to investigate the mechanism of nerve Na(+)-K(+)-ATPase activity regulation.

Alprostadil↗