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Biomedical subjects

F Umeda

Publications and source records attributed to F Umeda.

At least 55 records · Page 3Linked to original sources
PubMed1996

Risk factor analyses for macrovascular complication in nonobese NIDDM patients. Multiclinical Study for Diabetic Macroangiopathy (MSDM).

To examine the characteristic features of risk factors for macroangiopathy (MA) in nonobese Japanese NIDDM patients, 899 NIDDM patients with and without MA were registered from 40 facilities. Of these, 386 subjects were identified as having any form of MA (total MA); these included 211 with ischemic heart disease (IHD), 163 with cerebrovascular disease (CVD), and 77 with peripheral vascular disease (PVD). Univariate analyses revealed the following common risk factors for total MA, IHD, CVD, and PVD: age, hypertension, systolic blood pressure (sBP) or diastolic blood pressure (dBP), duration of diabetes, diabetic microangiopathy (retinopathy, nephropathy, and neuropathy), low HDL cholesterol level, and higher LDL cholesterol/HDL cholesterol ratio. Additional significant risk factors for specific conditions were also identified, respectively, as male sex for total MA, IHD, and PVD, smoking for IHD and PVD, and high fasting plasma glucose level for total MA and CVD. With stepwise multivariate logistic regression analysis, older age, duration of diabetes, smoking, and low LDL cholesterol/HDL cholesterol ratio were identified as significant and independent risk factors for total MA, IHD, CVD, and PVD. Other risk factors identified were high dBP for IHD, CVD, and PVD, high sBP for total MA, and low BMI for PVD. These results clearly demonstrated that duration of diabetes, smoking, hypertension, and dyslipidemia are major risk factors for MA in NIDDM patients. Since the mean BMI was similar for both groups (approximately 23 kg/m2) and there were no significant differences in immunoreactive insulin levels before and after 75-g oral glucose challenge testing, obesity and hyperinsulinism at the time of the analyses were not considered to play an important role for the pathogenesis of MA in Japanese NIDDM patients. By using the chi 2 test, cutoff points were determined for six of the most commonly measured risk factors. The cutoff point was the level beyond which a significantly higher prevalence of MA occurred. The cutoff points (rounded slightly upward in some cases) for fasting plasma glucose, sBP, dBP, serum total cholesterol level, serum triglyceride level, and BMI were 140 mg/dl, 140 mmHg, 80 mmHg, 180 mg/dl, 120 mg/dl, and 23 kg/m2, respectively. When these cutoff points were used as control criteria, the prevalence of MA was significantly lower in subjects whose risk factor measurements remained under the proposed control criteria for four or more of the six variables. In conclusion, in nonobese NIDDM patients, age, hypertension, and dyslipidemia were found to be risk factors for MA. Duration of diabetes was also demonstrated as an independent risk factor, indicating the close association of deranged glucose metabolism with the pathogenesis of MA in NIDDM patients. It seems to be crucial to control these risk factors for the prevention of MA in NIDDM patients.

Aged↗
PubMed1996

Secretory protein 7B2 response to oral glucose loading and intravenous glucagon injection in patients with diabetes mellitus.

Serum 7B2 concentrations in control subjects and patients with diabetes mellitus were measured following a 75 g oral glucose load and following intravenous glucagon infusion. In response to oral glucose, serum 7B2 levels increased in the controls (n = 10) and in the diabetic patients (n = 7). The increment of the serum 7B2 level was smaller in the diabetic patients than the controls. During the 75 g oral glucose tolerance test (75g OGTT), serum 7B2 levels were significantly positively correlated with serum C-peptide levels. In contrast, following intravenous glucagon infusion, serum 7B2 levels increased only in diabetic patients treated with oral hypoglycemic agents (n = 20) and did not increase in controls (n = 5): the group having the highest insulin secretion activity in the present study, nor in diet or insulin-treated diabetic patients. No correlation between serum 7B2 levels and serum CPR levels was observed in the intravenous glucagon infusion study. These data suggest that an extra-pancreatic source which produces the observed serum 7B2 increase following oral glucose intake can not be excluded and that 7B2 may not be secreted concomitantly with insulin from the pancreatic beta cell in response to intravenous glucagon injection.

Administration, Oral↗
PubMed1995

Inhibition of intercellular communication via gap junction in cultured aortic endothelial cells by elevated glucose and phorbol ester.

Gap junctional intercellular communication (GJIC) is important in coordinating the cells in maintaining tissue homeostasis and in regulating signal transmission. We examined the effect of elevated glucose on GJIC activity in cultured bovine aortic endothelial cells. GJIC activity was assessed by quantitating the transfer from cell to cell of directly microinjected fluorescent dye molecules. GJIC was activated in the subconfluent monolayer. In this condition, exposing the cells to elevated glucose (400 mg/dl) for 24 hrs significantly inhibited GJIC activity, as compared with low glucose (100 mg/dl). This inhibition of GJIC activity induced by elevated glucose was mimicked by addition of 12-O-tetradecanoylphorbol-13-acetate and was restored by addition of staurosporin (10(-8)M), a PKC inhibitor. These results suggest that inhibition of GJIC activity induced by elevated glucose probably through activation of PKC may be involved in the vascular endothelial cell dysfunction associated with diabetes.

Alkaloids↗
PubMed1995

Effect of dehydroepiandrosterone on glucose uptake in cultured human fibroblasts.

Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) reportedly have antidiabetic and antiobesity effects. The effect of DHEA on glucose uptake in cultured human fibroblasts was examined. Incubation of cells with supraphysiologic concentrations of DHEA (10(-5) mol/L) for > or = 10 hours enhanced 2-deoxyglucose (2-DG) uptake significantly (P < .05). Supraphysiologic concentrations of insulin (10(-7) mol/L) increased the sensitivity of glucose uptake to DHEA. Conversely, the sensitivity of glucose uptake to insulin was increased by incubating cells with 10(-6) mol/L DHEA. Both the abundance of transcripts encoding glucose transporter-1 (Glut-1) and the maximal velocity (Vmax) of 2-DG transport were increased in cultured fibroblasts incubated with DHEA. Cultured fibroblasts expressed a specific binding factor with low affinity for [3H]DHEA (maximal number of binding sites, 18,496 sites per cell; Kd, 298 nmol/L). Other androgen hormones exerted a less-marked effect on glucose uptake; DHEA-S had no effect. These results suggested that DHEA increases Glut-1 mRNA through binding to a specific factor in cultured human fibroblasts and thereby stimulates glucose uptake in these cells.

Adult↗
PubMed1995

Increased transendothelial permeation of albumin by high glucose concentration.

Vascular endothelial cells, which are polyfunctional, play an important role in the pathogenesis of diabetic complications. The increase in vascular permeability, ie, regulated by vascular endothelial cells, has been reported in patients with diabetes mellitus complicated by angiopathy. To determine the role of hyperglycemia in endothelial cell permeability, we examined the effect of high concentrations of glucose on the permeability of cultured bovine aortic endothelial cells. The permeations of albumin and fluorescein-labeled dextran (FD) across endothelial cell monolayers were increased when cultured with a high concentration of glucose (400 mg/dL). This increased permeation of albumin but not FD was temperature-dependent and was partially reduced by adding 100 mumol/L ponalrestat (ICI 128,436, Statil; ICI, Cheshire, UK), which is an aldose reductase inhibitor. Stimulation or inhibition of Na,K-adenosine triphosphatase (ATPase) in bovine aortic endothelial cells failed to alter their permeability. These findings suggest that high concentrations of glucose enhance transendothelial permeability of albumin in part by activating the polyol pathway, but independently of Na,K-ATPase activity.

Animals↗
PubMed1995

Enhancement of prostacyclin production in cultured bovine aortic endothelial cells by oxidized glycated low-density lipoprotein.

Oxidized low-density lipoprotein (oLDL) is implicated in the pathogenesis of atherosclerosis. The serum concentration of glycated LDL (gLDL) is increased in diabetics, and it is possible that oxidative modification of gLDL contributes to the increased incidence of atherosclerosis associated with diabetes. The mechanism and effect on prostacyclin (PGI2) production by cultured bovine aortic endothelial cells of oxidized glycated LDL (ogLDL) prepared in vitro have now been examined. Glycation of LDL was performed by incubating LDL with 20 mM glucose for 3 days. ogLDL was then prepared by incubation of gLDL with 1 microM CuSO4 for 12 h. Both the electrophoretic mobility and the thiobarbituric acid reactive substance content of ogLDL were greater than those of native LDL (nLDL) or gLDL. Binding, cell-association, and degradation of ogLDL in endothelial cells were significantly greater than those of nLDL and gLDL. The stimulatory effect of ogLDL on PGI2 production was significantly greater than that of nLDL or gLDL; this effect was dose dependent. Both cell-association and the stimulatory effect on PGI2 production of oLDL were dependent on the extent of oxidation in a biphasic manner. Endothelial cells thus appear to protect against atherosclerosis by removing atherogenic lipoproteins and by producing PGI2.

Animals↗
PubMed1995

Metabolism of oxidized glycated low-density lipoprotein in cultured bovine aortic endothelial cells.

The serum concentration of glycated low-density lipoprotein (gLDL) is increased in individuals with diabetes mellitus, which may be a contributing factor to the increased incidence of atherosclerosis in this population. Given the importance of oxidized LDL (oLDL) in atherosclerosis and that vascular endothelial cells express receptors for oLDL, oxidized glycated LDL (ogLDL) was prepared in vitro and its binding and degradation by cultured bovine aortic endothelial cells were examined. Glycation of native LDL (nLDL) isolated from normal human subjects was performed by incubation with 20 mM glucose at 37 degrees C for 3 days, and ogLDL was prepared by oxidation of gLDL with 1 microM CuSO4 at 37 degrees C for 12 hours. The electrophoretic mobility and thiobarbituric acid reactive substance (TBARS) value of ogLDL were greater than those of nLDL and gLDL. Both binding and degradation of ogLDL by cultured endothelial cells also were significantly greater than for nLDL and gLDL. Degradation of nLDL by endothelial cells was completely inhibited by ogLDL, whereas degradation of acetylated LDL was not inhibited by nLDL or ogLDL. Thus, the binding and degradation of ogLDL by endothelial cells do not appear to be mediated by the scavenger receptor. Although the exact mechanism is not clear, it appears that vascular endothelial cells may play a protective role against atherosclerosis by removing potential atherogenic lipoproteins.

Animals↗
PubMed1995

Effects of glucose and an aldose reductase inhibitor on albumin permeation through a layer of cultured bovine vascular endothelial cells.

The effects of high glucose concentrations on the selective permeability of a layer of cultured bovine vascular endothelial cells (ECs) were investigated. ECs were derived from the intima of the thoracic aorta and permeability to nonglycated albumin, glycated albumin, and fluorescein dextrans (FDs) of molecular mass to albumin was measured. ECs were cultured on a filter coated with type I collagen and preincubated in the presence of various glucose concentrations for 96 h. Human serum albumin was glycated by incubation with glucose in vitro. Nonglycated and glycated albumin were separated by affinity column chromatography. The permeation rates of nonglycated and glycated albumin as well as those of neutral and anionic FD through the EC layer were increased by preincubation of cells with high glucose concentrations (22.2 and 44.4 mmol/l). The permeation rate of glycated albumin was significantly less than that of nonglycated albumin at all glucose concentrations tested, whereas the permeation rate of anionic FD was significantly lower than that of neutral FD only at a physiological glucose concentration (5.6 mmol/l). The aldose reductase inhibitor ponalrestat partially inhibited the high glucose-induced increase in trans-endothelial permeation of albumin (both nonglycated and glycated), but had no effect on the increased permeation of FD. These results indicate that high glucose concentrations enhance trans-endothelial permeability to albumin and FD and may disturb the barrier function of vascular ECs. Furthermore, metabolism of glucose via the polyol pathway may contribute to abnormalities in trans-endothelial permeability.

Albumins↗
PubMed1995

Effect of dehydroepiandrosterone on glucose uptake in cultured rat myoblasts.

The effects of dehydroepiandrosterone (DHEA) on glucose uptake and on insulin sensitivity were studied in cultured rat myoblasts (L6 cells). Preincubation with supraphysiological doses of DHEA (10(-5) M approximately significantly enhanced (p < 0.05) the cellular uptake of [3H]-2-deoxyglucose. Glucose uptake was significantly increased in cells exposed to 10(-4)M DHEA for 10 hours (p < 0.005), and for 24 hours (p < 0.001), but not for 3 hours. An increase in DHEA sensitivity with an enhanced glucose uptake was observed in cells exposed to 10(-7)M of human insulin. Insulin sensitivity was increased by preincubating the cells with 10(-6)M of DHEA. Other androgens enhanced the effect on glucose uptake to a lesser extent. DHEA sulfate had no effect on L6 cells, suggesting that the effect may be specific for DHEA, not common to androgens, Sulfation of DHEA may negate the effect. In reciprocal plot analysis, the Km value for glucose transport was decreased by preincubation with DHEA (from 0.67 mM without DHEA, 0.56mM with 10(-5)M DHEA, and 0.25mM with 10(-4) M DHEA), although Vmax was unchanged, We conclude that DHEA increases the affinity of glucose transport in the plasma membrane of cultured rat myoblasts, leading to an enhanced glucose uptake and an increase in insulin sensitivity.

Animals↗
PubMed1995

Effects of phorbol ester on vasodilation induced by endothelium-dependent or endothelium-independent vasodilators in the mesenteric arterial bed.

The effects of phorbol ester, phorbol 12-myristate 13-acetate (PMA), on vasodilation induced by endothelium-dependent or independent vasodilators in the mesenteric arterial bed were examined. In mesentery precontracted with methoxamine, acetylcholine (ACh) produced a concentration-dependent vasodilation, but ACh-induced vasodilation was significantly reduced when the tonus of the mesentery was raised by an equieffective concentration of PMA. Sodium nitroprusside (SNP) and forskolin also caused a concentration-dependent relaxation in the mesenteric arterial bed pre-contracted with methoxamine, but could not induce relaxation in mesentery precontracted with PMA. In mesentery precontracted with PMA or methoxamine, ACh-induced vasodilation was significantly inhibited by tetraethylammonium (TEA), but not by ouabain, glibenclamide, or apamin. ACh-induced vasodilation was significantly inhibited by NG-nitro-L-arginine (L-NNA), whereas L-NNA was not capable of effectively inhibiting the ACh-induced vasodilation of the mesentery precontracted with PMA. These results suggest that stimulation of protein kinase C (PKC) by phorbol ester (PMA) in the mesenteric arterial bed inhibits the relaxation of vascular smooth muscle (VSM) in response to cyclic nucleotides. Furthermore, the endothelium of the mesenteric arterial bed may release endothelium-derived hyperpolarizing factor (EDHF), in addition to nitric oxide (NO), into the mesentery.

Acetylcholine↗
PubMed1995

Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway.

We have characterized effects of d-alpha-tocopherol (vitamin E) on activation of protein kinase C (PKC) and diacylglycerol (DAG) levels in retinal tissues of diabetic rats and correlated its effects to diabetes-induced changes in retinal hemodynamics. Membrane PKC specific activities were increased by 71% in streptozocin-induced diabetic rats compared with controls (P < 0.05). Western blot analysis showed that membrane PKC-beta II was increased by 133 +/- 5% (P < 0.05). Injection of d-alpha-tocopherol (40 mg/kg ip) every other day prevented the increases in membrane PKC specific activity and PKC-beta II protein by immunoblots. Diabetes-induced increases in DAG levels were also normalized by d-alpha-tocopherol treatment of 2 wk duration. Physiologically, angiographic abnormalities of retinal hemodynamics based on computerized video-based fluorescein angiography and associated with increases of DAG and membranous PKC levels were also prevented by d-alpha-tocopherol treatment in diabetic rats. The effect of d-alpha-tocopherol on retinal vascular cells was also studied. Exposure of retinal endothelial cells to 22 mM glucose for 3 days increased total DAG and [3H]palmitate-labeled DAG levels by 35 +/- 8 and 50 +/- 8% (P < 0.05), respectively, compared with exposure to 5.5 mM glucose. The presence of d-alpha-tocopherol (50 micrograms/ml) prevented the increases in total DAG and [3H]palmitate-labeled DAG levels in cells exposed to 22 mM glucose. These findings suggested that treatment with d-alpha-tocopherol can prevent diabetes-induced abnormalities in rat retinal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Insulin resistance associated with substitution of histidine for arginine 252 in the alpha-subunit of the human insulin receptor: trial of insulin-like growth factor I injection therapy to enhance insulin sensitivity.

Mutation of the insulin receptor gene can compromise the ability of the receptor to mediate insulin action. A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. The proband's consanguineous parents (diabetic mother and normal father) and her sister (impaired glucose tolerance), each of whom showed an exaggerated insulin response to an oral glucose load, were heterozygous for this mutation. Her brother showed a normal insulin response and lacked the mutation, as did 50 healthy Japanese control subjects. The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient's hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. Studies of the binding of 125I-labeled insulin to the proband's cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252-->His mutation decreased both cell surface expression and the affinity for insulin for the receptor. These observations suggest that the homozygous Arg252-->His mutation is responsible for the type A insulin resistance of the proband, whereas in the heterozygous state, the mutation results in mild insulin resistance indistinguishable from that observed in noninsulin-dependent diabetes mellitus.

Adolescent↗
PubMed1995

Impaired feedback inhibition of insulin secretion by hyperinsulinemia in patients with insulinoma.

By means of the euglycemic three step hyperinsulinemic clamp technique, suppression of endogenous C-peptide secretion by exogenous insulin infusion was evaluated in patients with insulinoma (n = 8) and healthy controls (n = 20). Euglycemic hyperinsulinemic clamp studies were performed with an artificial pancreas (STG-22 NIKKISO, Tokyo, Japan). Insulin (Actrapid human insulin) was infused at the rate of 1.12, 3, and 10 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dl, and high insulin levels were maintained in all subjects (833 +/- 78 microU/ml at the rate of 10 mU/kg/min insulin infusion). During the clamp studies, plasma C-peptide levels in normal subjects declined from 2.0 +/- 0.2 to 0.9 +/- 0.2 ng/ml, indicating suppression of endogenous insulin secretion by exogenous insulin infusion. In patients with insulinoma, plasma C-peptide levels were 3.1 +/- 1.6 ng/ml in the basal state, and were not suppressed even during exogenous hyperinsulinemia. We concluded that the feedback inhibition of insulin secretion by exogenous insulin infusion is attenuated in patients with insulinoma, and that the hyperinsulinemic clamp technique may be a useful method for the diagnosis of insulinoma.

Adult↗
PubMed1995

Glycation accelerates the oxidation of low density lipoprotein by copper ions.

We investigated the in vitro effect of glycation on LDL oxidation. Native LDL (nLDL) was glycated in 0, 5, 10, or 20 mM glucose. This glycated LDL (gLDL) was oxidized by 1 microM copper ion. Compared to nLDL and gLDL, oxidized gLDL (ogLDL) has a greater negative charge. The thiobarbituric acid reactive substance (TBARS) value of ogLDL increased with the glucose concentration tested during glycation in a dose-dependent manner. OgLDL glycated in 20 mM glucose had a significantly higher TBARS level than did oxidized LDL incubated without glucose. In conclusion, LDL glycated in vitro is prone to oxidation. Thus, glycated LDL, which increases in the diabetic state, may contribute to the pathogenesis of atherosclerosis in diabetic patients.

Copper↗
PubMed1995

Secretion of insulin and glucagon by the perfused pancreas of genetically obese (fa/fa) Zucker rats and its alteration with aging.

To evaluate the sequential changes in secretion of insulin and glucagon by the pancreas of Zucker fa/fa rats, we examined the secretion of these peptides by the perfused pancreas of the rats and by that of their lean littermates aged 9, 18, and 54 wks. Obese rats weighted significantly more than lean rats at all ages and had increased plasma insulin except for those at 54 wks of age. Isolated pancreas of obese rats at 9 wks showed greater insulin secretion response to glucose and arginine than that of lean rats at the same age. Insulin secretion response to arginine from pancreas of obese rats at 18 wks was also greater than that from pancreas of lean rats at 18 wks. Increased glucose concentration in the perfusion medium caused less suppression in obese rats than in lean rats. 10 mM arginine stimulation resulted in a higher secretion response in lean rats than in obese rats at 18 and 54 wks. Impairment of glucagon secretion was observed even at 54 wks of age, when the obese rats no longer had significantly increased plasma insulin. This suggested that abnormal glucagon secretion was due not only to hyperinsulinemia, but also to a possible defect in the secretory mechanism.

Aging↗