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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the streptozotocin (STZ)-treated diabetic rat, reduced glomerular arteriolar resistance leads to raised intraglomerular pressure. Because vasoconstrictor hormones, such as angiotensin II, stimulate arteriolar smooth muscle and mesangial cell contraction via the D-myo-inositol (MI)-dependent transmembrane signaling pathway, in diabetes extracellular D-glucose may inhibit MI transport causing MI depletion, reduced signaling, and hypocontractility. Therefore we studied the regulation of Na-dependent MI transport in the intact cells (mesangial and endothelial) of isolated glomeruli from STZ rats after 2 wk of diabetes, with and without insulin, compared with controls. Specific [3H]MI uptake per milligram glomerular protein (10-150 min, 37 degrees C) was observed in the presence of 0, 5.5, and 30 mM D-glucose using L-[14C]glucose as a marker of nonspecific uptake. D-Glucose competitively inhibited Na-dependent MI transport (maximum velocity) into diabetic and normal glomerular cells. At 5.5 mM D-glucose, MI uptake by diabetic non-insulin-treated glomeruli was increased to 191 +/- 14% (SE) above normal glomeruli. Insulin treatment resulted in less upregulation (116 +/- 11%) of normal MI transport. High glucose concentration did not alter the rate of [3H]MI efflux from preloaded glomerular cells. To determine whether diabetes alters available substrate for transmembrane signaling, after incubation for 120 min, the incorporation of [3H]MI into cellular membrane phosphoinositides and soluble D-myo-inositol phosphates of isolated diabetic and control glomerular cells was compared. Diabetic glomerular cells displayed a significant increase (P less than 0.005) in [3H]MI incorporation into these fractions compared with controls.
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PMID:Upregulation of D-myo-inositol transport in diabetic rat glomerular cells. 131 87

It has been proposed that abnormal myo-inositol metabolism may be a factor in the development of diabetic complications. Studies with animal models of diabetes and cultured cells have suggested that hyperglycemia by an unknown mechanism may alter myo-inositol metabolism and content. Recently, we have shown that L-fucose, a 6-deoxy sugar whose content has been reported to be increased in diabetes, is a potent inhibitor of myo-inositol transport. To examine the effect of L-fucose on myo-inositol metabolism, neuroblastoma cells were cultured in medium supplemented with L-fucose. L-Fucose is a competitive inhibitor of Na(+)-dependent, high-affinity myo-inositol transport. The Ki for inhibition of myo-inositol transport by L-fucose is about 3 mM. L-Fucose is taken up and accumulates in neuroblastoma cells. The uptake of L-fucose is inhibited by Na+ depletion, D-glucose, glucose analogues, phloridzin, and cytochalasin B. In contrast, neither myo-inositol nor L-glucose inhibits L-fucose uptake. Chronic exposure of neuroblastoma cells to 1-30 mM L-fucose causes a decrease in myo-inositol accumulation and incorporation into inositol phospholipids, intracellular free myo-inositol content, and phosphatidylinositol levels. Na+,K(+)-ATPase transport activity is decreased by about 15% by acute or chronic exposure of neuroblastoma cells to L-fucose. Similar defects occur when neuroblastoma cells are exposed chronically to 30 mM glucose. Cell myo-inositol metabolism and Na+/K(+)-pump activity are maintained when 250 microM myo-inositol is added to the L-fucose-supplemented medium. Unlike the effect of chronic exposure of neuroblastoma cells to medium containing 30 mM glucose, the resting membrane potential of neuroblastoma cells is not altered by chronic exposure of the cells to 30 mM L-fucose. The effect of L-fucose on cultured neuroblastoma cell properties occurs at concentrations of L-fucose which may exist in the diabetic milieu. These data suggest that increased concentrations of L-fucose may have a role in myo-inositol-related defects in mammalian cells.
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PMID:L-fucose is a potent inhibitor of myo-inositol transport and metabolism in cultured neuroblastoma cells. 131 50

A preferential impairment of the pancreatic B cell secretory response to D-glucose occurs in adult rats injected with streptozotocin during the neonatal period. Three possible explanations for such a preferential defect were investigated in the present study. First, the time course for 3-O-methyl-D-glucose uptake by islets suggested that the anomaly in hexose transport was mainly attributable to a decrease in the space accessible to the D-glucose analog commensurate with the decrease in B cell mass, rather than to a delayed equilibration of hexose concentration across the B cell plasma membrane. Second, the activity of glucose-6-phosphatase was found to be equally low in islets from diabetic and control rats, ruling out the futile cycling between D-glucose and D-glucose 6-phosphate as a cause for the preferential alteration of the secretory response to the hexose. Third, the activity of flavine adenine dinucleotide-linked glycerophosphate dehydrogenase was found to be decreased to a greater relative extent than the B cell mass. This coincided with an impaired generation of 3HOH from L-[2-3H] glycerol in intact islets. It is proposed, therefore, that an altered circulation in the glycerol phosphate shuttle may play a major role in the impaired process of glucose-stimulated insulin release in this model of noninsulin-dependent diabetes.
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PMID:Enzymic and metabolic anomalies in islets of diabetic rats: relationship to B cell mass. 131 52

Culture of the postimplantation rat conceptus in hyperglycemic medium causes developmental abnormalities and is associated with a diminished water-soluble myo-inositol content. We investigated the effect myo-inositol depletion has on lipid-soluble phosphoinositides, precursors, and water-soluble inositol phosphates. Rat conceptuses were cultured from gestational day 9.5 (presomite, early head fold) to day 10.5 (7-15 somites) in 6.7-73.3 mM D-glucose. Significant decreases in the phosphoinositides of the embryo were observed with increased culture D-glucose concentrations. PI was reduced 15-34%, PIP 18-46%, and PIP2 26-46%. Yolk sac phosphoinositides also were reduced but to a lesser degree. Culture in hyperglycemic media also mediated significant reductions of conceptus inositol phosphates. To investigate whether effects similar to those induced by D-glucose could be mediated by another agent capable of decreasing myo-inositol content, we used scyllo-inositol, a transported but nonmetabolized isomer of myo-inositol. Conceptuses cultured in medium containing scyllo-inositol (0.06-16.7 mM) had dose-dependent decreases of myo-[3H]inositol in water-soluble and lipid-soluble fractions. Incorporation of myo-[3H]inositol into phosphoinositides and inositol phosphates was decreased concomitantly. Developmental effects of D-glucose and scyllo-inositol were assessed in rat conceptuses cultured from day 9.5 (presomite, early head fold) to day 11.5 (22-28 somites). Culture in 40.0-73.3 mM glucose and 0.06-33.3 mM scyllo-inositol impaired growth while increasing dysmorphogenesis in a dose-dependent manner. The results suggest that decreases in conceptus myo-inositol and associated diminution of phosphoinositides, which are the inositol/lipid cycle precursors, are dysmorphogenic and may contribute to the etiology of diabetic embryopathy.
Diabetes 1992 Aug
PMID:Phosphoinositide metabolism in the developing conceptus. Effects of hyperglycemia and scyllo-inositol in rat embryo culture. 132 Oct 63

When either rat or human erythrocytes were incubated for 90-180 min in bicarbonate-buffered media prepared in 2H2O rather than 1H2O, the generation of 3HOH from D-[5-3H]glucose, the production of either 14CO2 or 14C-labelled acidic metabolites from D-[U-14C]glucose and the production of L-lactic acid from unlabelled D-glucose were decreased, to a variable extent but, in no case, by more than 30%. Hence, total substitution of 1H2O by 2H2O provides a suitable tool to study by NMR the generation of 2H-enriched L-lactic acid generated from exogenous D-[1-13C]glucose or D-[6-13C]glucose and, hence, to further explore the diabetes-induced alteration of hydrogen isotopes intermolecular transfer in the reaction catalyzed by phosphoglucoisomerase.
Diabetes Res 1992 Jan
PMID:Effect of 2H2O upon D-glucose metabolism in rat and human erythrocytes. 133 14

We previously reported that, in primary cultured adipocytes, chronic exposure to glucose plus insulin impairs the insulin-responsive glucose transport system. In this study, we examined regulation of glucose transport in BC3H1 myocytes as a model for muscle and found important differences between BC3H1 cells and adipocytes. In myocytes, chronic glucose exposure per se (25 mM) decreased basal glucose transport activity by 78% and insulin's acute ability to maximally stimulate transport by 68% (ED50 approximately 2.5 mM; T1/2 approximately 4 h). D-Mannose and 3-O-methyl-glucose diminished transport rates with approximately 100 and 50% of the potency of D-glucose, respectively, whereas L-glucose, D-fructose, and D-galactose were inactive. Chronic glucose exposure also reduced cell surface insulin binding by 30% via an apparent decrease in receptor affinity, and this effect was associated with a comparable rightward shift in the insulin-glucose transport dose-response curve. In other studies, persistent stimulation with 15 nM insulin also decreased maximally stimulated glucose transport activity, which was independent and additive to the regulatory effect of glucose. Moreover, glucose and insulin-induced insulin resistance via different mechanisms. Glucose (25 mM) reduced the number of cellular glucose transporter proteins by 84% and levels of GLUT1 transporter mRNA by 50% (whether normalized to total RNA or CHO-B mRNA). In contrast, chronic insulin exposure led to a 2.1-fold increase in GLUT1 mRNA but did not alter cellular levels of transporter protein. Cotreatment with glucose prevented the insulin-induced rise in GLUT1 mRNA. BC3H1 cells did not express GLUT4 mRNA that encodes the major transporter isoform in skeletal muscle. In conclusion, in BC3H1 myocytes 1) glucose diminished insulin sensitivity by decreasing insulin receptor binding affinity and decreased basal and maximally insulin-stimulated glucose transport rates via cellular depletion of glucose transporters and suppression of GLUT1 mRNA; 2) chronic insulin exposure exerted an independent and additive effect to reduce maximal transport activity; however, insulin increased levels of GLUT1 mRNA and did not alter the cellular content of glucose transporters; and 3) although BC3H1 cells are commonly used as a model for skeletal muscle, studies examining glucose transport should be interpreted cautiously due to the absence of GLUT4 expression. Nevertheless, the data generally support the idea that, in non-insulin-dependent diabetes mellitus, hyperglycemia and hyperinsulinemia can induce or exacerbate insulin resistance in target tissues.
Diabetes 1992 Mar
PMID:Glucose and insulin chronically regulate insulin action via different mechanisms in BC3H1 myocytes. Effects on glucose transporter gene expression. 137 73

High ascorbic acid (AA) levels in the aqueous humor and intraocular tissues, including the lens, are thought to protect against the harmful effects of photochemical and ambient oxidation reactions involving oxygen and its radicals. In addition, AA may have various metabolic functions, including structural collagen formation in intraocular tissues. Recent work showed that, in the guinea pig, reduced AA was concentrated in the aqueous and lens epithelium. These in vivo studies were extended to streptozotocin-induced diabetic rats and guinea pigs to explore the state of AA transport and passive L-glucose movement in the diabetic lens. A bolus dose of radiolabeled test molecules, including 14C-AA, 3H-L-glucose (L-glu), and 14C-3-O-methyl-D-glucose, was injected into the blood at time zero, and the time-dependent concentrations of these labeled molecules were determined as they move into the aqueous humor, lens epithelium and capsule, and interior compartments. These kinetic studies provided a unique measurement of the functioning state of passive and carrier transport mechanisms in situ in normal and diabetic animals. Diabetic animals (blood glucose, greater than 300 mg/dl) were categorized in terms of the length of time of uniform monitored drug-induced diabetes as short term (10-20 days); midterm (40-60 days), and long term (100+ days). In the rat lens epithelium, significant decrease occurred in the active movement of AA (control KEi, 0.693 +/- 0.062 [n = 12]; midterm drug-induced diabetes Ki, 0.192 +/- 0.054 [n = 10]; t-test P less than 0.001). The passive L-glu entry rate increased (control KEi, 0.0268 +/- 0.0053 [n = 12]; midterm drug-induced diabetes KEi, 0.0421 +/- 0.075 [n = 10]; t-test P less than 0.005). Thus, it was suggested that the drug-induced diabetic rat lens epithelium had lost some of its ability to concentrate AA to high levels and achieved epithelial levels only one- to twofold those of aqueous; control animals concentrated AA to levels of five- to eightfold those of aqueous within 20 min. By contrast, the rate of movement of L-glu from epithelium to stroma increased minimally (control KSi, 0.0116 +/- 0.021 [n = 12]; midterm drug-induced diabetes KSi, 0.0136 +/- 0.034 [n = 10]; t-test P less than 0.05). In addition, AA entry rate into lens cortex increased fourfold (control KSi, = 0.0018 +/- 0.0003 [n = 12]; midterm drug-induced diabetes KSi, 0.0081 +/- 0.024 [n = 10]; t-test P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in ascorbic acid transport into the lens of streptozotocin-induced diabetic rats and guinea pigs. 138 45

The VSMC is an important target for the injurious effects of hyperglycemia in vivo. PKC plays a key role in the regulation of VSMC contraction and growth. This study examines whether elevated extracellular glucose concentrations (10-30 mM [180-540 mg/dl]) activate PKC in cultured rat VSMCs in vitro. A new, rapid, and highly specific assay was used to determine in situ PKC activity in digitonin-permeabilized VSMCs. PKC activity in VSMCs responded rapidly to variations in extracellular glucose concentrations. PKC was activated significantly within 10 min of exposure to D-glucose (20 mM) versus glucose (5 mM). Moreover, with continued exposure to D-glucose (20 mM), PKC activation was sustained for up to 48 h. Reducing D-glucose concentrations to 5 mM restored PKC activity to control values within 1 h. PKC activation was also glucose-concentration dependent. A threshold of only 15 mM (270 mg/dl) was required to significantly and maximally activate PKC in VSMC. PKC was not activated in the presence of osmotic control media that contained either elevated mannitol or L-glucose concentrations. In marked contrast to the sustained PKC activation induced by D-glucose in VSMCs, the normal physiological PKC response to the pressor hormones, AII and AVP, was short-lived and returned to base line within minutes. Sustained PKC activation in the presence of elevated D-glucose concentrations in vitro could disturb the normal physiological regulation of VSMC function and growth and thereby may contribute to the apparent vasotoxicity of hyperglycemia in vivo.
Diabetes 1992 Nov
PMID:Characterization of glucose-induced in situ protein kinase C activity in cultured vascular smooth muscle cells. 139 22

The formation of excess sugar alcohol mediated by aldose reductase (AR) and its intracellular accumulation in lens with resultant hydration is thought to be the initiating mechanism in the pathogenesis of diabetic and galactosemic cataracts. AR is also involved in other diabetic complications including retinopathy and neuropathy. Therefore, there is heightened interest in developing effective AR inhibitors (ARIs) for possible clinical use in human diabetes. However, the evaluation of these drugs for potential clinical use requires that the compounds be evaluated in appropriate target tissues since AR from different tissues is known to exhibit differential susceptibility to ARIs. The relative efficacy of ARIs in human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) was studied by measuring the degree of inhibition of galactitol formation at various concentrations of ARI following incubation of cells in high galactose media for 72 hrs. Regardless of the structural characteristics of the ARIs investigated, higher doses were required to inhibit polyol synthesis in HRPE as compared to HLE cells. Based on ED50 values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 greater than AL-3152 greater than AL-1576 greater than tolrestat greater than statil greater than sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50 values could be due to differential binding to serum proteins in the culture medium. This possibility was examined by employing cultures of dog lens epithelium (DLE). These cells, which synthesize much higher levels of galactitol than HLE and HRPE, could be maintained in serum-free media for short periods (4 hrs) of time. The results, which demonstrate that the extent of polyol inhibition was the same in the presence or absence of serum, suggest that the differences in the potency of the inhibitors may reflect their inherent activity against AR in HLE and HRPE cells.
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PMID:The efficacy of aldose reductase inhibitors on polyol accumulation in human lens and retinal pigment epithelium in tissue culture. 140 94

The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with peripheral vascular disease has generated concern about the incidence and avoidance of contrast-induced nephrotoxicity (CIN). In this prospective study, we sought to identify those patients at greater risk of developing CIN and to evaluate the efficacy of vasodilator therapy with dopamine in limiting this complication. Baseline serum creatinine (Cr) concentrations were obtained on admission and daily for up to 72 hr after angiography in 222 patients undergoing 232 angiographic procedures. The preangiographic treatment was varied at 2-month intervals for 1 year. All patients received an intravenous infusion of 5% dextrose and 0.45% normal saline at a rate of 75 to 125 ml/hr. During the first interval patients received 12.5 g of 25% mannitol immediately prior to their contrast load, in addition to intravenous fluids. During the next 2-month period the patients were given renal dose dopamine intravenously (3 micrograms/kg/min) commencing the evening before angiography and continued to the next morning. During the latter half of the study the treatment regimens were modified so that the use of mannitol was restricted to patients with diabetes mellitus and dopamine to patients with serum creatinine concentrations of > or = 2 mg/dl. Postangiographic elevation in Cr occurred in 2, 10.4, and 62% of studies in patients with baseline creatinine levels of < or = 1.2 mg/dl, 1.3 to 1.9 mg/dl, and > or = 2.0 mg/dl, respectively. None of the patients receiving dopamine experienced an elevation in creatinine. There was no statistical correlation between age, diabetes, or medication with calcium channel blockers and CIN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contrast-induced nephrotoxicity: the effects of vasodilator therapy. 140 11


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