Biomedical subjects
H Bar-On
Publications and source records attributed to H Bar-On.
Schoenlein-Henoch syndrome in adults. A clinical and histological study of renal involvement.
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Contribution of floating fat triglyceride and of lecithin towards formation of secretory triglyceride in perfused rat liver.
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Acid lipase in fatty liver in rats.
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Effect of glucose and fructose administration on lipid metabolism in the rat.
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Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in the Psammomys obesus gerbil.
BACKGROUND: Numerous investigations have demonstrated the beneficial effect of vanadium salts on diabetes in streptozotocin (STZ)-diabetic rats, in rodents with genetically determined diabetes and in human subjects. The amelioration of diabetes included the abolition of hyperglycemia, preservation of insulin secretion, reduction in hepatic glucose production, enhanced glycolysis and lipogenesis and improved muscle glucose uptake through GLUT4 elevation and translocation. The molecular basis of vanadium salt action is not yet fully elucidated. Although evidence has been provided that the insulin receptor is activated, the possibility exists that cytosolic non-receptor tyrosine kinase, direct phosphorylation of IRS-1 and activation of PI3-K, leading to GLUT4 translocation, are involved. The raised phosphorylation of proteins in the insulin signaling pathway appears to be related to the inhibition of protein tyrosine phosphatase (PTPase) activity by vanadium salts. NOVEL EXPERIMENTS: The model utilized in our study was Psammomys obesus (sand rat), a desert gerbil which becomes hyperglycemic and hyperinsulinemic on an ad libitum high energy (HE) diet. In contrast to the previously investigated insulin deficient models, vanadyl sulphate was used to correct insulin resistance and hyperinsulinemia, which led to beta-cell loss. Administration of 5 mg/kg vanadyl sulfate for 5 days resulted in prolonged restoration of normoglycemia and normoinsulinemia in most animals, return of glucose tolerance to normal, and a reduction of hepatic phosphoenolpyruvate carboxykinase activity. There was no change in food consumption and in regular growth during or after the vanadyl treatment. Pretreatment with vanadyl sulfate, followed by transfer to a HE diet, significantly delayed the onset of hyperglycemia. Hyperinsulinemic-euglycemic clamp of vanadyl sulfate treated Psammomys demonstrated an improvement in glucose utilization. However, vanadyl sulfate was ineffective when administered to animals which lost their insulin secretion capacity on protracted HE diet, but substantially reduced the hyperglycemia when given together with exogenous insulin. The in vitro insulin activation of liver and muscle insulin receptors isolated from vanadyl treated Psammomys was ineffective. The in vivo vanadyl treatment restored muscle GLUT4 total protein and mRNA contents in addition to membrane GLUT4 protein, in accordance with the increased glucose utilization during the clamp study. These results indicate that short-term vanadyl sulfate treatment corrects the nutritionally induced, insulin resistant diabetes. This action requires the presence of insulin for its beneficial effect. Thus, vanadyl action in P. obesus appears to be the result of insulin potentiation rather than mimicking, with activation of the signaling pathway proteins leading to GLUT4 translocation, probably distal to the insulin receptor.
Dolichol-mediated enhanced protein N-glycosylation in experimental diabetes--a possible additional deleterious effect of hyperglycemia.
In liver cells from diabetic rats, an increased incorporation of labeled glucosamine into cellular and secretory proteins was found, when related to the incorporation of labeled leucine. This increased N-glycosylation was present in the face of decreased synthesis of hepatic cellular and secretory proteins evident from reduced leucine incorporation and diminished glycosyltransferase activity. To elucidate the mechanisms involved we incubated isolated hepatocytes with two N-glycosylation inhibitors: tunicamycin and 2-deoxyglucose. Tunicamycin exerted a marked inhibitory effect on the incorporation rate of labeled glucosamine into proteins in liver cells from diabetic rats, while 2-deoxyglucose had a negligible effect on this process in these cells. These diverse effects might be explained by the fact that tunicamycin acts through strong association with the enzyme catalyzing the first step in glycoprotein synthesis, namely, the transfer of UDP-GlcNAc to dolichol-P (indicating noncompetitive inhibition). This enzyme is reduced in liver cells from diabetic animals. On the other hand, 2-deoxyglucose exerts its effect by being attached to dolichol-P, preventing further elongation of oligosaccharide chain on the protein backbone. This latter effect might be eliminated by excess dolichol-P (indicating competitive inhibition). The dolichol content in liver extract from diabetic rats was about 2.5-fold higher compared with nondiabetic rats (51.6 micrograms/g versus 20.6 micrograms/g wet liver weight). These two lines of evidence confirm the notion that the enhanced enzymatic glycosylation in liver from diabetic animals is maintained by an increased hepatic dolichol concentration, which is most probably related to the hyperglycemia. Thus, the dolichol-N-glycosylation pathway may represent another detrimental aspect of hyperglycemia and may operate by dolichol mass action rather than through glycosylating enzyme activity.
Intestinal absorption of low molecular weight heparin in animals and human subjects.
INTRODUCTION: We had previously shown that the use of bile salts, which act as surfactants, facilitates the intestinal absorption of large molecules such as those of heparin and insulin. However, the bioavailability of unfractionated heparin (UFH) administered through the large intestine was low. The aim of the present study was to evaluate the absorption of low molecular weight heparin (LMWH) combined with bile salts through the gut mucosa in animals and human subjects. MATERIALS AND METHODS: LMWH (Fragmin, Kabi-Pharmacia, Stockholm) or UFH with or without sodium cholate (Sch) was administrated rectally in rats and healthy volunteers via a microenema. Absorption was estimated by the activated partial thromboplastin time (aPTT), the plasma anti-factor Xa activity and the plasma lipoprotein lipase (LPL) activation. RESULTS: In groups of 6 rats, LMWH at doses of 100--1,000 U with sodium cholate (10--20 mg/ml) was readily absorbed through the gut mucosa, as indicated by both, anti-factor Xa levels of up to 1 U/ml and a dose-dependent activation of LPL. The absorption was significantly superior to that of UFH with Sch or LMWH given without Sch (p < 0.001). The plasma anti-factor Xa levels in the 6 healthy volunteers who received a microenema containing 25,000 U of LMWH with 20 mg/ml of Sch were 0.38 U/ml at 15 min and 0.1 U/ml at 240 min. LPL activation and aPTT prolongation were also observed in these subjects. The plasma LMWH levels after rectal application were in the same range as those obtained after subcutaneous administration, however the elimination time (t 1/2) was shorter. There were no adverse reactions. CONCLUSIONS: Intestinal absorption of LMWH facilitated by Sch is both feasible and safe. A slow release formulation will be needed to prolong the plasma half-life.
The relationship between systolic blood pressure and microvascular resistance in non-diabetic and diabetic subjects.
Skin blood flow and microvascular resistance were measured in the feet of hypertensive and normotensive subjects by the non-invasive transient thermal clearance method. Skin blood flow decreased and microvascular resistance increased as a function of systolic brachial blood pressure for the non-diabetic subjects who were not treated by vasoactive medication. The relationship between blood flow and systolic blood pressure for diabetic patients and for patients who were treated by enalapril was poor. The average resistance for non-diabetic patients treated by enalapril was lower than that of untreated non-diabetic subjects. For diabetic patients no significant difference in resistance between enalapril treated and untreated patients was found. The results demonstrate that for non-diabetic patients the role of microvascular resistance in hypertension is significant while it is less important in diabetic patients.
The efficiency of sand rat metabolism is responsible for development of obesity and diabetes.
Two separate lines--diabetic and partially diabetes-resistant--have been isolated from the sand rat (Psammomys obesus), each with different growth characteristics in response to diets of varying digestible caloric densities (high energy, HE, 2.93 kcal/g, or low energy, LE, 2.38 kcal/g). Over a two week period all animals consumed similar quantities (c. 125 g) irrespective of the diet consumed. Weight gains were as follows: diabetic line on HE diet - 59.7 g, on LE - 46.2 g; non-diabetic animals from the diabetes-resistant line on HE - 44 g. Only animals from the diabetic line, fed the HE diet, developed hyperinsulinemia, obesity and diabetes. The energy cost of weight gain for the diabetic line fed either HE or LE diets was 6.0 - 6.3 kcal/g whereas for the diabetes-resistant line on the HE diet, the cost of growth was 50% higher at 9.3 kcal/g. These differences could be due either to alterations in the content of tissue laid down or to differences in energy expenditure. It has already been established that diet-induced obesity and diabetes develop in the diabetic line with features typical of insulin resistance in the metabolism of the pancreas, liver and peripheral tissues. Some of the animals of the diabetes-resistant line may also develop diabetes over a long time period and go through a phase of transient hyperinsulinemia-normoglycemia. This may represent an intermediate stage in the development of the diabetic syndrome and serve as a model of type 2 diabetes in man.
The disposition of valpromide in rats and the isolated perfused rat liver.
The pharmacokinetics and metabolism of valpromide (VPD) were investigated in intact rats and in the isolated perfused rat liver (IPL). The rats and the IPLs were divided into three groups. One was a control (untreated) group. The second consisted of intact rats and IPLs obtained from rats pretreated with phenobarbital. A third group of rats received VPD by oral administration. VPD was partially hydrolyzed to valproic acid (VPA) by the IPL following iv administration to intact rats. The fraction of the total body clearance of VPD which furnished VPA as a metabolite (fm) in the rats was 63%. The rate and extent of this conversion were greater in the phenobarbital-pretreated rats and in the IPLs than in the control group. Our studies showed that phenobarbital can induce the hydrolytic biotransformation of VPD to VPA. This is in addition to its known effect on oxidative metabolic pathways. In rats, as in humans and dogs, VPD is biotransformed to VPA in the liver. The complete oral bioavailability of VPD and the fact that the AUC of VPA obtained after oral administration of VPD was not higher than that obtained after the iv injection of VPD indicates that the gastrointestinal tract is not one of the metabolic sites of VPD to VPA conversion.
Clinical experience with ethacrynic acid with reference to a possible complication of the Schoenlein-Henoch type.
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Acute intra-abdominal bleeding as a manifestation of malignant hypertension.
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