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Biomedical subjects

Y Shechter

Publications and source records attributed to Y Shechter.

At least 73 records · Page 4Linked to original sources
PubMed1990

Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes.

Vanadate ions, low-molecular-weight phosphate analogues, mimic most of the rapid actions of insulin in various cell types. When administered orally to diabetic hyperglycemic rats, vanadate reaches the circulation, mimics insulin stimulation of glucose uptake and metabolism, and leads to normoglycemic and partial anabolic states. In addition, vanadate restores tissue responsiveness to insulin and hepatic glycogen levels and activates new synthesis of key enzymes for carbohydrate metabolism. This suggests that correcting hyperglycemia is sufficient to correct the typical metabolic alterations found in streptozocin-induced diabetic rats. Several weeks of oral administration of vanadate to diabetic rats has not produced detectable liver or kidney toxicity. The mechanism by which vanadate mimics the actions of insulin is still obscure. Unlike insulin, vanadate does not seem to stimulate the autophosphorylation and endogenous tyrosine phosphorylation of insulin-receptor kinase or other intracellular proteins either directly or by virtue of its known inhibitory effect on protein phosphotyrosine phosphatase. Results from many studies support a model in which vanadate activates glucose metabolism by either utilizing an alternative (insulin-independent) cascade or bypassing the early events of the insulin-dependent cascade. Either of these possibilities is of clinical importance, because early insulin events may become defective, as a result of severe hyperinsulinemia, and may contribute to insulin resistance. Alternative pathways by which vanadate may stimulate glucose metabolism, e.g., by increasing intracellular Ca2+ levels and/or regulating intracellular and intravesicular pH, are discussed. From a clinical perspective, studies should be continued in evaluating the level of vanadate toxicity after prolonged treatment and searching for agents that potentiate its insulin mimetic actions in vitro and in vivo.

Animals↗
PubMed1989

Inhibition of insulin-dependent lipogenesis and anti-lipolysis by protein tyrosine kinase inhibitors.

Protein tyrosine kinase (PTK) blockers which competitively inhibit the kinase activity of insulin receptors were synthesized and their properties examined. The best insulin receptor kinase (IRK) inhibitors possess either one hydroxyphenyl ring and two carboxyl groups or two phenyl rings and one carboxyl group. All the inhibitors, except tBoc-tyrosine aminomalonate, effectively block the IRK-catalyzed phosphorylation of exogenous substrate, but only partially block receptor autophosphorylation. These PTK blockers inhibit the insulin induced [14C]glucose assimilation into lipids (lipogenesis), but fail to inhibit the anti-lipolytic effect of the hormone. Only tBocTyr-aminomalonate was found to inhibit all the effects of insulin measured: insulin-stimulated phosphorylation of exogenous substrate, IRK autophosphorylation, insulin-dependent lipogenesis and the insulin-dependent anti-lipolytic effect. This inhibitor is the first blocker which is reported to block insulin-dependent anti-lipolysis. The inhibitors examined are devoid of general adverse effects since they have no effect on insulin-independent lipolysis, on [U14C]fructose assimilation or on (-)isoproterenol-stimulated lipolysis. These studies suggest that insulin-dependent lipogenesis and anti-lipolysis may be mediated by two distinguishable signalling pathways. This study also suggests that PTK inhibitors may become useful tools in the investigation of the signalling pathways of PTKs.

Adipose Tissue↗
PubMed1989

Vanadate stimulates in vivo glucose uptake in brain and arrests food intake and body weight gain in rats.

Vanadate, administered via drinking fluid (0.2-0.8 mg/ml in 80 mM NaCl), attenuated food intake and strongly suppressed body weight gain in normally-fed or 20-hour food-deprived rats. At 0.8 mg/ml for 4 days, oral vanadate significantly stimulated the rate of hexose uptake by brain tissue. When microinjected into the lateral cerebral ventricle at a dose of 82 nmol, vanadate strongly and specifically suppressed food intake and body weight gain in 20-hour food deprived rats previously maintained on tap water. This inhibitory effect was reversed by coadministration of 3-O-methyl glucose. Collectively, the results suggest that vanadate is capable of blocking food intake by a specific effect in the central nervous system that involves stimulation of local glucose uptake.

3-O-Methylglucose↗
PubMed1989

Adolescent girls in distress: a high-risk intersection.

Adolescent girls in distress are at high risk due to their location at the intersection of three populations at risk: adolescents, females, and those in social distress. The first part of this article specifies the parameters of the population in terms of behavioral and personality features, based on empirical research in Israel as well as the United States. The second part discusses the main characteristics of each of the three populations, with special emphasis on the components of transition in each. The third part develops an integrative theoretical model that illustrates the uniqueness of this group and its problems, and that may serve as a basis for the development of diagnostic and treatment tools for helping these girls. In this model, the profiles of adolescents in general, adolescent boys, adolescent girls, and adolescent girls in distress are compared. The comparison is made in terms of physical, cognitive, social, and emotional development, interpersonal relationships, and status in the family. Comparison of the profiles reveals that adolescent girls in distress are located at the extreme end of the spectrum of the six developmental areas. Implications of the findings are discussed in terms of the inconsistency between messages on various levels: explicit versus implicit; intrafamilial versus social; and expectation versus opportunity. It is concluded that the specific needs of this group require the establishment of an appropriate policy as well as a variety of strategies, including nonconventional techniques, for creating a multidimensional intervention program.

Adolescent↗
PubMed1988

Apparent involvement of protein kinase C in the central glucoregulatory action of insulin.

We have studied the possible involvement of the calcium- and phospholipid/diacylglycerol-dependent enzyme, protein kinase C (PKC) in mediating insulin action in the central nervous system (CNS) by testing the effect of direct activation or blockade of the CNS PKC system on the plasma glucose responses to central insulin injection in mice. Insulin (0.1-1 microgram), injected into the CNS, produced rapid transient hypoglycemia. This effect appeared to involve interaction of insulin with specific receptors, since insulin analogs exhibiting diminished receptor binding affinity and peripheral bioactivity compared to the native hormone were much less active (i.e., insulin much greater than acetyl 3 insulin greater than proinsulin greater than IGF-I) or not active at all (i.e., insulin chain A and chain B). Central injection of the specific PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.01-0.5 microgram), but not the inactive TPA analog, 4-alpha-phorbol or the unstable synthetic diacylglycerol analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), significantly enhanced the hypoglycemic response to co-administered insulin (0.5 microgram) or the insulin derivative, acetyl 3 insulin (2.5 micrograms). Central TPA had no effect on basal glucose levels. Furthermore, central administration of the selective PKC blockers, polymyxin B (PMB, 1-25 micrograms) or 1-beta-galactosylsphingosine (psychosine, 0.5-10 micrograms) but not their respective inactive analogs, polymyxin E and sphingomyelin, strongly inhibited the hypoglycemic response to insulin (1 microgram) or acetyl 3 insulin (5 micrograms). PMB and psychosine, injected alone had no effect on basal glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The use of post-binding agents in studying insulin action and its relation to experimental diabetes.

This review includes data related to two substances that modulate insulin mechanisms, both in vitro and in the whole animal model. It seems to us that these agents (vanadate and PMXB) will be of potential use in the next decade for basic and applied research. They may assist in characterizing the essential post-binding events involved in insulin action, which cannot presently be identified. As vanadate and PMXB modulate the effects of insulin both in vivo and in vitro, they may be of use in clinical and pathophysiological research as well. VO3- is a low molecular weight substance which permeates the intestinal tract and mimics the actions of insulin in target tissues. Studies that were summarized here may even suggest that VO3- is superior to insulin in stimulating its effects in tissues that are down-regulated or desensitized to the hormone itself. Both VO3- and PMXB may be useful in the treatment of diabetes in the future if long-range toxicity studies prove these agents to be clinically safe. PMXB has already been in use in medicine for several decades now.

Animals↗
PubMed1988

Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

In previous studies we reported that immunization of mice with ungulate insulins induced the development of antiinsulin antibodies, which include an idiotype that appeared to recognize the part of the insulin molecule recognized by the hormone receptor. The antiinsulin antibodies of this idiotype were replaced spontaneously by antiidiotypic antibodies. The antiidiotypic antibodies, which persisted for about 14 d, mimicked insulin and functioned as antibodies to the insulin receptor. They induced down regulation, desensitization and refractoriness of the insulin receptor and disturbances in glucose homeostasis in vivo (Shechter, Y., D. Elias, R. Maron, and I.R. Cohen., 1984; Elias, D., R. Maron, I.R. Cohen, and Y. Shechter. 1984, J. Biol. Chem. 259: 6411-6419). We now report that effects of the antiidiotypic antibodies on the insulin receptor effector system can be modified pharmacologically. Administration of the beta-adrenergic agonist isoproterenol during the period of insulin resistance (days 26-40 after primary immunization), largely restored fat cell responsiveness to insulin, and eliminated the appearance of fasting hyperglycemia. This restoration appeared to be caused by inhibition of both insulin receptor desensitization and refractoriness. In contrast, down regulation of insulin receptors was not reversed by isoproterenol treatment in vivo. The effects of treatment with isoproterenol persisted for 2-4 d after termination of treatment. The beta-antagonist, propranolol and more so, the beta 1a-antagonist metoprolol, specifically blocked the effect of isoproterenol at a molar ratio of 3-10:1. Oral administration of the cAMP phosphodiesterase inhibitor, aminophylline, was also effective in inhibiting the development of desensitization in fat cells. These results indicate that treatment with beta 1-adrenergic agonists in vivo, or other agents that elevate cellular cAMP levels, can inhibit the development of the "postbinding" defects induced by insulin-mimicking, antireceptor antibodies. These observations have both basic and clinical implications.

Adipose Tissue↗
PubMed1987

Vanadate ions: central nervous system action on glucoregulation.

Vanadate (VO-3), an essential trace element with insulin-mimetic actions, produces systemic hyperglycemia following central administration in mice. The hyperglycemic effect is due to specific action of vanadate or its reduced form, vanadyl (VO2+); other ions of similar atomic weight (Cr, Mn) or structure (phosphate) have no effect. The effect of central vanadate to raise circulating glucose is blocked by coadministration of 3-O-methylglucose or polymyxin B, which prevent insulin- and vanadate-stimulated glucose transport. Finally, the central hyperglycemic effect is prevented by treatments which block sympathetic outflow from the CNS or diminish the levels of circulating epinephrine. These results show that vanadate is able to influence peripheral glucoregulation by increasing sympathetic outflow from the CNS. Moreover, they suggest that this effect is linked to action of VO-3 or its reduced form, VO2+, to stimulate glucose transport into neuronal cells.

3-O-Methylglucose↗
PubMed1987

Centrally mediated hypoglycemic effect of insulin: apparent involvement of specific insulin receptors.

We have studied the involvement of central nervous system (CNS) insulin receptors in mediating the central hypoglycemic effect of insulin by using insulin derivatives modified at regions of the hormone necessary for receptor reactivity and peripheral bioactivity. Acetylation or succinylation of the 3 free amino groups of insulin at positions A1, B1 and B29 resulted in a corresponding decrease in lipogenic activity in isolated rat adipocytes, with concentrations of hormone required to produce half the maximal effect (ED50) being 0.15 ng/ml, 3 ng/ml and 50 ng/ml for native insulin, acetyl3 insulin and succinyl3 insulin, respectively. Moreover, the modified insulins exhibited diminished hypoglycemic effect following central administration in mice, with the doses needed for suppression of plasma glucose to 50% of basal levels being 1 microgram, 10 micrograms and 25 micrograms for native insulin, acetyl3 insulin and succinyl3 insulin, respectively. Because binding of insulin derivatives to CNS receptors can be predicted from their peripheral bioactivity, the present finding of parallel decrements in lipogenic activity in vitro and central hypoglycemic effect in vivo, following modification of insulin at regions implicated in receptor activation, is consistent with the view that insulin exerts its central effect on plasma glucose by interacting with specific CNS receptor sites which are closely related to the peripheral insulin receptors.

Animals↗
PubMed1987

Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. Characterization and mode of action.

The effect of oral administration of vanadate, in normalizing blood glucose levels of streptozotocin-treated rats (ST-rats), is further characterized and its mode of action is determined. We have examined the effects of two orally administered doses of sodium metavanadate. High concentrations of orally administered vanadate (0.8 mg/ml in drinking water) reduced blood glucose levels within 2-4 days of application and led to the appearance of hypoglycemia in test animals. Lower concentrations of vanadate (0.2 mg/ml in drinking water) also lowered blood glucose levels within 4 days, but did not lead to hypoglycemia for at least 3 weeks. These effects of vanadate were found to be reversible; hyperglycemia recurred within 2 days after removal of vanadate from the drinking water. In streptozotocin-treated rats receiving low vanadate treatment, circulating levels of vanadate were about 0.8 microgram/ml after 3 weeks of treatment. These rats became anabolic, while rats receiving high vanadate treatment remained catabolic. Subsequent to vanadate treatment, adipocytes derived from ST-rats responded to lower insulin concentrations. In addition, vanadate treatment lowered the increased insulin binding capacity of liver plasma membranes derived from ST-rats. Insulin binding capacity under these conditions approached that of control non-ST-rats. Basal rates of hexose uptake in muscle and liver tissues were doubled in vanadate-treated ST-rats. It is concluded that the oral administration of vanadate leads to normoglycemia by stimulating glucose uptake. Treatment with "low vanadate" leads to the formation of a stable anabolic and normoglycemic state in ST-rats and appears to restore insulin responsiveness of target tissues, without apparent signs of toxicity. Vanadate treatment did not impair either kidney or liver function, as assayed by the measurement of serum urea, creatinine, and glutamic-oxaloacetic transaminase.

Adipose Tissue↗
PubMed1987

Polymyxin B is an inhibitor of insulin-induced hypoglycemia in the whole animal model. Studies on the mode of inhibitory action.

The cyclic decapeptide, polymyxin B (PMXB), was found to inhibit hypoglycemia in mice receiving exogenous insulin (Amir, S., and Shechter, Y. (1985) Eur. J. Pharmacol. 110, 283-285). In this study, we have extended this observation to rats. Insulin-dependent hypoglycemia in rats is efficiently blocked at a 12:1 molar ratio of PMXB to insulin. This effect is highly specific, as it could not be mimicked by a variety of antibiotics or positively charged substances. Chemical modifications of PMXB have revealed that the ring structure, rather than the tail structure, is important for anti-insulin-like activity. Colistin A, which differs from PMXB by one conservative amino acid substitution in the ring structure, is devoid of this activity. Polymyxin B does not interact with insulin, nor does it alter the rate of insulin absorption and/or degradation, or the ability of insulin to bind to target tissues. This peptide inhibits hypoglycemia by blocking insulin-dependent activation of the hexose transport mechanism, as deduced by in vitro studies. The effect of insulin in stimulating hexose uptake (and subsequent glucose metabolism) in both isolated muscle tissue and adipocytes is blocked with little or no effect on the basal activities of these processes. Colistin A has no significant inhibiting effect. Other insulin-dependent activities, such as inhibition of lipolysis in adipocytes or synthesis of DNA in muscle cells, are not inhibited. It is concluded that PMXB inhibits, in a highly specific manner, the action of insulin in stimulating hexose transport and subsequent glucose metabolism, both in vitro and in the whole animal model.

Animals↗
PubMed1987

Early treatment by plasmapheresis in a woman with multiple abortions and the rare blood group p.

Women with the rare blood group p are known to have an increased rate of abortions. The case of a 36-year-old woman is presented who had had 7 spontaneous abortions in the first trimester and no live child. When treated by plasma exchange begun early in pregnancy and continued until the 29th week, she delivered a normal child. Time to begin, amount and length of time necessary to continue plasma exchange in these patients are considered. In addition, the question of which fraction of the anti-PP1Pk could be responsible for abortion is discussed. To our knowledge, this is the first case of a woman of p phenotype with no live children but with multiple abortions treated by this method, which should be seriously considered in similar cases.

Abortion, Habitual↗
PubMed1986

Effect of depletion of phosphate and bicarbonate ions on insulin action in rat adipocytes.

The effect of insulin on rat adipocytes was studied in isotonic buffers (pH 7.4) containing NaCl, CaCl2, MgSO4, KCl, and bovine serum albumin but no phosphate or bicarbonate anions. In phosphate- and bicarbonate-free buffers the dose-response curve to insulin is shifted to the right, the effects of the hormone on hexose uptake, glucose metabolism, and inhibition of lipolysis being observed at much higher (nearly 2 orders of magnitude) concentrations of insulin. The insulin binding capacity of the cells is only slightly changed. The dose-response curve for isoproterenol which stimulates lipolysis in the same cell type is almost the same in both Krebs-Ringer bicarbonate buffer and phosphate- and bicarbonate-free buffers. The dose-response curves for agents that mimic the action of insulin such as wheat germ agglutinin or vanadate ions are also shifted to the right. The dose-response curve to insulin can be returned to "normal" by readdition of either bicarbonate or phosphate. Almost complete recovery is obtained at either 10 mM bicarbonate or 24 mM phosphate, respectively. External Ca2+ ions which are not required for the proper action of insulin in fat cells maintained in Krebs-Ringer bicarbonate buffer, become essential for insulin action in bicarbonate-free buffer. The study indicates that depletion of bicarbonate and, to a lesser extent, phosphate anions, interferes with an essential insulin-dependent post-binding event. Also, in bicarbonate-free medium, external Ca2+ ions are essential for insulin-mediated processes. The implications of this study to the mode of action of insulin, and to physiological and clinical states of insulin desensitization are discussed.

3-O-Methylglucose↗
PubMed1986

Effect of depletion of bicarbonate or phosphate ions on insulin action in rat adipocytes. Further characterization of the receptor-effector system.

In the preceding paper (Shechter, Y., and Ron, A. (1986) J. Biol. Chem. 261, 14945-14950) we have shown that in fat cells, prepared and maintained in an isotonic buffer (pH 7.4) containing neither phosphate nor bicarbonate anions (Buffer A), the dose-response curve to insulin shifted to the right by about 2 logarithms and insulin binding affinity or capacity was only slightly decreased. In the current paper we demonstrate that progressive loss of insulin binding, either by treatment with trypsin or preincubating the cells with isoproterenol, correlates well with the reduced ability of the cells to elicit maximal lipogenesis in response to insulin. We further demonstrate in the "new" system that: the dissociation of labeled insulin from fat cells is not accelerated by the inclusion of unlabeled insulin in the medium; termination of lipogenesis in Buffer A occurs immediately; ligand-induced receptor internalization is grossly defective; and insulin is unable to stimulate lipogenesis at 15 degrees C. The data support the hypothesis that in the new experimental system all measurable binding sites are linked to a coupling mechanism. Each site behaves as an independent, separate entity and there are no site to site interactions. This leads to a linear relationship between binding and bioactivation, lack of negative or positive cooperatively, accelerated rate of termination, defective internalization, a shift to the right in the dose-response curve to insulin, and a lack of insulin response at a lower temperature. In more general terms, the study indicates that all measurable insulin receptors are chemically homogeneous in their potential capability to be coupled to an insulin effector (biologically relevant) system, and they do so under particular experimental conditions.

Adipose Tissue↗
PubMed1986

Selective oxidation and reduction of methionine residues in peptides and proteins by oxygen exchange between sulfoxide and sulfide.

Treatment of amino acids, peptides, and proteins with aqueous solution of dimethyl sulfoxide (Me2SO) and hydrochloric acid (HCl) resulted in the oxidation of methionine to methionine sulfoxide. In addition to methionine, SH groups are also oxidized, but this reaction proceeds after a lag period of 2 h. Other amino acids are not modified by aqueous Me2SO/HCl. The reaction is strongly pH-dependent. Optimal conditions are 1.0 M HCl, 0.1 M Me2SO, at 22 degrees C. The reaction exhibits pseudo-first order kinetics with Kobs = 0.23 +/- 0.015 M-1 min-1 at 22 degrees C. Incubation of methionine sulfoxide with dimethyl sulfide and HCl resulted in the conversion of methionine sulfoxide to methionine. This reaction is fast (t1/2 = 4 min at room temperature) and quantitative at relatively anhydrous condition (i.e. at H2O:concentrated HCl:dimethyl sulfide ratio of 2:20:1). Quantitative conversions of methionine sulfoxide back to methionine are obtained in peptides and proteins as well, with no observable other side reactions in amino acids and proteins. The wide applications of this selective oxidation and reduction of methionine residues are demonstrated and discussed.

Adrenocorticotropic Hormone↗