Dov Gefel

Historic perspective and recent developments on the insulin-like actions of vanadium; toward developing vanadium-based drugs for diabetes

Abstract Intensive studies have been carried out during the last two decades, on the insulinomimetic effects of vanadium. Vanadium compounds mimic most of the metabolic effects of insulin on the main tissues of the hormone in vitro. Vanadium therapy induces normoglycemia and improves glucose homeostasis in insulin deficient and insulin resistant diabetic rodents. Improved sensitivity to insulin in liver and muscle tissues of Type II diabetic patients following vanadium therapy was observed as well. The key mechanisms involved are inhibition of protein–phosphotyrosine phosphatases and activation of nonreceptor protein–tyrosine kinases, in an insulin-receptor tyrosine kinase independent fashion. Vanadate activates glucose-metabolism in vitro at a site preceding activation of phosphatidylinositol-3-kinase (PI3-kinase). Regarding inhibition of lipolysis, vanadate (but not insulin) acts at a site downstream to the activation of PI3 kinase. Additional vanadium-dependent mechanism, operating in vivo, is the restoration of glucose-6-phosphate levels in liver, muscle and adipose tissue of hyperglycemic diabetic rats. This is attributed to vanadate-dependent inhibition of liver glucose-6-phosphatase, and of nonspecific hexose-6-phosphatases of the diabetic muscle and adipose tissues. Initial clinical studies were already performed. Several beneficial effects were documented. The potential usage of vanadium in the future care of diabetes in human, however, depends on manipulations that would elevate the insulinomimetic efficacy of vanadium without increasing its toxicity. Organically chelated vanadium compounds, in particular, the l -isomer of Glu(γ) monohydroxamate ( l -Glu(γ)HXM) are active in potentiating the capacity of free vanadium to activate glucose metabolism, in vitro and in diabetic rats in vivo. l -Glu(γ)HXM differs from other vanadium ligands in being an amino acid derivative that permeates into peripheral tissues through the amino acid transport system. In rat adipocytes, l -Glu(γ)HXM itself activates partially glucose metabolism, by permeating into cell interior, associating with the minute quantity of intracellular vanadium, and turning it into an insulinomimetic active species. l -Glu(γ)HXM, associates with the vanadyl (+4) cation, and the vanadate (+5) anion, at neutral pH with nearly the same binding affinity. Both these oxidation states of vanadium are insulinomimetic. The therapeutical potency of l -Glu(γ)HXM·vanadium complexes is actively studied. Preliminary results on this issue are to be presented.

Insulin-like effects of vanadium: basic and clinical implications

Most mammalian cells contain vanadium at a concentration of about 20 nM, the bulk of which is probably in the reduced vanadyl (+4) form. Although this trace element is essential and should be present in the diet in minute quantities, no known physiological role for vanadium has been found thus far. In the late 1970s the vanadate ion was shown to act as an efficient inhibitor of Na+,K+-ATPase as well as of other related phosphohydrolases. In 1980 vanadium was reported to mimic the metabolic effects of insulin in rat adipocytes. During the last decade, vanadium has been found to act in an insulin-like manner in all three main target tissues of the hormone, namely skeletal muscles, adipose, and liver. Subsequent studies revealed that the action of vanadium salts is mediated through insulin-receptor independent alternative pathway(s). The investigation of the antidiabetic potency of vanadium soon ensued. Vanadium therapy was shown to normalize blood glucose levels in STZ-rats and to cure many hyperglycemia-related deficiencies. Therapeutic effects of vanadium were then demonstrated in type II diabetic rodents, which do not respond to exogenously administered insulin. Finally, clinical studies indicated encouraging beneficial effects. A major obstacle, however, is overcoming vanadium toxicity. Recently, several organically chelated vanadium compounds were found more potent and less toxic than vanadium salts in vivo. Such a newly discovered organic chelator of vanadium is described in this review.

Insulinlike Effects of Zinc Ion in Vitro and in Vivo: Preferential Effects on Desensitized Adipocytes and Induction of Normoglycemia in Streptozocin-Induced Rats

The effects of Zn2+ in mimicking insulin in vivo and in vitro are further characterized. Like insulin, Zn2+ stimulated the conversion of [U-14C]-, [1-14C]-, and [6-14C]glucose to lipids in rat adipocytes. Maximum stimulation of lipogenesis was 55–80% of maximum insulin response after preincubation (30 min at 37 degrees C) of adipocytes with ZnCl2 (0.4 mM). Under these conditions, the half-maximum effect was achieved at 0.17 ± 0.02 mM of ZnCl2. Similarly, an insulinlike effect of Zn2+ was observed on the oxidation of glucose by both pathways, glycolytic and hexose monophosphate shunt. In contrast, unlike insulin, Zn2+ did not inhibit lipolysis but rather exhibited a slight lipolytic activity. Also, the effect of Zn2+ on hexose influx did not exceed 14 ± 3% that of insulin. The stimulatory effects of Zn2+ were not related to generation of H2O2. Catalase (100 μg/ml) did not inhibit Zn2+-stimulated glucose oxidation and its incorporation into lipids. Zn2+ had an additive effect on either insulin- or vanadate-stimulated conversion of [1-14C]glucose to fat, and together, the effect was ∼ 140% of the maximum rate of lipogenesis. Chelation of intracellular Zn2+ by the cell-permeable chelator N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine did not significantly affect the ability of insulin to stimulate lipogenesis. Adipocytes derived from STZ rats were largely refractory to the modulating action of insulin. In contrast, the effect of Zn2+ on lipogenesis in these cells was more pronounced. It was more than fivefold that of the hormone, and the dose-response curve shifted to the left (ED50 = 85 ± 10 μM of ZnCI2).l.p. administration of ZnCI2 (100 mg/kg body wt) to hyperglycemic STZ rats reduced blood glucose levels within 3 h to normal values. Similarly, ZnCI2 administered orally to STZ rats (210 mg/kg body wt) reduced blood glucose concentration as much as 50% 2 h after treatment. We conclude that Zn2+ mimics several actions of insulin, both in vitro and in vivo, by a mechanism unrelated to insulin. The clinical implication of this study is discussed.

Insulin-like actions of vanadate are mediated in an insulin-receptor-independent manner via non-receptor protein tyrosine kinases and protein phosphotyrosine phosphatases

Most or all mammalian cells contain vanadium at a concentration of 0.1–1.0 μM. The bulk of the vanadium in cells is probably in the reduced vanadyl (IV) form. Although this element is essential and should be present in the diet in minute quantities, no known physiological role for vanadium has been found thus far. In the years 1975–1980 the vanadate ion was shown to act as an efficient inhibitor of Na+,K+-ATPase and of other related phosphohydrolyzes as well. In 1980 it was observed that vanadate vanadyl, when added to intact rat adipocytes, mimics the biological actions of insulin in stimulating hexose uptake and glucose oxidation. This initiated a long, currently active, field of research among basic scientists and diabetologists. Several of the aspects studied are reviewed here.

Genomic microsatellites identify shared Jewish ancestry intermediate between Middle Eastern and European populations.

BackgroundGenetic studies have often produced conflicting results on the question of whether distant Jewish populations in different geographic locations share greater genetic similarity to each other or instead, to nearby non-Jewish populations. We perform a genome-wide population-genetic study of Jewish populations, analyzing 678 autosomal microsatellite loci in 78 individuals from four Jewish groups together with similar data on 321 individuals from 12 non-Jewish Middle Eastern and European populations.ResultsWe find that the Jewish populations show a high level of genetic similarity to each other, clustering together in several types of analysis of population structure. Further, Bayesian clustering, neighbor-joining trees, and multidimensional scaling place the Jewish populations as intermediate between the non-Jewish Middle Eastern and European populations.ConclusionThese results support the view that the Jewish populations largely share a common Middle Eastern ancestry and that over their history they have undergone varying degrees of admixture with non-Jewish populations of European descent.

Evidence for a major gene affecting the transition from normoglycaemia to hyperglycaemia in Psammomys obesus

We investigated the mode of inheritance of nutritionally induced diabetes in the desert gerbil Psammomys obesus (sand rat), following transfer from low-energy (LE) to high-energy (HE) diet which induces hyperglycaemia. Psammomys selected for high or low blood glucose level were used as two parental lines. A first backcross generation (BC1) was formed by crossing F1 males with females of the diabetes-prone line. The resulting 232 BC1 progeny were assessed for blood glucose. All progeny were weaned at 3 weeks of age (week 0), and their weekly assessment of blood glucose levels proceeded until week 9 after weaning, with all progeny maintained on HE diet. At weeks 1 to 9 post weaning, a clear bimodal distribution statistically different from unimodal distribution of blood glucose was observed, normoglycaemic and hyperglycaemic at a 1:1 ratio. This ratio is expected at the first backcross generation for traits controlled by a single dominant gene. From week 0 (prior to the transfer to HE diet) till week 8, the hyperglycaemic individuals were significantly heavier (4–17%) than the normoglycaemic ones. The bimodal blood glucose distribution in BC1 generation, with about equal frequencies in each mode, strongly suggests that a single major gene affects the transition from normo- to hyperglycaemia. The wide range of blood glucose values among the hyperglycaemic individuals (180 to 500 mg/dl) indicates that several genes and environmental factors influence the extent of hyperglycaemia. The diabetes-resistant allele appears to be dominant; the estimate for dominance ratio is 0.97.

Genetics and the History of the Samaritans: Y-Chromosomal Microsatellites and Genetic Affinity between Samaritans and Cohanim

Abstract The Samaritans are a group of some 750 indigenous Middle Eastern people, about half of whom live in Holon, a suburb of Tel Aviv, and the other half near Nablus. The Samaritan population is believed to have numbered more than a million in late Roman times but less than 150 in 1917. The ancestry of the Samaritans has been subject to controversy from late Biblical times to the present. In this study, liquid chromatography/electrospray ionization/quadrupole ion trap mass spectrometry was used to allelotype 13 Y-chromosomal and 15 autosomal microsatellites in a sample of 12 Samaritans chosen to have as low a level of relationship as possible, and 461 Jews and non-Jews. Estimation of genetic distances between the Samaritans and seven Jewish and three non-Jewish populations from Israel, as well as populations from Africa, Pakistan, Turkey, and Europe, revealed that the Samaritans were closely related to Cohanim. This result supports the position of the Samaritans that they are descendants from the tribes of Israel dating to before the Assyrian exile in 722–720 BCE. In concordance with previously published single-nucleotide polymorphism haplotypes, each Samaritan family, with the exception of the Samaritan Cohen lineage, was observed to carry a distinctive Y-chromosome short tandem repeat haplotype that was not more than one mutation removed from the six-marker Cohen modal haplotype.