Role of Vanadium in Treating Diabetes

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1 The Journal of Trace Elements in Experimental Medicine 12: (1999) Role of Vanadium in Treating Diabetes Hiromu Sakurai,* Yae Fujisawa, Seiki Fujimoto, Hiroyuki Yasui, and Toshikazu Takino Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan Since insulin-dependent diabetes mellitus (IDDM), which causes many severe secondary complications, is characterized by hyperglyceria due to absolute deficiency of insulin, the diseases is controlled by daily injection of insulin. Therefore, the development of insulin replacements of mimetics upon oral administration is an important investigation. Recent studies indicate that vanadium, which is proposed to be one of essential trace elements in animals and humans, relates to both glucose and lipid metabolisms, and the metal in turn shows insulin-mimetic effect. Thus several types of vanadium complex have been proposed to be insulin mimetics. In 1990, we proposed first vanadyl-cysteinate complex, which normalized the blood glucose level of IDDM rats on oral administration. On the other hand, simple vanadium compounds such as vanadyl sulfate and sodium vanadate have been reported to be useful to treat human non-insulin-dependent diabetes mellitus (NIDDM). Based on the observations, we have developed several types of vanadyl complexes with different coordination modes such as VO(0 4 ), VO(N 4 ), VO(S 4 ), VO(O 2 N 2 ), VO(S 2 N 2 ) and VO(O 2 S 2 ), and found that vanadyl-methylpicolinate complex with long acting character and low toxicity is the most effective to treat IDDM as well as NIDDM rats, when administered orally. The mechanism was also studied with respect to the pharmacokinetic analysis and vanadium distribution in animals. J. Trace Elem. Exp. Med. 12: , Wiley-Liss, Inc. INTRODUCTION Diabetes mellitus (DM) is mainly classified into two types, insulin-dependent DM (IDDM) and noninsulin-dependent DM (NIDDM), after the definition according to WHO [1]. The numbers of patients suffering from DM are increasing daily, probably due to changes in lifestyle and food. All types of DM involve absolute or relative insulin deficiency. To treat NIDDM, synthesized therapeutics involving sulfonylureas, sulfonamides, biguanides, and triglydazone have been developed and clinically used. However, as yet, IDDM can be controlled only by daily subcutaneous (sc) injections of insulin; otherwise, it causes such secondary complications as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. To avoid the pain and stress of sc insulin injections as well as the secondary complications, it is important *Correspondence to: Hiromu Sakurai, Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto , Japan. Received 10 February 1999; Accepted 26 July Wiley-Liss, Inc.

2 394 Sakurai et al. to develop an orally active insulin replacement or mimetic to maintain quality of life (QOL) of DM patients. Recently, vanadium ions, including vanadyl (VO 2+, +4 oxidation state of vanadium) and vanadate (VO 2 +, +5 oxidation state of vanadium), and especially several types of vanadium complexes, have been reported to be effective via oral administration in experimental DM animals, such as streptozotocin(stz)-induced diabetic rats (STZ-rats) [2 4]. More recently, we found that several vanadyl complexes on oral administration are effective to treat hereditarily diabetic-inducing animals such as KKA y mice [5]. In clinical trials, it has been proposed that hepatic and peripheral insulin sensitivies in patients with IDDM and NIDDM were improved by giving simple vanadium compounds, such as vanadyl sulfate (VOSO 4 ) and sodium vanadate (NaVO 3 ), about a century ago in France [6] and, now, in [7 11]. These findings strongly indicate the need for investigations to establish safe and long-term effective vanadium compounds to treat DM. Here, we report our recent results on the study of developing orally active and long-term acting vanadium complexes. VANADIUM IN NATURE AND ITS PHYSIOLOGICAL ROLES Vanadium, which is a transition metal, atomic number 23, atomic weight , was discovered by Sefström in 1831 and named by him for the goddess Vanadis of Scandinavian legend (Fig. 1). Vanadium is the 21st abundant element in the earth s crust, the average concentration being at 35 ppm ( g/g), and is contained at 2 ppm ( g/g) in sea water. Since vanadium has a similar character to that of phosphate and is present in several oxidation states at +2 +5, many types of compounds have been prepared. Compounds with a +5 oxidation state are most stable. Usually, vanadium Fig. 1. Sefström and Vanadis. Reproduced with permission from: Weeks ME, Leicester, HM. Discovery of the elements, 7th edition. Journal of Chemical Education, American Chemical Society; 1968.

3 Vanadium Role in Treating Diabetes 395 ions bind with the oxygen atom to form oxo compounds such as VO 3 as vanadate and VO 2+ as vanadyl forms. The vanadic form of V 3+ is very unstable under air and oxidizes to vanadyl or the vanadate form [12 14]. Humans usually take vanadium at g through foods daily, and g of vanadium is estimated to be found in the human body. In each organ, vanadium is present at g and contributes to a wide variety of physiological roles. In tissues, 90% of vanadium is bound with proteins and 10% is present as low molecular ionic forms [15]. The importance of vanadium was noted in 1971 pertaining to the growth of rats and chicks, but this has not been established in humans. As far as we know, the following five living systems contain vanadium: (1) blood cells in limited species of ascidian, where the occurrence of an aquo vanadic compound has been proposed, (2) amanitata as a species of mushroom contains a purple-blue vanadyl complex, amavadin, (3) limited species of brown algae contain a metalloenzyme, bromoperoxidase, in the vanadate form at the resting state, (4) some species of macro-organism contain a vanadium nitrogenase, and (5) limited species of polychaete wohm. When vanadium compounds are administered to experimental animals, the metal is found in such organs as kidney, liver, pancreas, and born. Especially, the vanadate form exhibits toxicity times more than the vanadyl form in rats in terms of LD 50 value [16]. Extensive study has revealed biochemical and physiological activities of vanadium, and the characteristic roles are summarized in Figure 2 [15]. Among them, the most interesting and striking role is its insulin-mimetic or antidiabetic activity [2 4,17]. INSULIN-MIMETIC ACTION OF VANADIUM In the late 1960s, interesting findings were reported: ouabain (G-strophanthin), which has been used as a cardiac glycoside, inhibits Na +,K + -ATPase and exhibits insulin-mimetic activity with respect to glucose transport and metabolism in rat adipocytes [15]. However, vanadate has been found to be a potent inhibitor of Na +,K + -ATPase; thereby, vanadate was detected in the ATP product from Sigma (St. Louis, MO) [18]. (It might be useful to note that not only ATP, but also bovine serum albumin (BSA) contain vanadate to microgram/g protein concentration [19,20].) In addition, vanadium has been found to be present exclusively in the vanadyl state in almost all organs of rats given NaVO 3 or VOSO 4 [21]. These facts and the selective toxicity of vanadium compounds in rats, led us to use a vanadyl compound, VOSO 4, to examine the insulin-mimetic activity in in vitro evaluation, since vanadyl is less toxic than vanadate and more stable than the vanadic form. As expected, VOSO 4 was found to be effective in showing insulin-mimetic activity in terms of inhibition of the free fatty acid (FFA) release from rat adipocytes (Fig. 3) [22], as well as incorporation of glucose [23] into the adipocytes. In this way, the normoglycemic effect of vanadyl compounds was examined. NORMOGLYCEMIC EFFECTS OF VANADYL COMPOUND When STZ-rats were administered VOSO 4 by daily single intraperitoneal (ip) injection, hyperglyceria was normalized within 2 or 3 days. As long as daily adminis-

4 396 Sakurai et al. Fig. 2. Physiological roles of vanadium. tration was continued, normoglycemia was maintained. Although both serum glucose and FFA levels were improved and normalized, the insulin level did not improve, indicating that the action of VOSO 4 is not peripheral. In fact, similar levels of vanadium in normal STZ-rats and vanadyl-treated STZ-rats were found in almost organs examined, as determined by neutron activation analysis (NAA), which is the most reliable vanadium determination method in living systems. Results of glucose tolerance tests concluded that IDDM is indeed treated with the administration of VOSO 4 [22,23]. Orally administered VOSO 4 was also shown to be effective [24]. On the basis of these results, orally active and long-term acting vanadyl complexes have been developed. ORALLY ACTIVE AND LONG-TERM ACTING VANADYL COMPLEXES To develop orally active therapeutics of metal complexes, we had to take into account that they pass the stomach at a low ph value such as 1 2 and thus might decompose under such acidic conditions. Accordingly, we prepared several vanadyl complexes with different coordination modes to ascertain the stability, bioavailability, or gastrointestinal absorption of the complexes. The first notable result was that oral administration of vanadate, which was dissolved in drinking water, normalized blood glucose levels in STZ-rats [25]. However, our aim was to develop the therapeutics in vanadyl form. In 1990, we proposed the first orally active insulin-mimetic vanadyl complexes involving vanadyl-cysteine methylester, -malonate and -tartalate complexes, the normoglycemic actions of such complexes being dose-dependent [26]. Against the principle of Pearson s hard and soft acids and basis (HSAB), which proposes the formation of stable complexes due to combinations such as Lewis hard

5 Vanadium Role in Treating Diabetes 397 Fig. 3. Inhibitory effects of vanadium ions on the release of free fatty acids (FFA) from isolated rat adipocytes. acid-hard base or Lewis soft acid-soft base [27], the vanadyl-cysteine methylester complex with a hard acid (VO 2+ )-soft base (thiolate) combination and VO(S 2 O 2 ) coordination mode forms stable coordination bonds between VO 2+ and thiolates as well as amino groups [28,29]. Encouraged with the results, we have proposed the vanadyl-dithiocarbamate complexes with VO(S 4 ) coordination mode as orally active complexes [30,31]. On the basis of these results, we began our investigation to ascertain the structureactivity relationship of antidiabetic vanadyl complexes with different coordination modes, as shown in Figure 4 [3,4]. Establishment of a clear structure-activity correlation is difficult due to lack of available data, since essential factors of the complexes, such as physico-chemical properties and electronic changes under physiological conditions, hydrophobicity, gastrointestinal absorption, organ and subcellular distributions of vanadium and its complexes, contribute to each other. Nevertheless, we found that vanadyl-picolinate and its related complexes are good reagents, after the in vitro evaluation using rat adipocytes in terms of FFA release and in vivo tests on STZ-rats by daily ip injection and oral administration of the complexes [32]. Among them, vanadyl-6-methylpicolinate complex, which has a similar IC 50 value to that of the leading vanadylpicolinate complex but a moderate partition coefficient, has good insulin-mimetic activity, not only by ip injections (3 mgv/kg body weight for the first 2 days, 2 mgv/kg for 2 days, 1 mgv/kg body for 10 days), but by oral administration (10 mgv/kg body weight for 10 days, 5 mgv/kg for 10 days) without body weight loss and toxicity in STZ-rats. It is interesting to note that: (1) the serum glucose normalizing effect of the complex was continued for at least 80 days after ceasing its administration, and (2) the insulin-mimetic effect was observed at lower doses than those for the leading vanadyl-picolinate complex. Thus the vanadyl-6-methylpicolinate complex with a moderate partition coefficient and relatively good IC 50

6 398 Sakurai et al. Fig. 4. Insulin-mimetic vanadyl complexes with different coordination modes, proposed from our research group. value on FFA release from adipocytes is expected to be a potent and long-term acting insulin-mimetic compound to treat animals with IDDM [33]. On the basis of our results, we propose the vanadyl-6-methylpicolinate complex as a future therapeutic reagent. However, to develop a therapeutic compound, we must know its pharmacokinetic behavior. METALLOKINETIC ANALYSIS Recently, we proposed a new pharmacokinetic analysis method combined with an electron spin resonance (ESR) spectrometer and named in vivo blood circulation monitoring-esr (BCM-ESR) (Fig. 5). Using rats under anesthesia, the behaviors of many stable spin probes with a five or six member ring were successfully analyzed [34]. With the in vivo BCM-ESR method, we examined the metallokinetic features of VOSO 4, vanadyl-picolinate and -6-methylpicolinate complexes [35]. These compounds were given by single intravenous (iv) injection to rats at 37 C under anesthesia with pentobarbital, and ESR spectra were measured at room temperature every 30 sec and the data entered into a computer. Disappearance of the ESR signal due to vanadyl species in the blood was plotted against time after administration of the compounds. It was analyzed by one or two compartment model methods, depending on the structure of the vanadyl compound. The real-time ESR analysis of vanadyl species revealed that the clearance rate of the vanadyl species from the blood

7 Vanadium Role in Treating Diabetes 399 Fig. 5. In vivo blood circulation monitoring-electron spin resonance (BCM-ESR). of rats given VOSO 4 was higher than those given vanadyl-picolinate or -6- methylpicolinate complex in terms of half-life (t 1/2 ), being 5 min in VOSO 4 -treated rats and min in vanadyl complex-treated rats. The slow clearance rate of the vanadyl species in rats given two vanadyl complexes suggests a high distribution of vanadium in rat organs, which in turn indicates the long-term acting normoglyceric effects even after their withdrawal from the STZ-rats. The proposed metallokinetic analysis by the in vivo BCM-ESR method is useful, not only for a pharmacokinetic analysis of the vanadyl complex in experimental animals, which in the future may apply to human patients, but for understanding the results obtained from the diabetic patients reported recently [7 11]. CONCLUSIONS During our investigations to learn the relationship between structure and insulinmimetic activity for vanadyl complexes with various types of coordination modes, we found that the vanadyl-6-methylpicolinate complex is an orally active and long-term

8 400 Sakurai et al. acting potent compound. Its characteristics are supported by high distribution in rat organs as determined by the NAA method and by a slow clearance rate as analyzed by the in vivo BCM-ESR method, compared with VOSO 4. A biometal such as vanadium may prove useful for treating diseases such as diabetes. REFERENCES 1. WHO: Diabetes mellitus: Reports of a WHO study group. WHO Technical Report Series 1985;727, Orvig C, Thompson KH, Battell M, McNeill JH. Vanadium compounds as insulin mimetics. In Sigel H, Sigel A, editors. Vanadium and its roles in life: metal ions in biological systems, Vol. 31. New York: Marcel Dekker; 1995, p Sakurai H, Tsuji A. Antidiabetic action of vanadium complexes in animals: blood glucose normalizing effects, organ distribution of vanadium, and mechanism for insulin-mimetic action. In Nriagu JO, editor. Vanadium in the environment, Part 2: health effects. New York: Wiley & Sons; 1998, p Sakurai H, Fujii K, Fujimoto S, Fujisawa Y, Takechi K, Tasui H. Structure-activity relationship of insulin-mimetic vanadyl complexes with VO(N 2 O 2 ) coordination mode. In Tracey AS, Crans DC, editors. Vanadium compounds: chemistry, biochemistry, and therapeutic applications. ACS Symposium Series 711. Washington, DC: American Chemical Society, p Sakurai H, Fujisawa Y, Yasui H, Fujimoto S. Orally active vanadyl complexes to treat insulindependent and noninsulin-dependent diabetes mellitus. In: 33rd International Conference on Coordination Chemistry: the chemistry of metal ions in everyday life. Florence, Italy, 30 Aug 4 Sept, 1998, Abs p Lyonnet B, Martz X, Martin E. L emploi therapeutigue des derives du vanadium. Presse Med 1989; 1: Cohen N, Halberstam M, Shilimovich P, Chang CJ, Shamoon H, Rossetti L. Oral vanadyl sulfate improves hepatic and peripheral insulin-sensitivity in patients with non-insulin-dependent diabetes mellitus, J Clin Invest 1995;95: Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR. Metabolic effects of sodium metavanadate in human with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies. J Clin Endocrinol Metab 1995;80: Goldfine AB, Simonson DC, Folli F, Patti M-E, Kahn CR. In vitro and in vivo studies of vanadate in human and rodent diabetes. Mol Cell Biochem 1995;153: Halberstam M, Cohen N, Shilimovitch P, Rossetti L, Shamoon H. Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects. Diabetes 1996;45: Boden G, Chen X, Ruiz J, van Rossum GDV, Turco S. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with noninsulin-dependent diabetes mellitus. Metabolism 1996;45: Chasteen ND. The biochemistry of vanadium. Struc Bonding 1983;53: Kustin K, Macara IG. The new biochemistry of vanadium. Comments Inorg Chem 1982;2: Rehder D. Inorganic consideration on the function of vanadium in biological systems. In Siegel H, Siegel A, editors. Vanadium and its roles in life: metal ions in biological systems, Vol 31. New York: Marcel Dekker; 1995, p Stern A, Yin X, Tsang S-S, Davison A, Moon J. Vanadium as a modulator of cellular regulatory cascades and oncogene expressions. Biochem Cell Biol 1993;71: Hudson FTG. Vanadium: toxicology and biochemical significance. New York: Elsevier; 1964, p Brichard SM, Henguin J-C. The role of vanadium in the management of diabetes. Trends Pharmaco Sci 1995;16: Cantley Jr, LC Josepson L, Warner R, Yanagisawa M, Lechene C, Guidotti G. Vanadate is a potent (Na-K)-ATPase inhibitor found in ATP derived from muscle. J Biol Chem 1977;252: Sakurai H, Shimomura S, Fukuzawa K, Ishizu K. Occurrence of vanadium ions in serum albumins. Biochim Biophys Acta 1987;924: Sakurai H, Nishida M, Kida K, Koyama M, Takada J. Determination and characterization of vanadium ion in serum albumins. Inorg Chim Acta 1987;138:149.

9 Vanadium Role in Treating Diabetes Sakurai H, Shimomura S, Fukuzawa K, Ishizu K. Detection of oxovanadium (IV) and characterization of its ligand environment in subcellular fractions of the liver of rats treated with pentavalent vanadium (V). Biochem Biophys Res Commun 1980;96: Nakai M, Watanabe H, Fujisawa C, Kakegawa H, Satoh T, Takada J, Matsushita R, Sakurai H. Mechanism on insulin-like action of vanadyl sulfate: studies on interaction between rat adipocytes and vanadium compounds. Biol Chem Bull 1995;18: Sakurai H, Tshuchiya K, Nukatsuka M, Sofue M, Kawada J. Insulin-like effect of vanadyl ion on streptozotocin-induced diabetic rats. J Endocrinol 1990;126: Pederson RA, Ramanadham S, Bucham AMJ, McNeill JH. Long-term effects of vanadyl treatment on streptozocin-induced diabetes in rats. Diabetes 1989;38: Meyerovitch J, Farfel Z, Sack J, Shechter Y. Oral administration of vanadate normalizes blood glucose levels in streptozotocin-induced rats, J Biol Chem 1987;262: Sakurai H, Tshuchiya K, Nukatsuka M, Kawada J, Ishikawa S, Yoshida M, Komatsu M. Insulinmimetic action of vanadyl complexes. J Clin Biochem Nutr 1990;8: Pearson RG. Hard and soft acids and bases. J Am Chem Soc 1963;85: Sakurai H, Hamada Y, Shimomura S, Yamashita S, Ishizu K. Cysteine methylester-oxovanadium (IV) complex, preparation and characterization. Inorg Chim Acta 1980;46:L Sakurai H, Taira Z, Sakai N. Crystal structure of an L-cysteine methylester-vanadyl (IV) complex. Inorg Chim Acta 1980;151: Watanabe H, Nakai M, Komazawa K, Sakurai H. A new orally active insulin mimetic vanadyl complex: bis(pyrrolidine-n-carbodithioato)oxovanadium (IV). J Med Chem 1994;37: Sakurai H, Watanabe H, Tamura H, Yasui H, Matsushita R, Takada J. Insulin-mimetic vanadyldithiocarbamate complexes. Inorg Chim Acta 1998;283: Sakurai H, Fujii K, Watanabe H, Tamura H. Orally active insulin-mimetic vanadyl complex: bis(picolinate)oxovanadium (IV). Biochem Biophys Res Commun 1995;214: Fujimoto S, Fujii K, Yasui H, Matsushita R, Takada J, Sakurai H. Long-term acting and orally active vanadyl-methylpicolinate complex with hypoglycemic activity in streptozotocin-induced diabetic rats. J Clin Biochem Nutr 1997;23: Takechi K, Tamura H, Yamaoka K, Sakurai H. Pharmacokinetic analysis of free radicals by in vivo BCM (blood circulation monitoring)-esr method. Free Rad Res 1997;26: Yasui H, Takechi K, Sakurai H. Metallokinetic analysis on disposition of vanadyl complexes as insulin-mimetics in rats by BCM-ESR method. J Inorg Biochem (in press).

Synthesis and characterization of insulin enhancing vanadium (Ⅳ) and zinc (Ⅱ) metal coordinated complexes

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