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Diabetes mellitus (DM) is a serious problem worldwide and is becoming increasingly prevalent. Previously, we reported the use of various zinc (Zn) complexes as new anti-diabetic agents. In this study, we synthesized novel organo‑selenium (Se) Zn complexes with hydroxy-pyrone derivatives that have a Zn(Se 2 O 2 ) coordination mode. The results of in vitro insulin-mimetic analyses showed that the compound bis(3-hydroxy-2-methyl-4(H)-pyran-4-seleno)Zn ([Zn(hmps) 2 ]) exhibited the strongest activity among all the complexes. In the in vivo studies of Zn complexes with 3-hydroxy-2-methyl-4(H)-pyran-4-one, maltol, (hmpo) derivatives, [Zn(hmps) 2 ] exhibited a stronger anti-diabetic effect than bis(3-hydroxy-2-methyl-4(H)-pyran-4-one)Zn ([Zn(hmpo) 2 ]), which had a Zn(O 4 ) coordination mode. Additionally, we investigated the organ distribution of both Zn and Se by determining the amounts of these elements in the organs of [Zn(hmps) 2 ]-administered mice. We then evaluated the effect of treatment with Zn complexes on hepatic lipid accumulation and pancreatic islet hypertrophy by hematoxylin and eosin (HE) histological staining. Zn complexes were found to improve the hypertrophy in the pancreas. There were some reports that Se-containing Zn complexes such as di(2-selenopyridine-N-oxidato)Zn(II) ([ZPS]) were effective for treating diabetes mellitus, so in this study, we examined different types of zinc complexes with organo‑selenium ligands., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Since the discovery of the anti-diabetic effects of zinc (Zn) complex, we synthesized several Zn complexes and evaluated their effects using the KKA y type 2 diabetes mouse model. Recently, we demonstrated that organo-chalcogen (sulfur and selenium) Zn complexes elicit strong anti-diabetic effects. In this study, we treated leptin-deficient ob/ob mice with organo-chalcogen Zn complexes, and evaluated the resulting anti-diabetic effects in a mouse model of diabetes arising from pathogenic mechanisms different from those in KKA y mice. C57BL/6J ob/ob mice orally received either bis (3-hydroxy-2-methyl-4(H)-pyran-4-thiono)Zn, [Zn(hmpt)₂] or bis (3-hydroxy-2-methyl-4(H)-pyran-4-seleno)Zn, [Zn(hmps)₂], daily for 28 days. Both Zn complexes elicited potent blood glucose-lowering effects and improved HbA1c values. Moreover, glucose intolerance improved as evidenced by the oral glucose tolerance test, and fasting plasma insulin levels decreased in both types of Zn complex-treated mice. Zn concentrations in the liver and pancreas of [Zn(hmpt)₂]-treated mice and in the pancreas of [Zn(hmps)₂]-treated mice were increased, respectively. The results suggest that the present Zn complexes mainly exerted an anti-diabetic effect in the liver or pancreas. This study is the first to demonstrate that potent Zn complexes elicit anti-diabetic effects in not only KKA y but also ob/ob mice via a normalizing effect on insulin secretion and fasting blood glucose levels., Competing Interests: The authors declare no conflict of interest.

Zinc (Zn) is a trace element with anti-diabetes mellitus (anti-DM) effects. Zn complexes exhibit stronger insulin-like activity than Zn ions. Bis(hinokitiolato)zinc complex ([Zn(hkt) 2 ]) was recently reported to be a potent anti-DM candidate. We examined the effects of [Zn(hkt) 2 ] on insulin resistance and pancreatic islet cells through in vivo long-term ingestion studies. In an in vivo study, we performed 4-month long-term [Zn(hkt) 2 ] administration experiments in KK-A y mice as a type 2 DM animal model. Ingestion of [Zn(hkt) 2 ] resulted in lower blood glucose levels compared with the non-treated KK-A y mice (control group). Additionally, [Zn(hkt) 2 ] treatment decreased plasma insulin concentration compared with that of the non-treated KK-A y group. [Zn(hkt) 2 ] treatment resulted in a significant suppression of islet cell enlargement and a significantly decreased number of insulin-positive cells compared with the non-treated KK-A y control group. The [Zn(hkt) 2 ] treatment group showed the increasing tendency in the amount of Zn levels in peripheral organs; liver, muscle, adipose, and pancreas, compared with the non-treated KK-A y control group. However, the Zn level in the pancreas of the [Zn(hkt) 2 ] treatment group did not show the significant increase compared with the non-treated KK-A y control group. This accumulation of Zn in pancreas suggested that [Zn(hkt) 2 ] mainly effects on the peripheral tissue, and [Zn(hkt) 2 ] has the less effect on the pancreas directly. Thus, we concluded that [Zn(hkt) 2 ] exerted the main effect on peripheral organs by ameliorating insulin resistance.

Aims: Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability.We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKAy mice., Main Methods: Male type 2 diabetic KKAy mice were divided into 5 groups, and fed either a high-fat-diet (HFD),HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting., Key Findings: The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using amale type 2 diabetic KKAy mousemodel. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice., Significance: These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver.

Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-A(y) mice were exerted at the lowest dose administered (1.25-2.5 mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

Zn(II) complexes are expected to be useful in the treatment of diabetes mellitus because of the hypoglycemic effect produced by its insulin-mimetic activity. Previous reports indicated that Zn(II) complexes with coordinating sulfur exhibit higher insulin-mimetic activity. In this study, we investigated the pharmacological and pharmacokinetic differences between Zn(O(4)) and Zn(S(2)O(2)) coordination modes of tropolonato-Zn(II) complexes with insulin-mimetic activity. Among the tropolonato-Zn(II) complexes with various coordination modes, di(2-mercaptotropolonato)zinc(II) (ZT2) with the Zn(S(2)O(2)) coordination mode was found to exhibit the highest in vitro insulin-mimetic activity with respect to inhibition of free fatty acid (FFA) release and enhancement of glucose uptake in isolated rat adipocytes treated with adrenaline. On comparing investigations of the antidiabetic effect in vivo, ZT2 was found to exhibit potent hypoglycemic activity and improve insulin resistance in type 2 diabetic KKA(y) mice at a low orally administered daily dose. Di(tropolonato)zinc(II) (ZT1), which has the Zn(O(4)) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the (65)Zn tracer method, ZT2 was found to be absorbed at a significantly slower rate with a longer half-life than was ZT1. These results suggest that the potent hypoglycemic activity of ZT2 might be attributed to its long half-life.

Retinoid X receptor (RXR) agonists are reported to exhibit blood glucose-lowering action owing to peroxisome proliferator-activated receptor (PPAR)/RXR or liver X receptor (LXR)/RXR activation, but may also cause adverse effects such as blood triglyceride elevation. In order to examine the feasibility of separating the glucose-lowering action from the adverse effects, we examined the effects of RXR agonists (NEt-TMN), NEt-3IB, and NEt-3IP, which have different heterodimer-activating patterns, in KKA(y) type 2 diabetes model mice. We found that NEt-3IB induced lower degrees of hepatomegaly and blood triglyceride (TG) elevation than the other RXR agonists, even though all of them showed similar blood glucose-lowering action on repeated administration. These findings indicate that structural modification of RXR agonists is a potentially effective strategy to reduce adverse effects while retaining desired activities.

In recent years, people all over the world have suffered from various diseases such as cancer, myocardial infarction, osteoporosis, hypertension, and diabetes mellitus (DM). Especially, DM, well-known as one of lifestyle-related diseases, has been regarded as a serious problem, because it is difficult to fully recover. The number of patients suffering from DM in 2007 was reported to be approximately 200 million people worldwide. However, insulin preparations and synthetic therapeutics, which are clinically used treatment of DM, have been associated with problems such as physical and mental pain due to daily injections and certain severe side effects, respectively. Zn, which is an essential trace element in animals and humans and plays an important role in maintenance of their lives, has been indicated to exhibit insulin-like activity. Since the finding of insulin-like effects of Zn, several Zn complexes have been proposed as a new type of anti-diabetic therapeutics which is differ from existing medicines. In this symposium, we introduce the anti-diabetic effect, complication relieving effect, and action mechanism of bis(2-mercaptopyridine-N-oxidato)Zn complex with Zn(S(2)O(2)) coordination mode.

In recent years, the number of patients suffering from diseases, such as cancer, apoplexy, osteoporosis, hypertension, and type 2 diabetes mellitus is increasing worldwide. Type 2 diabetes, a lifestyle-related disease, is recognized as a serious disease. Various types of pharmaceutics for diabetes have been used. Since the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized for many years, we have been developing the anti-diabetic metal complexes as new candidates. We found that several zinc(II) (Zn) complexes exhibit glucose-lowering activity for treating type 2 diabetes. High doses of salicylates have been known to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients. These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating type 2 diabetes. Because aspirin, acetyl salicylic acid, has a chelating ability, we used it as a ligand to Zn. Several Zn-salicylate complexes were prepared and their biological activities were examined in this study. The complexes with an electron-withdrawing group in the ligand exhibited higher in vitro insulinomimetic activity than those of Zn complexes with an electron-donating group in the ligand. When bis(aspirinato)Zn (Zn(asp)₂) complex was orally administered on KK-A(y) mice with hereditary type 2 diabetes, the diabetic state was improved. In addition, this complex exhibited normalizing effects on serum adiponectin level and high blood pressure in metabolic syndrome. In conclusion, Zn(asp)₂ complex is newly proposed as a potent anti-diabetic and anti-metabolic syndrome agent.

We found alpha-glucosidase inhibitory (alpha-GI) effect of metal ions and their complexes which showed the high blood glucose lowering effect in diabetic model animals. The Cu(II) ion and its complexes showed strong alpha-GI activity greater than clinically used acarbose in in vitro studies. Furthermore, in in vivo experiments, alpha-GI action was newly discovered in normal ddy mice. These results suggested that one of action mechanisms of the anti-diabetic metal ions and complexes is related to the alpha-GI effects.

Vanadyl sulfate (VOSO(4)) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO(4) improved the type 2 diabetic state with respect to plasma glucose, HbA(1c), and fructosamine levels. The development of toxicity by increasing the administration of VOSO(4) should be avoided. One method was the utilization of vanadyl complexes with coordination compounds that are low-toxic and low-molecular-weight ligands to enhance the permeation of the metal ion to lipid bilayer membrane. Over a decade we have focused on a variety of heterocyclic compounds as bidentate ligands for metal ions. Vanadyl and zinc(II) complexes of 1-substituted 3-hydroxy-2-methyl-4(1H)-pyridinethiones, 4,5,6-substituted 1-hydroxy-2(1H)-pyrimidinones, 4-(p-substituted)phenyl-3-hydroxythiazole-2(3H)-thiones, 3-hydroxypyrone, 1-alkyl- or 1-phenylalkyl-3-hydroxy-2(1H)-pyridinethiones, optically active 1-substituted 3-hydroxy-4(1H)-pyridinethiones, and 5-dialkylsulfonamido- or 5,7-bis(dialkylsulfonamido)-8-hydroxyquinolines were prepared, and their insulin-mimetic activities were evaluated in terms of IC(50) values which stand for a 50% inhibitory concentration of the free fatty acid release from isolated rat adipocytes. In this article, the relationship between the insulin-mimetic activity and the partition coefficient, the chirality, the substituent effect, molecular weight, the pK(a) value, and the coordination mode was discussed. In vivo blood glucose-lowering effects of the vanadyl complex with 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone in streptozotocin (STZ)-induced diabetic rats and the zinc(II) complexes with 4-(p-chlorophenyl)thiazole- and 4-methylthiazole-2(3H)-thione in KK-A(y) mice were also discussed.

This tutorial review introduces the current state of metallopharmaceutics development by focusing on the topics of anti-diabetic vanadium and zinc complexes. Over thousands of years, people have produced many types of inorganic compounds, and the modern concept of chemotherapy was achieved by Ehrlich, who used an arsenic-containing compound to treat syphilis. Since then, many metallopharmaceutics have been developed worldwide. This review will be helpful to researchers who are interested in the current states of not only metallopharmaceutics but also anti-diabetic metal complexes.

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)(2)] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)(2)] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)(2)-related complexes by the blood circulation monitoring-electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC(50) (IC(50) is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P (com)). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)(2) than in the blood of rats that received VO(3hp)(2) or bis(kojato)oxovanadium(IV); VO(alx)(2) also exhibited higher log P (com) and 1/IC(50) values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.

CYP2E1 is known to be induced in streptozotocin (STZ)-treated diabetic rats (STZ rats), and its induction is improved by insulin. We have examined the age-dependent changes of CYP2E1 in the liver microsomes of type 1 diabetic STZ rats, the effects of VOSO4 on the contents of total P450 and CYP2E1, and the activities of CYP2E1 in terms of p-nitrophenol hydroxylation. The contents of P450 and CYP2E1 and CYP2E1 activity were enhanced with the development of diabetes. When the hyperglycemia of STZ rats was improved by daily intraperitoneal injections of VOSO4 for 10 days at the doses of 7 mg/kg body weight for 5 days, 5 mg/kg for the following 3 days, and then 2.5 mg/kg for 2 days, the P450 and CYP2E1 levels and CYP2E1 activity were lowered than those in the untreated STZ rats. To understand the mechanism underlying CYP2E1-dependent hydroxylation activity, the production of reactive oxygen species was examined in the NADPH-liver microsomal systems by ESR spin-trapping. Singlet oxygen (1O2) was detected in all microsomal systems, while superoxide anion radical(*O2-) and hydroxyl radical (*OH) were not. On the basis of these results, we conclude that (1) CYP2E1 level and activity are enhanced in the diabetic state, however, they are improved by VOSO4 treatment, and (2) 1O2 is generated during CYP2E1-dependent substrate oxygenation.

Chronic oral administration of vanadyl sulfate has recently been shown to improve the state of type 2 diabetic subjects. Mild gastrointestinal symptoms and side effects, however, have been observed in some subjects. To find safer and more effective dosages, we have developed an enteric-coated capsule containing solid vanadyl sulfate (ECC/VS), which enhances the bioavailability of vanadyl sulfate to almost double that of vanadyl sulfate solution. ECC/VS was chronically administered to treat streptozotocin-induced diabetic rats (STZ-rats), an animal model of type 1 diabetes mellitus, and an equivalent blood-glucose-lowering effect was observed at half the doses of vanadyl sulfate alone. In addition, we observed almost the same total vanadium levels in the serum after chronic administration of ECC/VS as those of vanadyl sulfate alone, suggesting that plasma vanadium levels correlate with the hypoglycaemic activity of vanadyl sulfate. These results indicate that oral ECC/VS improves the diabetic state by enhancing the uptake of vanadium in STZ-rats. These findings will be useful in designing clinical trials of vanadyl sulfate for diabetic subjects.

To treat patients suffering from diabetes mellitus, we developed several types of orally active vanadyl complexes to replace painful insulin injections, and prepared them in the form of enteric-coated capsules containing vanadium compounds. Pharmacokinetic analysis demonstrated that these capsules enhance the bioavailability of pharmacologically active vanadyl species.

Throughout the world, the number of patients suffering from diabetes mellitus (DM) is increasing on a daily basis, probably due to change in lifestyle. DM is mainly classified as either insulin-dependent Type 1 or non-insulin-dependent Type 2, according to the definition of WHO. To treat DM, which has many severe complications, several types of insulin preparations and synthetic drugs for Type 1 and Type 2 DM, respectively, have been developed and are in clinical use. However, there are several problems concerning the insulin preparations and synthetic drugs, such as physical and mental pain due to daily insulin injections and defects involving side effects, respectively. Consequently, a new class of therapeutic agents is anticipated. For this purpose, vanadium-containing complexes are expected to treat or improve both types of DM by using unique characteristics of the transition metal. In this article, the current state of research on insulin-mimetic vanadium complexes are reviewed, with special focus on the paramagnetic vanadyl (+4 oxidation state of vanadium) complexes with different coordination modes. To analyse the blood glucose-lowering effects of the vanadyl complexes, new results on the organ distribution and pharmacokinetic analysis of the vanadyl state in the blood of rats are also described.

The insulinomimetic effect of vanadium is the most remarkable and important among its several biological actions. Vanadyl ion (+4 oxidation state of vanadium) and its complexes have been found to normalize the blood glucose levels of both type 1 and 2 diabetic animals. We have developed insulinomimetic vanadyl complexes having different coordination modes, emphasizing the possible usefulness of vanadyl-picolinate [VO(pa)(2)] and its related complexes with the VO(N(2)O(2)) coordination mode. In order to apply these complexes clinically in the future, the relationship between the chemical structure, insulinomimetic action, organ distribution of vanadium, and blood disposition of vanadyl species must be closely investigated. In the present investigation, we studied the blood disposition of the vanadyl-picolinate complexes in healthy rats, and tried to understand comprehensively the relationship between the structures, insulinomimetic activity, and metallokinetic parameters of the complexes, which had been recently prepared and specifically synthesized for the present study, by using an in vivo blood circulation monitoring -- electron spin resonance (BCM-ESR) method for analyzing ESR signals due to paramagnetic metal ions and complexes in the blood in real time. Metallokinetic parameters were estimated based on the blood clearance curves in terms of a two-compartment pharmacokinetic model, and vanadyl species were indicated to be distributed in peripheral tissues and gradually eliminated from the circulating blood, depending on their chemical structures. Vanadyl concentrations in the blood of rats given bis(5-iodopicolinato)oxovanadium(IV) [VO(5ipa)(2)] and bis(3-methylpicolinato)oxovanadium(IV) [VO(3mpa)(2)] with electron-withdrawing and donating groups, respectively, remained significantly higher and longer, due to their slower clearance rates from the blood, than in rats given other complexes, suggesting that the high exposure and long residence of vanadyl species bring about the high normoglyceric effect in diabetic animals. We then examined the relationship between insulinomimetic activity and metallokinetic parameters in the family of VO(pa)(2) for further development of insulinomimetic vanadyl complexes. IC(50), the 50% inhibitory concentration of the complexes on the free fatty acid release from isolated rat adipocytes treated with epinephrine, was found to be sufficiently correlated with metallokinetic parameters such as area under the concentration curve, mean residence time, total clearance, and distribution volume at steady-state. Furthermore, the in vivo antidiabetic activity of the complexes was enhanced with increasing exposure and residence of vanadyl species in the blood of animals. On the basis of these results, we concluded that in vitro insulinomimetic activity, metallokinetic character, and in vivo antidiabetic action of vanadyl-picolinate complexes are closely related to their chemical structures.

In recent years, there have been improvements in the treatment of type 2 diabetes by oral administration of vanadyl sulfate (VOSO4, VS). The maintenance of vanadyl levels in the blood of subjects with type 2 diabetes was found to be important for the insulinomimetic activity of VS. However, owing to low bioavailability of VS and the development of mild gastrointestinal symptoms and side-effects in some subjects, it is necessary to design more effective and safer dosages of VS. After discovering that VS is absorbed more thoroughly at the ileum than at other gastrointestinal sites, we investigated the absorption processes following oral administration of VS by preparing enteric-coated capsules (ECC). Although Cmax values were unchanged by the dosage forms, Tmax and MRT values associated with the enteric-coating capsulation were prolonged when compared with those observed with use of gelatin capsules (GC). An important finding was that the bioavailability of VS from ECC (9.8%) was almost double that of VS from either GC (4.0%) or the solution (4.8%). Administration of VS-containing ECC to diabetic patients is proposed to improve vanadyl absorption over that achieved by the administration of either GC or the solution.

Vanadium(v) compounds with 3,5-difluoropicolinic acid (HpicFF) and 3-hydroxypicolinic acid (H2hypic) and zinc(ii) compounds with HpicFF, H2hypic and 4-methylhydroxypicolinic acid (HpicCH2OH) in the presence or absence of pyridine (py), 4-(dimethylamino)pyridine (DMAP), and 1,10-phenanthroline (phen) have been synthesized and characterized. The crystal structures of NH4[VO2(picFF)2]·1.6H2O (3·1.6H2O), NH4[VO2(hypic)2]·H2O (4·H2O), [Zn(picFF)2(H2O)2] (5), [Zn(picFF)2(py)2]·py (6·py), [Zn(picFF)2(DMAP)2]·UGRAPHIC DISPLAY="INLINE" ID="UGT1" SRC="UGT1"/H2O (7·UGRAPHIC DISPLAY="INLINE" ID="UGT2" SRC="UGT2"/H2O), [Zn(picFF)2(phen)]·2CHCl3 (8·2CHCl3), [Zn(Hhypic)2(MeOH)2] (10), [Zn(Hhypic)2(DMAP)(H2O)] (11) and [Zn(Hhypic)2(phen)] (12) were determined by X-ray crystallography. The spatial arrangement of the vanadium(v) complex 3 possesses carboxylate oxygen atoms in a mutual trans orientation while crystal structure 4 represents the first crystallographic evidence for the formation of an isomer with two picolinato nitrogen atoms in a mutual trans position. Two different spatial arrangements were found in the zinc(ii) complexes with trans (5, 10 and 11) and cis (6, 7, 8 and 12) octahedral geometry. Insulin-mimetic activity of the selected VIVO, VVO2 and ZnII complexes was studied by in vitro inhibition of the free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. All the studied metal complexes showed insulin-mimetic activity. Vanadium complexes 1–4 exhibit activities similar to VOSO4 with the Hhypic complexes being more active than the picFF ones. The zinc complexes also exhibited some insulin-mimetic activity, with the Hhypic complex (9) being more active than the other two, however, the insulin-mimetic activity of these complexes did not show more potent activity than ZnSO4. [ABSTRACT FROM AUTHOR]

Since many Zn complexes have been developed to enhance the insulin-like activity and increase the exposure and residence of Zn in the animal body, these complexes are recognized as one of the new candidates with action mechanism different from existing anti-diabetic drugs. However, the molecular mechanism by which Zn complexes exert an anti-DM effect is unknown. Therefore, we evaluated the activity of Zn complexes, especially related to the phosphorylation of insulin signaling pathway components. We focused on the insulin-like effects of the bis(hinokitiolato)zinc complex, [Zn(hkt)], using 3T3-L1 adipocytes. [Zn(hkt)] was taken up by cells and induced Akt phosphorylation in a time-dependent manner. Additionally, it showed inhibitory activity against PTP1B and PTEN, which are major negative regulators of insulin signaling. It did not promote the phosphorylation of IR (insulin receptor)-β or IRS (insulin receptor substrate)-1 by itself, but in combination with insulin, it enhanced the phosphorylation of IRβ. We conclude that [Zn(hkt)] has effects on the proteins of insulin signaling pathway without insulin receptor mediation, and [Zn(hkt)] promotes insulin function and shows the anti-DM effects. Thus, [Zn(hkt)] may be the basis for improved DM treatments. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-Ay mice were exerted at the lowest dose administered (1.25–2.5mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM. [Copyright &y& Elsevier]

The article focuses on a study which synthesized and evaluated the meso-Tetrakis(4-sulfonatophenyl), an orally active insulin-mimetic vanadyl-porphyrin complex. The vanadyl-porphyrin complex was evaluated for its in vivo insulin-mimetic activity. Changes in the blood glucose level of streptozotocin-induced diabetic mice were observed. The study concluded that the complex have a significant hypoglycemic activity in diabetic mice.

To treat both insulin-dependent type 1 and non-insulin-dependent type 2 diabetic mellitus, two potent antidiabetic vanadyl pyridone complexes, bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), (VO(opt)2) and bis(1-oxy-2-pyridonato)oxovanadium(IV), (VO(opd)2), were proposed on the basis of the results of diabetic model animals by using a concept of equivalent transformation, which has been proved to be effective in changing the chemical property of a compound. Their physico-chemical properties, chemical specications, in vitro insulin–mimetic activity in isolated rat adipocytes, in vivo antidiabetic activity in both type 1 and type 2 diabetic animals, and metallokinetic feature of the vanadyl species in the blood flow of live rats by using blood circulation monitoring-electron paramagnetic resonance (BCM-EPR) were examined. Both complexes exhibited higher in vitro insulin–mimetic activity than VOSO4, and the activity of VO(opt)2 was superior to that of VO(opd)2. However, on oral administration to type 1 diabetic rats, VO(opd)2 was more effective at lower dose than VO(opt)2. The results are supported by chemical specifications and metallokinetic (kinetic of metal disposition) parameters. [Copyright &y& Elsevier]

Diabetes mellitus (DM), which develops many secondary complications such as atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormality, diabetes retinopathy and ocular disorders, is classified as either insulin-dependent type 1 or non-insulin-dependent type 2, according to the definition of WHO. Although several types of insulin preparations for type 1 DM and those of synthetic drugs for type 2 DM have been developed and clinically used, they have several problems such as physical and mental pain due to daily insulin injections and defects involving side effects, respectively. In the 21st century, a new class of pharmaceuticals should be introduced. For this reason, metallopharmaceutical compounds containing vanadium and zinc ions are expected to treat both types of DM, by making effective use of unique characteristics of the metals. In this article, the current state of development of insulin-mimetic vanadium and zinc complexes with different coordination modes are reviewed, focusing on the preparations and coordination structures of the complexes and in vitro and in vivo evaluations as well as the possible mechanism. [Copyright &y& Elsevier]