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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.

Background: Type-2 diabetics have an increased risk of cardiomyopathy, and heart failure is a major cause of death among these patients. Growing evidence indicates that proinflammatory cytokines may induce the development of insulin resistance, and that anti-inflammatory medications may reverse this process. We investigated the effects of the oral administration of zinc and acetylsalicylic acid, in the form of bis(aspirinato)zinc(II)-complex Zn(ASA)2, on different aspects of cardiac damage in Zucker diabetic fatty (ZDF) rats, an experimental model of type-2 diabetic cardiomyopathy., Methods: Nondiabetic control (ZL) and ZDF rats were treated orally with vehicle or Zn(ASA)2 for 24 days. At the age of 29-30 weeks, the electrical activities, left-ventricular functional parameters and left-ventricular wall thicknesses were assessed. Nitrotyrosine immunohistochemistry, TUNEL-assay, and hematoxylin-eosin staining were performed. The protein expression of the insulin-receptor and PI3K/AKT pathway were quantified by Western blot., Results: Zn(ASA)2-treatment significantly decreased plasma glucose concentration in ZDF rats (39.0 ± 3.6 vs 49.4 ± 2.8 mM, P < 0.05) while serum insulin-levels were similar among the groups. Data from cardiac catheterization showed that Zn(ASA)2 normalized the increased left-ventricular diastolic stiffness (end-diastolic pressure-volume relationship: 0.064 ± 0.008 vs 0.084 ± 0.014 mmHg/µl; end-diastolic pressure: 6.5 ± 0.6 vs 7.9 ± 0.7 mmHg, P < 0.05). Furthermore, ECG-recordings revealed a restoration of prolonged QT-intervals (63 ± 3 vs 83 ± 4 ms, P < 0.05) with Zn(ASA)2. Left-ventricular wall thickness, assessed by echocardiography, did not differ among the groups. However histological examination revealed an increase in the cardiomyocytes' transverse cross-section area in ZDF compared to the ZL rats, which was significantly decreased after Zn(ASA)2-treatment. Additionally, a significant fibrotic remodeling was observed in the diabetic rats compared to ZL rats, and Zn(ASA)2-administered ZDF rats showed a similar collagen content as ZL animals. In diabetic hearts Zn(ASA)2 significantly decreased DNA-fragmentation, and nitro-oxidative stress, and up-regulated myocardial phosphorylated-AKT/AKT protein expression. Zn(ASA)2 reduced cardiomyocyte death in a cellular model of oxidative stress. Zn(ASA)2 had no effects on altered myocardial CD36, GLUT-4, and PI3K protein expression., Conclusions: We demonstrated that treatment of type-2 diabetic rats with Zn(ASA)2 reduced plasma glucose-levels and prevented diabetic cardiomyopathy. The increased myocardial AKT activation could, in part, help to explain the cardioprotective effects of Zn(ASA)2. The oral administration of Zn(ASA)2 may have therapeutic potential, aiming to prevent/treat cardiac complications in type-2 diabetic patients.

We recently demonstrated that the pre-treatment of rats with zinc and acetylsalicylic acid complex in the form of bis(aspirinato)zinc(II) [Zn(ASA)2] is superior to acetylsalicylic acid in protecting the heart from acute myocardial ischemia. Herein, we hypothesized that Zn(ASA)2 treatment after the onset of an acute myocardial injury could protect the heart. The rats were treated with a vehicle or Zn(ASA)2 after an isoproterenol injection. Isoproterenol-induced cardiac damage [inflammatory infiltration into myocardial tissue, DNA-strand breakage evidenced by TUNEL-assay, increased 11-dehydro thromboxane (TX)B2-levels, elevated ST-segment, widened QRS complex and prolonged QT-interval] was prevented by the Zn(ASA)2 treatment. In isoproterenol-treated rats, load-independent left ventricular contractility parameters were significantly improved after Zn(ASA)2. Furthermore, Zn(ASA)2 significantly increased the myocardial mRNA-expression of superoxide dismutase-1, glutathione peroxidase-4 and decreased the level of Na(+)/K(+)/ATPase. Postconditioning with Zn(ASA)2 protects the heart from acute myocardial ischemia. Its mechanisms of action might involve inhibition of pro-inflammatory prostanoids and upregulation of antioxidant enzymes.

Purpose: Neointima formation following angioplasty is a serious consequence of endothelial damage in arteries. Inflammatory mediators and lack of endothelial regulatory mechanisms lead to migration and proliferation of smooth-muscle cells and thus to restenosis. This study examines the effect of the novel bis (aspirinato) zinc (II) complex on neointima formation in a rat model of carotid balloon-injury., Methods: Rats underwent balloon-injury of the right common carotid artery, then received PEG400 vehicle (untreated-group), acetylsalicylic-acid (ASA-group), zinc-chloride (Zn-group) and bis (aspirinato) zinc (II) complex (Zn(ASA) 2-group) orally for 18 consecutive days. From harvested carotid arteries, histology, immunohistochemistry and mRNA expression analysis were performed., Results: Compared to the untreated-group, Zn (ASA) 2-treatment significantly lowered stenosis ratio (54.0 ± 5.8% to 25.5 ± 3.9%) and reduced neointima/media ratio (1.5 ± 0.2 to 0.5 ± 0.1). Significantly higher alpha smooth muscle actin mRNA and protein expression were measured after Zn (ASA)2 and Zn-treatment in comparison with the untreated and ASA-groups while the expression of matrix-metalloproteinase-9 was significantly higher in these groups compared to Zn (ASA)2. The presence of collagen in media was significantly decreased in all treated groups. mRNA expressions of nuclear factor kappa-b, transforming growth-factor-β and proliferating cell nuclear antigen were significantly down-regulated, whereas a20 was up-regulated by Zn (ASA)2 treatment compared to the untreated and ASA-groups., Conclusion: This study proves the effectivity of the novel bis (aspirinato) zinc complex in reducing neointima formation and restenosis after balloon-injury and supports the hypothesis that inhibition of smooth-muscle transformation/proliferation plays a key role in the prevention of restenosis.

The relationship between biometals, such as zinc (Zn(2+)), vanadium, copper, cobalt, and magnesium ions, and diabetes therapy has been recognized for several years. In particular, the antidiabetic activities of Zn(2+) and oxovanadium (VO(2+)) complexes have been measured using biochemical approaches. In the present study, diabetic KK-A(y) mice were treated with bis(1-oxy-2-pyridine-thiolato)Zn(2+) (Zn(opt)2) and bis(1-oxy-2-pyridine-thiolato)VO(2+) (VO(opt)2) for 4 weeks, and the antidiabetic activities of these metal complexes were evaluated using biochemical and morphological methods. Additionally, zinc gluconate (Zn(glc)2) and bis(ethylmaltolato)VO(2+) (VO(emal)2) were used as reference compounds. Pancreatic islet cells were smaller, and there was a tendency towards a lower islet cell area ratio in Zn(opt)2-treated mice compared with nontreated KK-A(y) mice. Furthermore, plasma insulin concentrations were significantly reduced to 27.2% of insulin concentrations in nontreated KK-A(y) mice. These results suggest that Zn(opt)2 administration provides morphological and biochemical improvements in hyperinsulinaemia. In contrast, in mice that received Zn(glc)2 and VO(2+) complexes, the islet cell size and islet cell area ratio did not differ from those in nontreated controls. Zn(opt)2- and VO(opt)2-treated mice exhibited significantly lower fat deposition and fat deposition area ratio in the liver (63.6% and 65.8% of nontreated KK-A(y) mice, respectively) compared to those observed in nontreated KK-A(y) mice. The differences in morphological improvements of the pancreas and liver owing to Zn(opt)2 or VO(opt)2 treatment may be explained by differences in the sites of actions of Zn(2+) and VO(2+) complexes in different organs in KK-A(y) mice. In conclusion, Zn(opt)2 exhibited superior antidiabetic effects over those of VO(opt)2, and this was owing to greater amelioration of the morphological parameters of the liver and pancreas.

The increasing prevalence of diabetes mellitus (DM) worldwide has underscored the urgency of developing an efficient therapeutic agent. Recently, Zn complexes have been attracting attention due to their antidiabetic activity. In this study, we designed and synthesized a new Zn complex, Zn-3,4-heptanedione-bis(N (4)-methylthiosemicarbazonato) (Zn-HTSM), characterized its physicochemical properties, and examined its antidiabetic activity in KK-A(y) type 2 DM model mice. It was demonstrated that Zn-HTSM has adequate lipophilicity for the cellular permeability, shows potent hypoglycemic activity, and improves glucose intolerance in KK-A(y) mice. We also analyzed the levels of serum adipokines after continuous oral administration of Zn-HTSM. The level of serum leptin of KK-A(y) mice is significantly reduced by the treatment of Zn-HTSM. Nevertheless, the levels of serum insulin and adiponectin were not improved. These data suggested that the Zn-HTSM acts on the leptin metabolism. Our present studies indicate that Zn-HTSM is a candidate oral antidiabetic agent for the treatment of type 2 DM.

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.)

The variety of physiologic and biologic functions of zinc is fascinating and could be applicable to medicine. Our previous studies demonstrated that the absorption of zinc after oral administration to rats is dose-dependent. In order to clarify the detailed mechanism of the dose-dependent in vivo absorption, the transport of zinc across intestinal epithelial cells was investigated using Caco-2 monolayers and isolated rat intestinal membranes. The permeation of zinc across Caco-2 monolayers is concentration-dependent, and both saturable and nonsaturable components are involved. The Michaelis constant and maximum transport rate for saturable transport are 11.7 μM and 31.8 pmol min(-1) cm(-2), respectively; the permeability coefficient for nonsaturable trasnport is 2.37×10(-6) cm s(-1). These parameters for permeation across membranes isolated from duodenum, ileum, and jejunum of rats are similar with those of Caco-2 cells. The comparison of the parameters for permeation across isolated intestinal membrane suggests that the major site of intestinal zinc absorption in rats is the duodenum. The maximum rate of zinc transport across the isolated intestinal membrane (V(max)) shows no correlation with mRNA expression of ZIP4, ZIP5 or ZnT1 in rats, but shows an inverse correlation with that of metallothioneins (MTs). This finding may be partly explained by the buffering role of metallothionein in intestinal absorption. The saturable transport of zinc is not simply determined only by the influx transporter, ZIP4, since three influx and efflux transporters are involved in the transport of zinc.

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.

Results from an investigation in an in vivo model of STZ-induced diabetic rats demonstrate that compound bis(1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate)zinc(II), Zn(dmpp)(2), significantly lowers the blood glucose levels of individuals, thus showing evidence of glucose lowering activity. The compound was selected from a set of eight zinc(II) complexes of 3-hydroxy-4-pyridinones with diverse lipophilicity that were prepared and characterized in our laboratory. Assessment of insulin-like activity of the complexes was firstly performed in vitro by measuring the inhibition of FFA release in isolated rat adipocytes. The results indicate that compounds bis(2-methyl-3-hydroxy-4-pyridinonate)zinc(II), Zn(mpp)(2) and Zn(dmpp)(2) display significantly higher activity than that of the respective positive control thus suggesting its selection for in vivo tests. Safety evaluation of the active zinc(II) compounds was performed in freshly isolated rat hepatocytes. The results support that cell viability is not significantly different from the control set after 1 and 2h of incubation with both zinc(II) complexes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The variety of physiologic and biologic functions of zinc is expected to enable the development of zinc-related medicines. In this study, the distribution of endogenous zinc, the disposition after intravenous injection, and the intestinal absorption of zinc were investigated in vivo using rats from the viewpoints of pharmaceutical science and pharmacokinetics. High levels of endogenous zinc were observed in bone, testis, and liver. RT-PCR analysis on the mRNA of metallothionein in tissues clarified that it is significantly correlated with the distribution of zinc, suggesting that zinc is accumulated in tissues as a complex with MT. Following intravenous injection, uptake of zinc was high in liver, spleen, pancreas, kidney, and intestine. Fractional absorptions of zinc after oral administration to fasted rats were greater than those to fed rats, suggesting that some factors in diet inhibit the absorption of zinc. In fasted rats, fractional absorption was slightly decreased in high-dose group, suggesting the involvement of carrier-mediated transport. Study utilizing an in situ closed-loop method also indicated saturable intestinal absorption of zinc. These findings will further the research and development of zinc-related medicines by providing basic and important information on zinc., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The insulinomimetic activity of a Zn(ii) complex is reported. The effects of the Zn(ii) complex with ascorbic acid (Vitamin C; VC), methylmethionine sulfonium chloride (Vitamin U; VU) and l-carnitine were assessed in diet-induced metabolic syndrome model rats. Zn(VU)(2)Cl(2) and Zn(VC)Cl(2) were suggested to be useful supplementary materials for preventing metabolic syndrome by reducing visceral adipose tissues or accelerating blood fluidity.

Several Zn(II) complexes (2a-e) of 1-arylmethyl-2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxylates (1a-e), known drug candidates for diabetic complications, were synthesized and proved to have in vitro insulin-mimetic activities, suggesting that these complexes are potential chemotherapeutics that are effective against both diabetes and diabetic complications.

The number of worldwide patients suffering from diabetes mellitus (DM) is forecasted to increase over time. The development of compounds without severe side effects for type 2 DM is required not only to treat DM but also to improve the quality of life (QOL) of patients. In this paper, we have described the synthesis of novel first transition metal complexes with S2O2 coordination mode and discussed their anti-diabetic activities. Di(1-oxy-2-pyridinethiolato)Zn complex (Zn(opt)2) with Zn(S2O2) coordination mode displayed higher insulin mimetic with anti-diabetic activity, compared to the ZnCl2 or clinically used medicine (pioglitazone). In addition, Zn(opt)2 improved the insulin and adiponectine levels in the plasma. The gastrointestinal absorption of the Zn complex was found to be higher than that of ZnCl(2). Based on these results, we propose that the Zn(opt)2 complex with Zn(S2O2) coordination mode is a novel candidate for the treatment of type 2 DM; through oral administration.

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.

In developing new insulin-mimetic zinc(II) complexes with various ligands including a biodegradable polymer, we prepared and characterized a Zn(gamma-pga) complex in solution as well as in solid, and investigated its in vitro insulin-mimetic activity and in vivo antidiabetic effect in type-2 diabetic KKA(y) mice. The in vitro insulin-mimetic activity of the Zn(gamma-pga) complex was considerable better than that of ZnSO(4). The Zn(gamma-pga) complex normalized the hyperglycemia in KKA(y) mice within 21 d when administrated orally at doses of 10-20 mg (0.15-0.31 mmol) Zn per kg body mass for 30 d. In addition, the impaired glucose tolerance, elevated HbA(1c) levels and metabolic syndromes were significantly improved in Zn(gamma-pga)-treated KKA(y) mice relative to those administrated with saline and ZnSO(4).

We prepared 4 new Zn(II) complexes with Zn(O4), Zn(N(2)O(2)), and Zn(S2O2) coordination modes and evaluated their insulinomimetic activities in an in vitro study. The insulinomimetic activities of bis(pyrrole-2-carboxylato)zinc (Zn(pc)2), bis(alpha-furonic acidato)zinc (Zn(fa)2), bis(thiophene-2-carboxylato)zinc (Zn(tc)2), and bis(thiophene-2-acetato)zinc (Zn(ta)2) complexes were found to be higher than that of zinc sulfate (ZnSO4). Zn(ta)2 showed the highest insulinomimetic activity among the Zn(II) complexes because of its high lipophilicity.

We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]zinc(II) ([Zn(tpps)]), and investigated its in vitro insulin-mimetic activity and in vivo hypoglycemic effect in type 2 diabetic KKA(y) mice. The results were compared with those of previously proposed insulin-mimetic zinc(II) complexes and zinc sulfate (ZnSO(4)). The in vitro insulin-mimetic activity of [Zn(tpps)] was considerably better than that of bis(allixinato)zinc(II) ([Zn(alx)(2)]), bis(maltolato)zinc(II) ([Zn(mal)(2)]), bis(2-aminomethylpyridinato)zinc(II) ([Zn(2-ampy)(2)](2+)), and ZnSO(4). In particular, the order of in vitro insulin-mimetic activity of the complexes was determined to be: [Zn(tpps)]>[Zn(alx)(2)]>[Zn(mal)(2)]>[Zn(2-ampy)](2+)>ZnSO(4). [Zn(tpps)] normalized the hyperglycemia of KKA(y) mice within 21 days when administered orally at doses of 10-20 mg (0.15-0.31 mmol) Zn per kg body mass for 28 days. In addition, metabolic syndromes such as insulin resistance, the degree of renal disturbance, and the degree of liver disturbance were significantly improved in [Zn(tpps)]-treated KKA(y) mice relative to those administered with saline and ZnSO(4). The improvement in diabetes was validated by the results of oral glucose-tolerance tests and the decrease in the HbA(1c) level observed. In contrast, ZnSO(4) and the ligand H(2)tpps did not lower the elevated blood glucose level under the same experimental conditions. Based on these observations, [Zn(tpps)] is proposed to be the first orally active zinc(II)-porphyrin complex for the efficacious treatment of not only type 2 diabetes but also metabolic syndromes in animals.

Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx)(2)) with allixin, which is isolated from dry garlic, with a Zn(O(4)) coordination environment, exhibited high anti-diabetic effects in obesity-linked type 2 diabetic KKA(y) mice. However, this complex exhibited low activity when administered orally. To improve the effect of Zn(alx)(2), we prepared a novel Zn(II) complex with the allixin-derivative bis(1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4- thionato)Zn(II), abbreviated as Zn(II)-thioallixin-N-methyl (Zn(tanm)(2)), having a Zn(S(2)O(2)) coordination environment; this complex has extremely high in vitro insulin-like activity. Because Zn was extensively absorbed from the gastrointestinal tract when Zn(tanm)(2) was orally administered, its anti-diabetic effects were examined in KKA(y) mice. Daily oral administrations of Zn(tanm)(2) for 4 weeks in KKA(y) mice significantly improved hyperglycemia, glucose intolerance, insulin resistance, hyperleptinemia, obesity, and hypertension. Interestingly, Zn(tanm)(2) increased depressed plasma adiponectin levels in the mice. Here, we propose that Zn(tanm)(2) will be an orally active therapeutic for obesity-linked type 2 diabetes and metabolic syndromes.

Control of the glucose level in the blood plasma has been achieved in vitro and in vivo by administration of vanadium and zinc in form of inorganic salts. It has been shown that elements are poorly absorbed in their inorganic forms and required high doses which have been associated with undesirable side effects. Many researchers, therefore, have focused on metal complexes that were prepared from VOSO(4) or ZnSO(4) and low-molecular-weight bidentate ligands. Seven kinds of 1-hydroxy-4,6-disubstituted and 1-hydroxy-4,5,6-trisubstituted-2(1H)-pyrimidinones were synthesized by reaction of N-benzyloxyurea and beta-diketones and subsequent removal of the protecting group. Six kinds of 1-hydroxy-4-(substituted)amino-2(1H)-pyrimidinones were synthesized by the substitution reaction of 1-benzyloxy-4-(1',2',4'-triazol-1'-yl)-2(1H)-pyrimidinone with various alkyl amines or amino acids. Treatment with VOSO(4) and ZnSO(4) or Zn(OAc)(2) afforded vanadyl(IV) and zinc(II) complexes which were characterized by means of (1)H NMR, IR, EPR, and UV-vis spectroscopies, and combustion analysis. The in vitro insulin-mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC(50)) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Vanadyl complexes of 4,6-disubstituted-2(1H)-pyrimidinones showed higher insulin-mimetic activities than those of 4,5,6-trisubstituted ones. On the other hand, Zn(II) complexes showed lower insulin-mimetic activities than VOSO(4) and ZnSO(4) as positive controls. It was found that the balance of the hydrophilicity and/or hydrophobicity is important for higher insulin-mimetic activity. The in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were lowered from hyperglycemic to normal levels after the treatment with bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium(IV) by daily intraperitoneal injections. The improvement in glucose tolerance was also confirmed by an oral glucose tolerance test.

Several metal ions and their complexes have been known to mimic the action of insulin in in vitro and in vivo systems. We prepared a family of Zn(II) complexes derived from amino ligands with Zn(Nn) (n=3 and 4) coordination modes, the insulinomimetic activity being estimated by an inhibitory effect of free fatty acid release from isolated rat adipocytes treated with epinephrine. In comparison with the positive controls VOSO(4) and ZnSO(4), Zn(II)-amine complexes with stability constants (log beta) lower than 11.5 exhibited higher insulinomimetic activities. Among them, a bis(2-aminomethyl pyridinato)Zn(II) (Zn(2-ampy)(2)(2+)) complex with the highest insulinomimetic activity and a higher stability constant but lower than 11.5 was selected, and subjected to in vivo evaluation in KK-A(y) mice with a genetically type 2 diabetes mellitus. The high blood glucose level of the mice was lowered by daily intraperitoneal injections of Zn(2-ampy)(2)(2+) at a dose of 2 mg Zn/kg body weight for 14 days. Based on the results, Zn(2-ampy)(2)(2+) with Zn(N(4)) coordination mode was proposed to have both a high in vitro insulinomimetic activity and an in vivo blood glucose lowering effect.

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)(2), exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)(2) as the leading compound, we examined the in vitro and in vivo structure-activity relationships of Zn(ma)(2) and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)(2), exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (log P) of the ligand, indicating that the activity of Zn(ma)(2)-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)(2) and Zn(ma)(2) were then compared, and both complexes were found to normalize hyperglycemia in KK- A(y) mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)(2) improved glucose tolerance in KK- A(y) mice much more than did Zn(ma)(2), indicating that Zn(alx)(2) possesses greater in vivo anti-diabetic activity than Zn(ma)(2). In addition, Zn(alx)(2) improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK- A(y) mice. On the basis of these observations, we conclude that the Zn(alx)(2) complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.

Zinc (Zn), an essential trace element, and its complexes have recently been known to exhibit insulinomimetic activities. However, the action mechanism of Zn(II) has yet been obscure. The purpose of the present study was to estimate the action mechanism of the Zn(II) complexes. We found first that Zn given in the chemical forms such as Zn(maltolate)2 and Zn(threoninate)2 complexes is highly uptaken in the isolated rat adipocytes compared with that of Zn(picolinate)2. Then, the action mechanism for the insulinomimetic activities was examined in terms of free fatty acid release from the adipocytes. Four Zn(II) compounds, ZnSO4, Zn(picolinate)2, Zn(maltolate)2, and Zn(threoninate)2, inhibited the free fatty acid release from the adipocytes treated with epinephrine (adrenaline). By using several inhibitors for fatty acids and glucose metabolisms in the adipocytes, the following results were obtained. (1) Zn(picolinic acid)2 complex acts on the insulin receptor and PI3-k, which relate to the glucose uptake, as indicated by the experiments using hydroxy-2-naphthalenylmethyl phosphonic acid tris acetoxy methyl ester (HNMPA-(AM)3) and wortmannin, respectively. (2) ZnSO4, and Zn(maltolate)2 and Zn(threoninate)2 complexes affect a glucose transporter 4 (GLUT 4), which is involved in the glucose uptake as indicated by the results using cytochalasin B. (3) Four Zn(II) compounds affect the activation of the phosphodiesterase as indicated by the experiments using cilostamide. These results indicate that the Zn(II) compounds promote the glucose uptake into the adipocytes by affecting at least three sites in the adipocytes, which in turn normalize the blood glucose levels in the experimental diabetic animals., (Copyright 2004 Elsevier Inc.)

Following the finding of in vitro insulinominetic activities of new prepared Zn(II) complexes with amide ligands (2-picolinamide (pa-a) and 6-methyl-2-picolinmethylamide (6mpa-ma)) in isolated rat adipocytes treated with epinephrine in terms of inhibition of free fatty acid release, their blood glucose normalizing effects were observed on daily intraperitoneal injections for 14 d in a type 2 diabetes mellitus model animal, KK-Ay mice. The blood glucose levels of KK-Ay mice were maintained in a normal range during the administration of both complexes. After the administration of each complex for 14 d, the improvement of glucose metabolism was confirmed as judged by the glucose tolerance test.

Zinc(II) complexes of alpha-amino acids and their derivatives with a Zn(N2O2) coordination mode were found to have in vitro insulinomimetic activity as estimated with the inhibition of free fatty acid release in isolated rat adipocytes treated with epinephrine. It was revealed that the insulinomimetic activities of zinc(II) complexes with over-all stability constants (log beta) less than 10.5 are higher than those of ZnSO4 and VOSO4. The high blood glucose level of KK-Ay mice with type 2 diabetes mellitus was lowered by daily intraperitoneal injections of a zinc(II) complex, cis-[Zn(L-Thr)2(H2O)2], for 14 d. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.

High blood glucose levels of KK-A(y) mice with type 2 diabetes mellitus were normalized by daily intraperitoneal (ip) administration of a zinc(II) complex, bis(maltolato)zinc(II) (Zn(Mal)(2)) with a Zn(O(4)) coordination mode, following the finding of strong in vitro insulinomimetic activity in isolated rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. The blood glucose level was maintained in the normal range during administration of the Zn(Mal)(2) complex for 14 days and improvements in the glucose tolerance were confirmed by an oral glucose tolerance test., (Copyright 2001 Academic Press.)