bis(maltolato)oxovanadium(iv) and Diabetes-Mellitus--Type-2

3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for diabetes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transferrin for systemic circulation and transport to tissues, with preferential uptake in bone. These bis-ligand oxovanadium(IV) (VOL(2)) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-diabetic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal limits. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Organometallic Compounds; Pyrones; Vanadates

Vanadyl sulfate (VOSO(4)) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks at a dose of 25, 50, or 100 mg vanadium (V) daily [Goldfine et al., Metabolism 49 (2000) 1-12]. Elemental V was determined by graphite furnace atomic absorption spectrometry (GFAAS). There was no correlation of V in serum with clinical response, determined by reduction of mean fasting blood glucose or increased insulin sensitivity during euglycemic clamp. To investigate the effect of administering a coordinated V, plasma glucose levels were determined in streptozotocin (STZ)-induced diabetic rats treated with the salt (VOSO(4)) or the coordinated V compound bis(maltolato)oxovandium(IV) (abbreviated as VO(malto)(2)) administered by intraperitoneal (i.p.) injection. There was no relationship of blood V concentration with plasma glucose levels in the animals treated with VOSO(4), similar to our human diabetic patients. However, with VO(malto)(2) treatment, animals with low plasma glucose tended to have high blood V. To determine if V binding to serum proteins could diminish biologically active serum V, binding of both VOSO(4) and VO(malto)(2) to human serum albumin (HSA), human apoTransferrin (apoHTf) and pig immunoglobulin (IgG) was studied with EPR spectroscopy. Both VOSO(4) and VO(malto)(2) bound to HSA and apoHTf forming different V-protein complexes, while neither V compound bound to the IgG. VOSO(4) and VO(malto)(2) showed differences when levels of plasma glucose and blood V in diabetic rodents were compared, and in the formation of V-protein complexes with abundant serum proteins. These data suggest that binding of V compounds to ligands in blood, such as proteins, may affect the available pool of V for biological effects.

Topics: Animals; Apoproteins; Biological Availability; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Electron Spin Resonance Spectroscopy; Fasting; Humans; Hypoglycemic Agents; Immunoglobulin G; Male; Pyrones; Rats; Rats, Wistar; Serum Albumin; Streptozocin; Transferrin; Treatment Outcome; Vanadates; Vanadium; Vanadium Compounds

Diabetes is associated with impairment of angiogenesis such as reduction of myocardial capillary formation. Our previous studies demonstrate that disruption of Angiopoietin-1 (Ang-1)/Tie-2 signaling pathway contributes to the diabetes-associated impairment of angiogenesis. Protein tyrosine phosphatase (PTP) has a critical role in the regulation of insulin signal by inhibition of tyrosine kinase phosphorylation. In present study, we examined the role of protein tyrosine phosphatase-1 (SHP-1) in diabetes-associated impairment of Ang-1/Tie-2 angiogenic signaling and angiogenesis. SHP-1 expression was significantly increased in diabetic db/db mouse hearts. Furthermore, SHP-1 bond to Tie-2 receptor and stimulation with Ang-1 led to SHP-1 dissociation from Tie-2 in mouse heart microvascular endothelial cell (MHMEC). Exposure of MHMEC to high glucose (HG, 30 mmol/L) increased SHP-1/Tie-2 association accompanied by a significant reduction of Tie-2 phosphorylation. Exposure of MHMEC to HG also blunted Ang-1-mediated SHP-1/Tie-2 dissociation. Knockdown of SHP-1 significantly attenuated HG-induced caspase-3 activation and apoptosis in MHMEC. Treatment with PTP inhibitors restored Ang-1-induced Akt/eNOS phosphorylation and angiogenesis. Our data implicate a critical role of SHP-1 in diabetes-associated vascular complications, and that upregulation of Ang-1/Tie-2 signaling by targeting SHP-1 should be considered as a new therapeutic strategy for the treatment of diabetes-associated impairment of angiogenesis.

Topics: Angiopoietin-1; Animals; Apoptosis; Caspase 3; Cell Line; Cells, Cultured; Diabetes Mellitus, Type 2; Endothelial Cells; Heart; Mice; Myocardium; Neovascularization, Physiologic; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyrones; Receptor, TIE-2; Signal Transduction; Vanadates

Topics: Adult; Animals; Body Weight; Child; Diabetes Mellitus, Type 2; Eating; Humans; Insulin; Protein Tyrosine Phosphatases; Pyrones; Receptor, Insulin; Signal Transduction; Vanadates

The molecular basis of insulin resistance, a major risk factor for development of Type II diabetes, involves defective insulin signaling. Insulin-mediated signal transduction is negatively regulated by the phosphotyrosine phosphatase, PTP1B, and numerous studies have demonstrated that organo-vanadium compounds, which are nonselective phosphotyrosine phosphatase inhibitors, have insulin-mimetic properties. However, whether or not vanadium compounds can prevent the transition from insulin resistance to overt diabetes is unknown. We compared the ability of bis(maltolato)oxovanadium(IV) (BMOV), an orally bioavailable organo-vanadium compound, and rosiglitazone maleate (RSG), a known insulin sensitizer, to prevent development of diabetes in Zucker diabetic fatty (ZDF) rats. Treatment began at 6 weeks of age when animals are insulin resistant and hyperinsulinemic, but not yet hyperglycemic, and ended at 12 weeks of age, which is 4 weeks after ZDF rats typically develop overt diabetes. BMOV-treated ZDF rats did not develop hyperglycemia, showed significant improvement in insulin sensitivity, and retained normal pancreatic islet morphology and endocrine cell distribution, similar to RSG-treated animals. BMOV and RSG treatment also prevented the hyper-phagia and polydipsia present in untreated ZDF rats; however, BMOV-treated ZDF rats gained much less weight than did RSG-treated animals. Circulating levels of adiponectin decreased in untreated ZDF rats compared to lean controls, but these levels remained normal in BMOV-treated ZDF rats. In contrast, in RSG-treated ZDF rats, plasma adiponectin levels were nearly 4-fold higher than in lean control rats, primarily as a result of a large increase in the amount of low-molecular weight forms of adiponectin in circulation. These data demonstrate that phosphatase inhibition offers a new approach to diabetes prevention, one that may have advantages over current approaches.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose Tolerance Test; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Obesity; Pancreas; Protein Tyrosine Phosphatases; Pyrones; Rats; Rats, Zucker; Time Factors; Vanadates

The PI-3 kinase signalling pathway is an important pathway in mediating the glucoregulatory effects of insulin and skeletal muscle (SKM) is the major tissue involved in glucose utilization. In diabetes this pathway is impaired, either due to lack of insulin as in Type I diabetes, or due to insulin resistance as in Type 2 diabetes. Bis(maltolato)-oxovanadium IV (BMOV), an insulin mimetic/enhancing agent, produces a marked glucose lowering effect in models of both types of diabetes. Some in vitro studies have shown that phosphatidylinositol 3 kinase (PI-3 kinase) activity is enhanced by vanadium. In the present study we looked at changes in PI-3 kinase expression and activity in SKM from STZ-diabetic and fa/fa Zucker rats treated with BMOV for 3 weeks. Although BMOV treatment completely normalized glucose levels in STZ-diabetic rats, no effect was observed on basal or insulin-stimulated PI-3 kinase activity. In fatty Zucker rats, activation of PI-3 kinase activity after insulin injection was impaired as compared to age matched lean controls, but BMOV again did not affect the activity. These results suggest that although PI-3 kinase is an important signalling factor in glucose utilization, vanadium treatment does not reduce hyperglycemia through activation of SKM PI-3 kinase in vivo.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Insulin; Male; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Pyrones; Rats; Rats, Wistar; Rats, Zucker; Signal Transduction; Vanadates

In this study, the in vivo effects of insulin and chronic treatment with bis(maltolato)oxovanadium (IV) (BMOV) on protein kinase B (PKB) activity were examined in the liver and skeletal muscle from two animal models of diabetes, the STZ-diabetic Wistar rat and the fatty Zucker rat. Animals were treated with BMOV in the drinking water (0.75-1 mg/ml) for 3 (or 8) weeks and sacrificed with or without insulin injection. Insulin (5 U/kg, i.v.) increased PKBalpha activity more than 10-fold and PKBbeta activity more than 3-fold in both animal models. Despite the development of insulin resistance, insulin-induced activation of PKBalpha was not impaired in the STZ-diabetic rats up to 9 weeks of diabetes, excluding a role for PKBalpha in the development of insulin resistance in type 1 diabetes. Insulin-induced PKBalpha activity was markedly reduced in the skeletal muscle of fatty Zucker rats as compared to lean littermates (fatty: 7-fold vs. lean: 14-fold). In contrast, a significant increase in insulin-stimulated PKBalpha activity was observed in the liver of fatty Zucker rats (fatty: 15.7-fold vs. lean: 7.6-fold). Chronic treatment with BMOV normalized plasma glucose levels in STZ-diabetic rats and decreased plasma insulin levels in fatty Zucker rats but did not have any effect on basal or insulin-induced PKBalpha and PKBbeta activities. In conclusion (i) in STZ-diabetic rats PKB activity was normal up to 9 weeks of diabetes; (ii) in fatty Zucker rats insulin-induced activation of PKBalpha (but not PKBbeta) was markedly altered in both tissues; (iii) changes in PKBalpha activity were tissue specific; (iv) the glucoregulatory effects of BMOV were independent of PKB activity.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Insulin; Liver; Male; Muscle, Skeletal; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyrones; Random Allocation; Rats; Rats, Wistar; Rats, Zucker; Tissue Extracts; Vanadates

Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) (BMOV) was studied in streptozotocin (STZ)-induced neonatal non-insulin-dependent-diabetic (NIDDM) rats. Intraperitoneal injection of STZ (90 mg kg(-1)) in Wistar rat pups (day 2 old) produced mild hyperglycemia, impaired glucose tolerance and insulin resistance at the age of 3 months. Treatment with BMOV (0.23 mM kg(-1)) in drinking water for 6 weeks produced a significant decrease in elevated serum glucose levels without any significant change in serum insulin levels in diabetic rats. BMOV treatment significantly decreased integrated area under the glucose curve without any significant change in integrated area under the insulin curve indicating improved glucose tolerance. Treatment also significantly increased K(ITT) value of diabetic rats indicating increased insulin sensitivity. BMOV treatment significantly reduced hypercholesterolemia in diabetic rats. Treatment also significantly decreased serum triglyceride levels in both diabetic and non-diabetic rats. The data suggest that chronic BMOV treatment improves glucose and lipid homeostasis. These effects appear to be due to the insulin sensitizing action of vanadium.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Hypercholesterolemia; Hypoglycemic Agents; Insulin; Male; Pyrones; Rats; Rats, Wistar; Vanadates