bis(maltolato)oxovanadium(iv) and Obesity

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 insulin signalling pathway consists of a series of phosphorylation and dephosphorylation steps inside the target cell. Phosphotyrosine phosphatase 1B (PTP1B) dephosphorylates phosphotyrosine (pTyr) residues present on the insulin receptor (IR). In this study we examined the effect of bis(maltolato)oxovanadium(IV) (BMOV) on PTP1B and its possible role in the amelioration of insulin resistance. Fourteen to sixteen week old fatty Zucker rats (F), an animal model of insulin resistance, were treated with BMOV in drinking water for 3 weeks (FT) along with age matched lean littermate controls. The fatty rats responded to vanadium with a significant decrease in plasma insulin, (F = 5.1+/-0.8 FT = 3.3+/-0.7 ng/ml). During insulin resistance the activity of PTP1B has been shown to increase, thus diminishing insulin signalling in the target tissues. Hence, PTP1B is an important target for anti-diabetic drug research. In our investigation we found that the PTP1B activity was increased to 200% in the skeletal muscle of untreated Zucker fatty rats compared to lean littermates. Three weeks of BMOV treatment reduced the activity of PTP1B by 25% in fatty treated rats, in vivo, compared to untreated fatty rats. There was no significant change in the activity of PTP1B in the lean treated rats. There was also no difference in the gene expression of PTP1B in the skeletal muscle of different groups of rats. Vanadium compounds also inhibited PTP1B in vitro. These results indicate that PTP1B may be a potential target for the action of BMOV at least in the Zucker fatty rat model.

Topics: Animals; Blood Glucose; Body Weight; Enzyme Inhibitors; Insulin; Male; Muscle, Skeletal; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Pyrones; Rats; Rats, Zucker; Vanadates

Vanadium, a potent nonselective inhibitor of protein tyrosine phosphatases, has been shown to mimic many of the metabolic actions of insulin both in vivo and in vitro. The mechanism(s) of the effect of vanadium on the decrease in appetite and body weight in Zucker fa/fa rats, an insulin-resistant model, is still unclear. Because insulin may inhibit hypothalamic neuropeptide Y (NPY), which is known to be related to appetite, and increase leptin secretion in adipose tissue, we studied the possibility that the changes in appetite produced by vanadium may be linked to altered NPY levels in the hypothalamus. We also examined effects of vanadium on leptin. Zucker lean and fatty rats were chronically treated with bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, in the drinking water. Plasma and adipose tissue leptin levels were measured by radioimmunoassay and immunoblotting, respectively. Hypothalamic NPY mRNA and peptide levels were measured using in situ hybridization and immunocytochemistry, respectively. BMOV treatment significantly reduced food intake, body fat, body weight, plasma insulin levels, and glucose levels in fatty Zucker rats. Fifteen minutes after insulin injection (5 U/kg, intravenous [IV]), circulating leptin levels (+100%) and adipose leptin levels (+60%) were elevated in BMOV-treated fatty rats, although these effects were not observed in untreated fatty rats. NPY mRNA levels in the arcuate nucleus (ARC) (-29%), NPY peptide levels in ARC (-31%), as well as in the paraventricular nucleus (PVN) (-37%) were decreased with BMOV treatment in these fatty rats. These data indicate that BMOV may increase insulin sensitivity in adipose tissue and decrease appetite and body fat by decreasing NPY levels in the hypothalamus. BMOV-induced reduction in appetite and weight gain along with normalized insulin levels in models of obesity, suggest its possible use as a therapeutic agent in obesity.

Topics: Adipose Tissue; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Blood Glucose; Cell Nucleus; Disease Models, Animal; Hypoglycemic Agents; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Insulin; Leptin; Male; Neuropeptide Y; Obesity; Pyrones; Rats; Rats, Zucker; RNA, Messenger; Vanadates; Vanadium

This is a preliminary study in which both acute and chronic oral administration of bis(maltolato)oxovanadium (IV) (BMOV) was examined in the Zucker diabetic fatty (ZDF) rat, an animal model that develops overt hyperglycemia in the presence of hyperinsulinemia followed by beta-cell depletion. At 9-10 weeks of age, in the presence of hyperglycemia, hyperinsulinemia and hyperlipidemia, an acute oral gavage dose response was conducted to determine glucose-lowering properties of BMOV, time of response and effect of BMOV on plasma insulin levels. Doses of BMOV greater than 0.2 mmol/kg resulted in plasma glucose levels of less than 9 mmol/l. The highest dose administered (0.8 mmol/kg) significantly reduced plasma insulin (initial: 2.83+/-0.2, final: 1.23+/-0.09 nmol/l, P<0.05) and plasma triglyceride (initial: 4.94+/-0.33, final: 1.55+/-0.07 mmol/l, P<0.05) levels. At 15 weeks of age, in the presence of hyperglycemia, hyperlipidemia and normal insulin levels, BMOV was administered orally in the drinking water for a 10-week period to determine the effect of treatment on glucose, insulin and lipid levels. BMOV treatment significantly reduced plasma glucose levels (final BMOV-treated: 13.25+/-1.43, untreated: 28.71+/-0.6 mmol/l, P<0.05) and effectively preserved pancreatic beta-cell function. These data suggest a role for BMOV as a therapeutic agent in non-insulin-dependent diabetes mellitus through improvement in glucose homeostasis and preservation of insulin reserves.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus; Dose-Response Relationship, Drug; Hypoglycemic Agents; Insulin; Male; Obesity; Pyrones; Rats; Rats, Zucker; Time Factors; Triglycerides; Vanadates