bis(maltolato)oxovanadium(iv) and Body-Weight

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

The aim of this study was to determine if there was a synergistic or additive effect of a thiazolidinedione derivative (rosiglitazone (ROS)) and a vanadium compound (bis(ethylmaltolato)oxovanadium(IV) (BEOV)) on plasma glucose and insulin levels following chronic oral administration to Zucker diabetic fatty (ZDF) rats. Whole-blood vanadium levels were determined at time 0 and at days 1, 6, and 18. The doses of BEOV (0.1 mmol/kg) and ROS (2.8 micromol/kg) were selected to produce a glucose-lowering effect in 30% (ED30) of animals. Both drugs were administered daily by oral gavage as suspensions in 1% carboxymethylcellulose (CMC) in a volume of 2.5 mL/kg. The total volume administered to all rats was 5 mL/(kg.day). The combination of BEOV and ROS was effective in lowering plasma glucose levels to <9 mmol/L in 60% of fatty animals as compared with 30% for BEOV and 10% for ROS alone. The age-dependent decrease in plasma insulin levels associated with beta-cell failure in the ZDF rats did not occur in the BEOV-treated fatty groups. There was no effect of any treatment on body weight; however, there was a significant reduction in both food and fluid intake in fatty groups treated with BEOV. There were no overt signs of toxicity and no mortality in this study. Both BEOV and ROS were effective in lowering plasma glucose levels, as stated above, and there was at least an additive effect when BEOV and ROS were used in combination.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Drug Administration Schedule; Drug Therapy, Combination; Insulin; Intubation, Gastrointestinal; Male; Pyrones; Rats; Rats, Zucker; Rosiglitazone; Thiazolidinediones; 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 treatment, in vivo, corrects the severe hyperglycemia observed in streptozotocin (STZ)-diabetic rats. A number of metabolic effects of vanadium have been demonstrated in vitro and might contribute importantly to normalization of glucose homeostasis. However, many in vitro effects of vanadium occur at concentrations substantially higher than those achieved in vivo. Effects of vanadium on white adipose tissue have been particularly well characterized in vitro. To examine the relationship between in vitro and in vivo actions of vanadium, we examined the effects of vanadium treatment on acute glucose tolerance and adipose tissue GLUT4 control in vivo. In agreement with previous studies, vanadium treatment of STZ-diabetic rats restored normoglycemia with no appreciable restoration of insulin secretion. GLUT4 expression in white adipose tissue was reduced by 22% in STZ-diabetic rats compared with controls. Vanadium treatment did not significantly alter GLUT4 expression in controls, but completely restored normal expression levels in STZ-diabetic rats. In overnight-fasted control animals, GLUT4 translocation to the plasma membrane (PM) was maximally elevated (by 50%) in adipose tissue within 5 to 10 minutes after an intravenous (IV) glucose challenge. No glucose-induced translocation of GLUT4 was detected in diabetic rats, and peak PM GLUT4 content was 40% lower than in controls. Vanadium treatment did not increase peak PM GLUT4 content in either control or diabetic animals in response to a glucose load. Finally, the suppression of whole-body acute glucose tolerance in diabetic animals was only partially normalized by vanadium treatment. We conclude: (1) that concentrations of vanadium effective for maintaining normoglycemia in vivo (typically below 30 micromol/L) promote normal GLUT4 expression, but do not influence the subcellular localization of GLUT4 in white adipose tissue and (2) that in vivo effects of vanadium may not necessarily reflect the actions observed in vitro at supraphysiologic concentrations.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Cell Membrane; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Pyrones; Rats; Rats, Wistar; Time Factors; Vanadates; Vanadium

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

1. Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non-ketotic, streptozotocin-diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3-ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied. 2. Oral administration of the three organic vanadium compounds (125 mg vanadium element 1(-1) in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly. 3. Activities and mRNA levels of key glycolytic enzymes (glucokinase and L-type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc. 4. VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin-like properties. 5. There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds. 6. In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin-like properties.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disinfectants; Glucokinase; Glucose; Hydroxybutyrates; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Islets of Langerhans; Ligands; Liver; Liver Glycogen; Male; Muscles; Organometallic Compounds; Pentanones; Phosphoenolpyruvate Carboxykinase (GTP); Pyrones; Pyruvate Kinase; Rats; Rats, Wistar; RNA, Messenger; Time Factors; Vanadates; Vanadium Compounds