The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Nazma Zaheer Baquer - One of the best experts on this subject based on the ideXlab platform.
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Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na_3VO_4 and Trigonella—a promising Antidiabetic Agent
Molecular and Cellular Biochemistry, 2005Co-Authors: Anju Preet, Bihari L. Gupta, Mohamed R. Siddiqui, Pramod K. Yadava, Nazma Zaheer BaquerAbstract:Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo . Vanadium compound, sodium orthovanadate, Na_3VO_4, is well known for its hypoglycaemic effects. However, Na_3VO_4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na_3VO_4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic Agent, to reduce its toxicity without compromising its Antidiabetic potential. The efficacy of the lower doses of Na_3VO_4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na_3VO_4. Results suggest that lower doses of Na_3VO_4 may be used in combination with TSP as an efficient Antidiabetic Agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.
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restoration of ultrastructural and biochemical changes in alloxan induced diabetic rat sciatic nerve on treatment with na3vo4 and trigonella a promising Antidiabetic Agent
Molecular and Cellular Biochemistry, 2005Co-Authors: Anju Preet, Bihari L. Gupta, Mohamed R. Siddiqui, Pramod K. Yadava, Nazma Zaheer BaquerAbstract:Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic Agent, to reduce its toxicity without compromising its Antidiabetic potential. The efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient Antidiabetic Agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.
Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic stereoselectivity of troglitazone an Antidiabetic Agent in the kk mouse
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Takashi Izumi, S. Enomoto, K. Hoshiyama, Kunihiro Sasahara, Yuichi SugiyamaAbstract:Troglitazone, an oral Antidiabetic Agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 °C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1·3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2·5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. ©1997 by John Wiley & Sons, Ltd.
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pharmacokinetics of troglitazone an Antidiabetic Agent prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Takashi Izumi, Kunihiro Sasahara, Kazuko Hosiyama, Sachiko Enomoto, Yuichi SugiyamaAbstract:Sulfation and glucuronidation, the major routes of metabolism of troglitazone, an Antidiabetic Agent, were examined in vitro using hepatic cytosol and microsomes prepared from KK mice, an animal model of non-insulin-dependent diabetes mellitus. Stereoselectivity was observed for both conjugation reactions, and the metabolic intrinsic clearance of glucuronidation was about 3- to 100-fold higher than that of sulfation for each stereoisomer. In addition, the metabolic intrinsic clearance of glucuronidation exhibited an 8-fold difference among stereoisomers. The predicted metabolic clearance for each stereoisomer, calculated from the in vitro data based on a dispersion model, was comparable to the measured metabolic clearance in vivo , ranging from 27 to 93%. We also attempted to predict the in vivo metabolic clearance from in vitro metabolism data, to investigate species differences in the stereoselectivity of the conjugation reactions in normal animals, i.e., ddY mice and rats. For ddY mice the in vivo hepatic glucuronidation clearance was 170-fold higher than the corresponding sulfation clearance, whereas for rats the sulfation clearance was 6-fold higher than the glucuronidation clearance. The hepatic sulfation clearance in mice and rats predicted from in vitro metabolism data was 5.3- and 1.1-fold higher, respectively, than that in vivo, calculated from the plasma disposition of parent drug and biliary excretion of metabolites. For glucuronidation, the predicted values in mice and rats were 1.0- and 0.33-fold higher, respectively. These results suggest that semiquantitative extrapolation of in vitro stereoselective metabolism of troglitazone, by conjugation, to the in vivo situation is possible.
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Pharmacokinetic stereoselectivity of troglitazone, an Antidiabetic Agent, in the KK mouse.
Biopharmaceutics & drug disposition, 1997Co-Authors: Takashi Izumi, S. Enomoto, K. Hoshiyama, Kunihiro Sasahara, Yuichi SugiyamaAbstract:Troglitazone, an oral Antidiabetic Agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 degrees C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1.3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2.5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low.
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prediction of the human pharmacokinetics of troglitazone a new and extensively metabolized Antidiabetic Agent after oral administration with an animal scale up approach
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Takashi Izumi, S. Enomoto, Kunihiro Sasahara, K Hosiyama, A Shibukawa, Takayuki Nakagawa, Yuichi SugiyamaAbstract:We have attempted to predict the human pharmacokinetics of troglitazone after oral administration based on animal data. Troglitazone is a new Antidiabetic Agent that exhibits a high-metabolic clearance and is metabolized mainly in the liver to sulfate and glucuronide conjugates. The prediction of the area under the plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans after oral administration was initially attempted by use of allometric equations involving the oral plasma clearance of total (CLp.o.) or unbound drug (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and animal body weight. The exponents in the allometric equations between the clearances and body weights were 0.63 to 0.82 with high correlation coefficients (r > .98), and there was no marked difference in predictability by the three methods. Next, the prediction of the range of plasma profiles after oral administration to humans was attempted by the following series of steps: (1) calculation of the exponent and coefficients in the allometric relationships between body weight and parameters, such as total body plasma clearance (CLi.v.) and various distribution volumes (Vss, V beta and Vc) based on animal data; (2) estimation of the absorption rate constant (ka) from allometric relationship to body weight, and estimation of F value from the predicted AUCp.o. (3) description of the plasma concentration-time profiles after oral administration by an equation involving the allometric exponents and coefficients, ka, F and body weight. The observed and simulated plasma profiles were similar and the predicted AUCp.o. values were 60 to 120% of those observed. These methodologies will be useful for predicting the human pharmacokinetics after oral dosing from animal data.
Anju Preet - One of the best experts on this subject based on the ideXlab platform.
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Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na_3VO_4 and Trigonella—a promising Antidiabetic Agent
Molecular and Cellular Biochemistry, 2005Co-Authors: Anju Preet, Bihari L. Gupta, Mohamed R. Siddiqui, Pramod K. Yadava, Nazma Zaheer BaquerAbstract:Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo . Vanadium compound, sodium orthovanadate, Na_3VO_4, is well known for its hypoglycaemic effects. However, Na_3VO_4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na_3VO_4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic Agent, to reduce its toxicity without compromising its Antidiabetic potential. The efficacy of the lower doses of Na_3VO_4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na_3VO_4. Results suggest that lower doses of Na_3VO_4 may be used in combination with TSP as an efficient Antidiabetic Agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.
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restoration of ultrastructural and biochemical changes in alloxan induced diabetic rat sciatic nerve on treatment with na3vo4 and trigonella a promising Antidiabetic Agent
Molecular and Cellular Biochemistry, 2005Co-Authors: Anju Preet, Bihari L. Gupta, Mohamed R. Siddiqui, Pramod K. Yadava, Nazma Zaheer BaquerAbstract:Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic Agent, to reduce its toxicity without compromising its Antidiabetic potential. The efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient Antidiabetic Agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.
Takashi Izumi - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic stereoselectivity of troglitazone an Antidiabetic Agent in the kk mouse
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Takashi Izumi, S. Enomoto, K. Hoshiyama, Kunihiro Sasahara, Yuichi SugiyamaAbstract:Troglitazone, an oral Antidiabetic Agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 °C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1·3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2·5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low. ©1997 by John Wiley & Sons, Ltd.
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pharmacokinetics of troglitazone an Antidiabetic Agent prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Takashi Izumi, Kunihiro Sasahara, Kazuko Hosiyama, Sachiko Enomoto, Yuichi SugiyamaAbstract:Sulfation and glucuronidation, the major routes of metabolism of troglitazone, an Antidiabetic Agent, were examined in vitro using hepatic cytosol and microsomes prepared from KK mice, an animal model of non-insulin-dependent diabetes mellitus. Stereoselectivity was observed for both conjugation reactions, and the metabolic intrinsic clearance of glucuronidation was about 3- to 100-fold higher than that of sulfation for each stereoisomer. In addition, the metabolic intrinsic clearance of glucuronidation exhibited an 8-fold difference among stereoisomers. The predicted metabolic clearance for each stereoisomer, calculated from the in vitro data based on a dispersion model, was comparable to the measured metabolic clearance in vivo , ranging from 27 to 93%. We also attempted to predict the in vivo metabolic clearance from in vitro metabolism data, to investigate species differences in the stereoselectivity of the conjugation reactions in normal animals, i.e., ddY mice and rats. For ddY mice the in vivo hepatic glucuronidation clearance was 170-fold higher than the corresponding sulfation clearance, whereas for rats the sulfation clearance was 6-fold higher than the glucuronidation clearance. The hepatic sulfation clearance in mice and rats predicted from in vitro metabolism data was 5.3- and 1.1-fold higher, respectively, than that in vivo, calculated from the plasma disposition of parent drug and biliary excretion of metabolites. For glucuronidation, the predicted values in mice and rats were 1.0- and 0.33-fold higher, respectively. These results suggest that semiquantitative extrapolation of in vitro stereoselective metabolism of troglitazone, by conjugation, to the in vivo situation is possible.
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Pharmacokinetic stereoselectivity of troglitazone, an Antidiabetic Agent, in the KK mouse.
Biopharmaceutics & drug disposition, 1997Co-Authors: Takashi Izumi, S. Enomoto, K. Hoshiyama, Kunihiro Sasahara, Yuichi SugiyamaAbstract:Troglitazone, an oral Antidiabetic Agent, is an equal mixture of four stereoisomers involving two asymmetric centres. In the present study, the stereoselectivity of in vitro epimerization in plasma and organ homogenate and in vivo plasma disposition in the KK mouse, an animal model of non-insulin-dependent diabetes, was examined. In the incubation experiments at 37 degrees C, there was a fivefold to eightfold acceleration of epimerization at the 5 position of the thiazolidine ring in KK mouse plasma compared with that in buffer. However, no inversion at the 2 position of the chroman ring was observed. In addition, there was an approximately 1.3-fold difference in the epimerization rates among stereoisomers at the 2 position of the chroman ring. However, there were no differences in the values of the equilibrium constants of epimerization, and the ratio of epimerization among stereoisomers at the 5 position of thiazolidine ring was almost unity. The acceleration of epimerization is thought to be due to the high degree of protein binding because of the relationship between the initial epimerization rate and the dilution ratio of the plasma. Although acceleration of epimerization was also observed in the 20% homogenates of liver, kidney, and intestine of the KK mouse, the degree of stereoselectivity was lower than in plasma. The analysis of the plasma disposition after intravenous administration of troglitazone stereoisomers, using a kinetic model, indicated that the metabolic clearance in the liver showed a 2.5-fold maximum difference among stereoisomers and that the stereoselectivity of epimerization was low.
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prediction of the human pharmacokinetics of troglitazone a new and extensively metabolized Antidiabetic Agent after oral administration with an animal scale up approach
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: Takashi Izumi, S. Enomoto, Kunihiro Sasahara, K Hosiyama, A Shibukawa, Takayuki Nakagawa, Yuichi SugiyamaAbstract:We have attempted to predict the human pharmacokinetics of troglitazone after oral administration based on animal data. Troglitazone is a new Antidiabetic Agent that exhibits a high-metabolic clearance and is metabolized mainly in the liver to sulfate and glucuronide conjugates. The prediction of the area under the plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans after oral administration was initially attempted by use of allometric equations involving the oral plasma clearance of total (CLp.o.) or unbound drug (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and animal body weight. The exponents in the allometric equations between the clearances and body weights were 0.63 to 0.82 with high correlation coefficients (r > .98), and there was no marked difference in predictability by the three methods. Next, the prediction of the range of plasma profiles after oral administration to humans was attempted by the following series of steps: (1) calculation of the exponent and coefficients in the allometric relationships between body weight and parameters, such as total body plasma clearance (CLi.v.) and various distribution volumes (Vss, V beta and Vc) based on animal data; (2) estimation of the absorption rate constant (ka) from allometric relationship to body weight, and estimation of F value from the predicted AUCp.o. (3) description of the plasma concentration-time profiles after oral administration by an equation involving the allometric exponents and coefficients, ka, F and body weight. The observed and simulated plasma profiles were similar and the predicted AUCp.o. values were 60 to 120% of those observed. These methodologies will be useful for predicting the human pharmacokinetics after oral dosing from animal data.
Ramon Gomis - One of the best experts on this subject based on the ideXlab platform.
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Functional regeneration of pancreatic β-cell population by tungstate treatment: pancreatic β-cell functional regeneration by tungstate
International Journal of Clinical Practice, 2004Co-Authors: A. Barberà, Ramon GomisAbstract:Summary Sodium tungstate is an effective Antidiabetic Agent. Oral administration of sodium tungstate normalised glycaemia and increased insulinaemia in neonatal streptozotocin rats that displayed symptoms mimicking symptoms associated with diabetes. Tungstate treatment increases extra-islet β-cell replication without modifying intraislet β-cell replication rates. Moreover, the treatment induces an increase in insulin-positive cells located close to ducts, as well as PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. Remarkably, after tungstate withdrawal, animals remained normoglycaemic.
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the Antidiabetic Agent sodium tungstate activates glycogen synthesis through an insulin receptor independent pathway
Journal of Biological Chemistry, 2003Co-Authors: Jorge Dominguez, Ma Carmen Munoz, Delia Zafra, Isabel Sanchezperez, Susanna Baque, Martine Caron, Ciro Mercurio, Albert Barbera, Rosario Perona, Ramon GomisAbstract:Abstract Sodium tungstate is a powerful Antidiabetic Agent when administered orally. In primary cultured hepatocytes, tungstate showed insulin-like actions, which led to an increase in glycogen synthesis and accumulation. However, this compound did not significantly alter the insulin receptor activation state or dephosphorylation rate in cultured cells (CHO-R) or in primary hepatocytes, in either short or long term treatments. In contrast, at low concentrations, tungstate induced a transient strong activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) after 5–10 min of treatment, in a similar way to insulin. Moreover, this compound did not significantly delay or inhibit the dephosphorylation of ERK1/2. ERK1/2 activation triggered a cascade of downstream events, which included the phosphorylation of p90rsk and glycogen synthase-kinase 3β. Experiments with a specific inhibitor of ERK1/2 activation and kinase assays indicate that these proteins were directly involved in the stimulation of glycogen synthase and glycogen synthesis induced by tungstate without a direct involvement of protein kinase B (PKB/Akt). These results show a direct involvement of ERK1/2 in the mechanism of action of tungstate at the hepatic level.
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effects of tungstate a new potential oral Antidiabetic Agent in zucker diabetic fatty rats
Diabetes, 2001Co-Authors: Maria Munoz, Ramon Gomis, A. Barberà, Jorge Dominguez, Josefa Fernandezalvarez, Joan J GuinovartAbstract:Tungstate was orally administered to 7.5-week-old male Zucker diabetic fatty (ZDF) rats that already showed moderate hyperglycemia (180 ± 16 mg/dl). The animals became normoglycemic for ∼10 days. Then, glycemia started to rise again, although it did not reach the initial values until day 24, when levels stabilized at ∼200 mg/dl for the duration of the experiment. Untreated ZDF rats showed steadily increased blood glucose levels between 7.5 and 10 weeks of age, when they reached a maximum value of 450 ± 19 mg/dl, which was maintained throughout the experiment. In addition, tolerance to intraperitoneal glucose load improved in treated diabetic rats. Serum levels of triglycerides were elevated in untreated diabetic rats compared with their lean counterparts (ZLC). In the liver of diabetic animals, glucokinase (GK), glycogen phosphorylase a (GPa), liverpyruvate kinase (L-PK), and fatty acid synthase (FAS) activities decreased by 81, 30, 54, and 35%, respectively, whereas phosphoenolpyruvate carboxykinase (PEPCK) levels increased by 240%. Intracellular glucose-6-phosphate (G6P) decreased by 40%, whereas glycogen levels remained unaffected. Tungstate treatment of these rats induced a 42% decrease in serum levels of triglycerides and normalized hepatic G6P concentrations, GPa activity, and PEPCK levels. GK activity in treated diabetic rats increased to 50% of the values of untreated ZLC rats. L-PK and FAS activity increased to higher values than those in untreated lean rats (1.7-fold L-PK and 2.4-fold FAS). Hepatic glycogen levels were 55% higher than those in untreated diabetic and healthy rats. Tungstate treatment did not significantly change the phosphotyrosine protein profile of primary cultured hepatocytes from diabetic animals. These data suggest that tungstate administration to ZDF rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabolism and a decrease in lipotoxicity.