Vanadate Induction of L-type Pyruvate Kinase mRNA in Adult Rat Hepatocytes in Primary Culture

Miralpeix, Montserrat; Decaux, Jean‐François; Kahn, Axel; Bartrons, Ramón

doi:10.2337/diab.40.4.462

Cited by 25 publications

(7 citation statements)

References 21 publications

(45 reference statements)

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“…In the liver of STZ‐induced diabetic rats, the levels of Fru‐2,6‐P 2 and 6‐phosphofructo‐2‐kinase activity decreased and the phosphorylation of the bifunctional enzyme increased, correlating with a fall in hepatic Fru‐2,6‐P 2 , ketonaemia and glycaemia [24–26]. Similar results have been reported in diabetic mouse liver, underscoring the role played by Fru‐2,6‐P 2 in the control of fuel metabolism [27].…”

Section: Introductionsupporting

confidence: 53%

Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals

et al. 2009

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The ubiquitous isoform of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (uPFK‐2), a product of the Pfkfb3 gene, plays a crucial role in the control of glycolytic flux. In this study, we demonstrate that Pfkfb3 gene expression is increased in streptozotocin‐induced diabetic mouse liver. The Pfkfb3/‐3566 promoter construct linked to the luciferase reporter gene was delivered to the liver via hydrodynamic gene transfer. This promoter was upregulated in streptozotocin‐induced diabetic mouse liver compared with transfected healthy cohorts. In addition, increases were observed in Pfkfb3 mRNA and uPFK‐2 protein levels, and intrahepatic fructose‐2,6‐bisphosphate concentration. During streptozotocin‐induced diabetes, phosphorylation of both p38 mitogen‐activated protein kinase and Akt was detected, together with the overexpression of the proliferative markers cyclin D and E2F. These findings indicate that uPFK‐2 induction is coupled to enhanced hepatocyte proliferation in streptozotocin‐induced diabetic mouse liver. Expression decreased when hepatocytes were treated with either rapamycin or LY 294002. This shows that uPFK‐2 regulation is phosphoinositide 3‐kinase–Akt–mammalian target of rapamycin dependent. These results indicate that fructose‐2,6‐bisphosphate is essential to the maintenance of the glycolytic flux necessary for providing energy and biosynthetic precursors to dividing cells.

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Section: Introductionsupporting

confidence: 53%

Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals

et al. 2009

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“…The corrective action of vanadium salts was attributed to the enhancement of glucose oxidation and metabolism through activation and/or induction of the reduced hepatic glycolytic enzymes together with suppression of the overexpressed gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase (PEPCK)18, 37–42. The activity and gene expression of a large group of insulin dependent enzymes was enhanced, e.g.…”

Section: Introductionmentioning

confidence: 99%

Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in thePsammomys obesus gerbil

Shafrir

Spielman

Nachliel

et al. 2001

Diabetes Metab. Res. Rev.

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The model utilized in our study was Psammomys obesus (sand rat), a desert gerbil which becomes hyperglycemic and hyperinsulinemic on an ad libitum high energy (HE) diet. In contrast to the previously investigated insulin deficient models, vanadyl sulphate was used to correct insulin resistance and hyperinsulinemia, which led to beta-cell loss. Administration of 5 mg/kg vanadyl sulfate for 5 days resulted in prolonged restoration of normoglycemia and normoinsulinemia in most animals, return of glucose tolerance to normal, and a reduction of hepatic phosphoenolpyruvate carboxykinase activity. There was no change in food consumption and in regular growth during or after the vanadyl treatment. Pretreatment with vanadyl sulfate, followed by transfer to a HE diet, significantly delayed the onset of hyperglycemia. Hyperinsulinemic-euglycemic clamp of vanadyl sulfate treated Psammomys demonstrated an improvement in glucose utilization. However, vanadyl sulfate was ineffective when administered to animals which lost their insulin secretion capacity on protracted HE diet, but substantially reduced the hyperglycemia when given together with exogenous insulin. The in vitro insulin activation of liver and muscle insulin receptors isolated from vanadyl treated Psammomys was ineffective. The in vivo vanadyl treatment restored muscle GLUT4 total protein and mRNA contents in addition to membrane GLUT4 protein, in accordance with the increased glucose utilization during the clamp study. These results indicate that short-term vanadyl sulfate treatment corrects the nutritionally induced, insulin resistant diabetes. This action requires the presence of insulin for its beneficial effect. Thus, vanadyl action in P. obesus appears to be the result of insulin potentiation rather than mimicking, with activation of the signaling pathway proteins leading to GLUT4 translocation, probably distal to the insulin receptor.

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“…Indeed, L-PK mRNA concentration decreases in diabetes, and increases following insulin administration [32,33]. Moreover, vanadate can mimic insulin by increasing L-PK mRNA in cultured hepatocytes [15]. As expected, L-PK mRNA level was reduced to 15 % of the control value in the liver of diabetic rats.…”

Section: Resultsmentioning

confidence: 66%

“…Noguchi et al [33] have suggested that insulin may increase transcription of the L-PK gene by stimulating the synthesis of some unknown protein. Recently, Miralpeix et al [15] have shown that vanadate mimics insulin action on L-PK and glucokinase transcription and, similar to insulin [34], vanadate cannot increase the L-type PK m R N A content in the absence of glucose. This indicates that neither vanadate nor insulin has a direct role on transcription of the L-type P K gene by itself, since glucose is required for its mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

“…Vanadate normalized glucokinase activity, which was almost absent in the liver of diabetic animals. The increase in glucokinase activity was due to an increase in its mRNA [15] and was correlated with the increase in glucose uptake [9]. Furthermore, vanadate activated hepatic glucose consumption through an increase in fructose 2,6-bisphosphate (Fru-2,6-P2) and 6-phosphofructo-2-ki-nase (PFK-2) activity [10,16].…”

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confidence: 99%

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Oral administration of vanadate to diabetic rats restores liver 6-phosphofructo-2-kinase content and mRNA

et al. 1992

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Vanadate and insulin were administered to diabetic (streptozotocin) rats to compare their effects on the activity and mRNA content of 6-phosphofructo-2-kinase and L-type pyruvate kinase in the liver. The activity of 6-phosphofructo-2-kinase in livers of diabetic rats was about 40% of that found in normal rats. A similar decrease was found for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase content, measured by immunoprecipitation, and for mRNA, measured by hybridization of Northern blots. Administration of vanadate to the diabetic rats led to a progressive recovery of 6-phosphofructo-2-kinase activity, and 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase content and mRNA. This recovery, which was complete after 15 days of oral treatment, was also obtained after 60 h of insulin administration. L-type pyruvate kinase activity and mRNA were also decreased by about 70% in livers of diabetic rats. Both parameters normalized after 15 days of vanadate treatment, whereas insulin administration (60 h) raised L-pyruvate kinase mRNA three-fold above control values. Oral treatment for 15 days with vanadate can thus mimic the effect of insulin on both pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase in livers of diabetic rats.

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Vanadate Induction of L-type Pyruvate Kinase mRNA in Adult Rat Hepatocytes in Primary Culture

Cited by 25 publications

References 21 publications

Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals

Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals

Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in thePsammomys obesus gerbil

Oral administration of vanadate to diabetic rats restores liver 6-phosphofructo-2-kinase content and mRNA

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