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PubMed1989

Attenuation of ischemic renal injury with fructose 1,6-diphosphate.

Fructose 1,6-diphosphate (FDP) has been shown to attenuate tissue injury associated with ischemia and shock by enhancing the anaerobic carbohydrate utilization and by inhibiting oxygen-free-radical generation by the neutrophils. Previously, we have reported that FDP prevents ischemic renal failure if administered prior to the ischemic insult. The present study was designed to determine whether this agent could prevent renal damage when administered during the postischemic reperfusion period. Rats were subjected to 30 min of bilateral renal artery occlusion and infused with FDP (350 mg/kg body wt) beginning 10 min after release of the renal artery clamps. Control rats received an equal volume of glucose/saline solution. A third group of rats were sham operated. Twenty-four hours after injury, BUN, creatinine, and fractional sodium excretion values were less in FDP-treated rats than in control rats (P less than 0.001, P less than 0.005, and P less than 0.001, respectively) and not different from values observed in sham-operated rats. Inulin clearance was greater (P less than 0.001) in FDP-treated rats than in control rats (665 +/- 38 microliters/min/g kidney wt). Renal histology was also better preserved in the FDP-treated group. These data suggest that FDP infused after the initiation of an acute ischemic insult provides significant, but not complete, functional and histologic protection from renal damage.

Animals↗
PubMed1989

Vanadate counteracts glucagon effects in isolated rat hepatocytes.

The incubation of isolated rat hepatocytes with vanadate increased the concentration of fructose 2,6-bisphosphate without modifying 6-phosphofructo-2-kinase activity. Vanadate also reverted and prevented the decrease of fructose 2,6-bisphosphate levels, of the "active" form of the 6-phosphofructo 2-kinase and of the pyruvate kinase activity ratio produced by glucagon, by probably counteracting the increase in cyclic AMP concentration.

Animals↗
PubMed1994

Effects of fructose-1,6-bisphosphate on brain polyamine biosynthesis in a model of transient cerebral ischemia.

We evaluated the effects on cerebral ischemia of a treatment with fructose-1,6-bisphosphate, a compound known to possess protective effects on acute ischemic injury in a variety of different tissues. We investigated the ability of the compound, administered either 15 minutes before or 15 minutes after the ischemic insult, in reducing the ischemia-induced changes in polyamine brain levels. The experiments were performed in adult, chloral hydrate-anesthetized Mongolian gerbils that underwent a 15 minutes ligation of the common carotid arteries followed by recirculation. Animals were sacrificed 1, 8 and 24 hours and immediately after the release of the occlusion. Polyamine brain levels were not modified during ischemia. Putrescine began to increase after eight hours from the release of the occlusion and we found it significantly increased after 24 hours in the hippocampus and striatum. We did not detect any significant changes in spermidine brain levels either during ischemia or during recirculation. Conversely, spermine appeared to decrease in the hippocampus while it did not show changes in striatum and medulla-pons. The activity of ornithine decarboxylase, a key enzyme in the biosynthesis of polyamines, resulted enhanced at the end of the ischemic period in all the brain regions tested and showed a peak at eight hours of recirculation in striatum and hippocampus whereas returned to control values in the medulla-pons. Fructose-1,6-bisphosphate significantly reduced the ischemia induced changes in polyamine brain content when administered before the ischemic insult while did not show protective properties when administered post-ischemically.

Animals↗
PubMed1996

Streptozotocin-induced diabetes increases fructose 2,6-biphosphate levels and glucose metabolism in thymus lymphocytes.

Acute effect of streptozotocin-induced diabetes on several parameters of glucose metabolism was investigated in thymus lymphocytes (thymocytes). The cells from diabetics rats accumulated in vitro about 2-fold more fructose 2,6-bisphosphate (Fru-2, 6-P2) in the presence of increasing glucose concentration than cells from normal rats. An increased production of lactate was also observed. Phosphofructokinase-1 (PFK-1) and phosphofructokinase-2 (PFK-2) activities were enhanced in cells from diabetic rats compared with those from normal rats. [U-14C]glucose incorporation into glycogen was also increased in cells from diabetic rats and the 14CO2 liberation was lesser than in cells from normal animals. From these data it may be concluded that the response of thymocytes to streptozotocin-induced diabetes is similar to that observed in other extrahepatic tissues.

Animals↗
PubMed1996

Characterization of nitric oxide dependent changes in carbohydrate hepatic metabolism during septic shock.

The role of nitric oxide in the alterations of liver carbohydrate metabolism during septic shock has been studied in fed and starved animals injected with bacterial lipopolysaccharide (LPS). One h after LPS injection an hyperglycemic peak was observed followed by hypoglycemia when the plasma nitric oxide concentration increased. However, in animals pharmacologically treated with nitric oxide donors only hypoglycemia was observed. In isolated hepatocytes from LPS treated rats an impairment of the gluconeogenic flux was observed accompanied by a decrease in the mRNA levels of the glucose transporter GLUT-2 and phosphoenolpyruvate carboxykinase, at the time that increased the mRNA levels of the inducible form of nitric oxide synthase. These results suggest that part of the effects observed in response to LPS challenge are due to early signaling molecules (cytokines and other factors molecules) whereas other effects can be attributed to nitric oxide synthesis which in turn has specific effects on hepatic metabolism.

Animals↗
PubMed1984

Insulin resistance in the obese hyperglycemic (ob/ob) mouse. Failure of hyperinsulinemia to activate hepatic pyruvate kinase (PK).

In obese hyperglycemic (ob/ob) mice, as compared to controls, hepatic pyruvate kinase (PK) activity was enhanced by 35.63% (214.75 +/- 13.60 nmol/min/mg protein v 158.33 +/- 10.47, P less than 0.01) when measured at saturating (6.6 mmol/L) concentration of the substrate phosphoenolpyruvate (total activity), but the activity recorded at subsaturating (1.3 mmol/L) substrate concentration (active fraction) was unchanged (86.37 +/- 6.42 v 85.66 +/- 13.59) or even decreased if expressed as percent of the total activity (40.21 +/- 2.56% v 54.10 +/- 5.07, P less than 0.05). Since insulin induces the synthesis of hepatic PK and favors the conversion of the inactive (phosphorylated) to the active (dephosphorylated) form, these findings suggest that in ob/ob mice the striking hyperinsulinemia, although it is able to increase the hepatic content of PK, fails to activate this enzyme. This may favor gluconeogenesis in these animals. The hepatic concentration of PK effectors (fructose-1,6-P2 and phosphoenolpyruvate) was unchanged in ob/ob mice, and the in vitro effect of the activator fructose-1,6-P2 (15 mumol/L), which would favor the activation (dephosphorylation) of PK, was preserved. It is suggested that hepatic PK in ob/ob mice is resistant to activation by insulin.

Animals↗
PubMed1987

Effect of glipizide on hepatic fructose 2,6-bisphosphate concentration and glucose metabolism.

Glipizide raised, in a dose-dependent manner, the concentration of fructose 2,6-bisphosphate in hepatocytes isolated from 24-hour fasted rats and incubated in the presence of 10 mmol/L glucose. Simultaneously, the rate of L-lactate production, as well as the rate of 3H2O formation from (3-3H)glucose, increased markedly. The concentration of glipizide calculated as corresponding to the half-maximal effect in these metabolic parameters was 12 to 15 mumol/L. In hepatocytes isolated from fed rats, either normal or made diabetic by treatment with alloxan, glipizide inhibited the conversion of both (U-14C)pyruvate and (U-14C)lactate to (14C)glucose; an inverse correlation was established between hepatocyte fructose 2,6-bisphosphate levels and the rate of gluconeogenesis. The increase of fructose 2,6-bisphosphate concentration elicited by glipizide, which occurs without a significant modification of either 6-phospho-fructo 2-kinase activity or hepatocyte cyclic AMP levels, seems to be related to a significant accumulation of hexose 6-phosphates (glucose 6-phosphate and fructose 6-phosphate) in the hepatic cells.

Animals↗
PubMed1990

Effect of streptozotocin diabetes on the glycolytic flux and on fructose 2,6-bisphosphate levels in isolated rat enterocytes.

In epithelial cells isolated from rat small intestine and incubated in the presence of 1 mM glucose, streptozotocin-induced diabetes reduced, by 46 and 29%, respectively, the rates of both glucose utilization and L-lactate formation. These effects were accompanied by a significant decrease of enterocyte fructose 2,6-bisphosphate concentration (about 50%) and of the glycolytic flux through the reaction catalyzed by 6-phosphofructo 1-kinase. The diminution of enterocyte fructose 2,6-bisphosphate levels caused by diabetes occurred in spite of an increase of hexose 6-phosphate concentration, and was associated with a reduction in the amount of active form of 6-phosphofructo 2-kinase; total activity of this enzyme was not significantly modified. Diabetes also caused an acceleration in the rate of 3-O-methyl-D-(14C) glucose uptake and increased hexokinase activity in enterocytes. Lactate dehydrogenase, pyruvate kinase and 6-phosphofructo 1-kinase activities were not found to be significantly different in epithelial cells isolated from control or diabetic animals. Our results indicate that a reduction of the glycolytic flux in enterocytes could collaborate to increase intestinal glucose absorption in the diabetic state.

Animals↗
PubMed1991

Inhibition of gluconeogenesis by tolbutamide in isolated rat hepatocytes: modulation of glucose-6-phosphate substrate cycle.

In hepatocytes isolated from 24-hour fasted rats, the oral hypoglycemic agent tolbutamide (1 mmol/L) inhibited glucose formation from different concentrations (1 to 20 mmol/L) of galactose, dihydroxyacetone, glycerol, and a mixture of L-lactate:pyruvate (molar ratio, 10:1). Parallel to the reduction of gluconeogenesis, tolbutamide stimulated L-lactate formation when cells were incubated with either galactose, dihydroxyacetone, or glycerol. All these tolbutamide effects occurred without significant modification of hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) levels. Only when glucose was included in the incubation medium was the inhibition of gluconeogenesis caused by the sulfonylurea accompanied by a significant increment of the cellular F-2,6-P2 concentration. Under these conditions, tolbutamide potentiated the effect of glucose in promoting the increase of this regulatory metabolite, as well as the stimulation of glycolysis; in addition, tolbutamide increased the cellular pool of hexose-6-phosphates and the rate of tritium release from (2-3H)glucose. These results support the hypothesis that tolbutamide regulates hepatic glucose metabolism, at least, by modulating the glucose-6-phosphate substrate cycle.

Animals↗
PubMed1992

Fructose 2,6-bisphosphate levels and modulation of glycolysis by histamine, cholecystokinin, and forskolin in isolated rabbit gastric glands.

In isolated rabbit gastric glands incubated in the presence of 1 mmol/L glucose, the content of fructose 2,6-bisphosphate (F-2,6-P2) was 5.7 +/- 0.5 pmol/mg dry weight. This value was progressively incremented by increasing glucose concentration in the incubation medium, and was almost doubled at 10 mmol/L glucose. Under these conditions, a close correlation could be established between the levels of F-2,6-P2 and the rate of L-lactate formation (r = .98; P less than .05). Both histamine (0.1 mmol/L) and cholecystokinin octapeptide (CCK-OCT; 0.1 mumol/L) increased L-lactate production, without significant changes in either F-2,6-P2 concentration or the amount of 6-phosphofructo-2-kinase in active form. In contrast, forskolin, which markedly increased the glandular content of cyclic adenosine monophosphate (cAMP), partially blocked glucose consumption and caused a significant reduction in both F-2,6-P2 levels and the proportion of 6-phosphofructo-2-kinase in active form. Furthermore, forskolin partially blocked the rate of glucose uptake by isolated gastric glands. Our results suggest a regulatory role of F-2,6-P2 in the control of the glycolytic flux in response to glucose, but not in its response to histamine or CCK-OCT.

3-O-Methylglucose↗
PubMed1992

Effects of tolbutamide on fructose-2,6-bisphosphate formation and ketogenesis in hepatocytes from diabetic rats.

To assess the extrapancreatic action of sulfonylurea directly in the diabetic, effects of tolbutamide on hepatocyte fructose-2,6-bisphosphate (F-2,6-P2) formation and ketone production were investigated using isolated hepatocytes from streptozotocin (STZ)-induced diabetic rats. The basal level of hepatocyte F-2,6-P2 was significantly higher in diabetic rats within 2 weeks after STZ (40 mg/kg body weight) injection compared with that in the nondiabetic control group. Ultimately, a marked decrease in the F-2,6-P2 level was observed at 4 weeks after STZ administration (10% of the control). Although the addition of tolbutamide further increased the hepatocyte F-2,6-P2 level during the first week after STZ injection, no significant effect was observed after the second week and on from the initial STZ. Treatment of diabetes with insulin restored the stimulatory effect of tolbutamide on the hepatocyte F-2,6-P2 formation. Tolbutamide, independently of insulin treatment, lowered the ketone production of hepatocytes from diabetic rats. The present results indicate that insulin is necessary, in advance, for sulfonylurea to stimulate the liver F-2,6-P2 formation, while tolbutamide inhibition of hepatocyte ketone production is independent of insulin. These results provide further support for the role of sulfonylurea in regulating hepatic energy metabolism in the diabetic.

3-Hydroxybutyric Acid↗
PubMed1995

Suppression of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db mice.

The orally effective antidiabetic agent Troglitazone (CS-045) exerts hypoglycemic effects in various insulin-resistant obese and/or diabetic animals. Since increased hepatic gluconeogenesis is a major cause of hyperglycemia in these diabetic animals, we evaluated the effect of long-term Troglitazone treatment on hepatic gluconeogenesis. Troglitazone was administered for 7 days to normal ddY mice, diabetic KK mice, diabetic C57BL/KsJ-db/db mice, and its heterozygote, db/+ mice, as a 0.1% or 0.2% food admixture. Troglitazone significantly decreased plasma glucose in diabetic KK and db/db mice, but not in normal ddY and db/+ mice. 14C incorporation into blood glucose from NaH14CO3 was measured to assess hepatic gluconeogenesis in diabetic KK and normal ddY mice. Hepatic gluconeogenesis was significantly increased in diabetic KK mice (P < .01) as compared with normal mice, and was significantly suppressed (P < .05) after 7 days of Troglitazone treatment (approximately 200 mg/kg/d). Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) were significantly decreased but fructose-1,6-bisphosphate (FBP) was not significantly increased in the liver of diabetic db/db mice treated with Troglitazone for 7 days (approximately 80 mg/kg/d) as compared with control db/db mice. These changes in G6P, F6P, and FBP corresponded with the activity of fructose-1,6-bisphosphatase (Fru-1,6P2ase) and 6-phosphofructo-1-kinase (6-PF-1K), which determined the content of F6P and FBP. Namely, Fru-1,6P2ase was significantly decreased in Troglitazone-treated db/db mice as compared with control mice, whereas 6-PF-1K activity was not affected by Troglitazone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Modulation of glycogen phosphorylase activity and fructose 2,6-bisphosphate levels by glibenclamide and meglitinide in isolated rat hepatocytes: a comparative study.

The influence of glibenclamide and meglitinide, or 4-[2-(5-chloro-2-methoxybenzamide)ethyl]-benzoic acid, a compound similar to the nonsulfonylurea moiety of glibenclamide, on glycogen phosphorylase a activity, fructose 2,6-bisphosphate (F-2,6-P2) level, and cytoplasmic free-Ca2+ concentration has been studied in isolated rat hepatocytes. Both glibenclamide and meglitinide caused a transient and dose-dependent activation of glycogen phosphorylase, with half-maximal effects corresponding to 3.7 +/- 1.6 and 9.6 +/- 3.3 mumol/L, respectively. This enzyme activation occurred without significant changes in hepatocyte cyclic adenosine monophosphate (cAMP) levels and was accompanied by an increase in cytoplasmic concentration of free Ca2+. Parallel to these effects, glibenclamide increased the cellular content of F-2,6-P2, with this effect being associated with a reduction in the rate of glucose formation from a mixture of [14C]lactate/pyruvate. Under similar conditions, meglitinide caused a significant reduction of F-2,6-P2 levels and accelerated the gluconeogenic flux. The mechanism by which meglitinide decreases hepatocyte F-2,6-P2 levels seems to be mediated by stimulation of fructose-2,6-bisphosphatase. This comparative study may help to elucidate which among the hepatic effects of glibenclamide are exerted specifically by the sulfonylurea moiety.

Adenine Nucleotides↗
PubMed1993

Fructose-1,6-bisphosphate fails to ameliorate delayed neuronal death in the CA1 area after transient forebrain ischaemia in gerbils.

Fructose-1,6-bisphosphate has been shown to reduce ischaemic-induced brain damage in rabbits and gerbils. In view of these findings, we investigated the effects of fructose-1,6-bisphosphate on delayed neuronal death, following bilateral forebrain ischaemia, in the gerbil hippocampus at the fourth day of reperfusion. We subjected gerbils to bilateral forebrain ischaemia for 20 min. Fructose-1,6-bisphosphate was administered: intraperitoneally at a dose of 1 g/kg in saline in hr before the occlusion or at a dose of 1 g/kg 1 hr before the occlusion and every 24 hr for 3 days; or intraventricularly at a dose of 0.1 g/kg just after the carotid occlusion. No significant differences in the number of dying cells in the CA1 area were found between each group of treated animals when compared with controls. This study suggests that fructose-1,6-bisphosphate, administered according to these three different schedules, fails to ameliorate delayed neuronal death after 20 min of bilateral forebrain ischaemia in the CA1 area of the gerbil hippocampus.

Animals↗