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PubMed1977

Plasma glucagon suppression by phenformin in man.

In an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p less than 0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p less than 0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments of alpha-amino nitrogen were not affected by phenformin. Thls, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.

Adult↗
PubMed2003

Effects of phenformin on the proliferation of human tumor cell lines.

Phenformin is a biguanide that has been largely used in the past for its anti-diabetic activity. A large body of evidence suggests additional effects of phenformin including antitumoral activity in different animal models in vivo. Thus, the present study has been conducted in order to elucidate possible mechanisms involved in the antitumoral effects of phenformin. In various tumoral cell lines (SH-SY5Y neuroblastoma and LNCaP prostate adenocarcinoma cells), increasing concentrations of phenformin (50-500 microM) induced a concentration-dependent inhibition of cell proliferation. This effect was not dependent on the ability of the drug to reduce glucose levels and was accompanied by induction of apoptotic cell death as measured by cytofluorometric analysis. In addition, a short-time incubation of SH-SY5Y cells with phenformin induced enhanced and transient expression of the cell cycle inhibitor p21 suggesting that phenformin causes inhibition of cell cycle progression prior to induction of apoptosis. These results demonstrate an activity at the cellular level of phenformin that supports its antitumoral effect observed in vivo.

Adenocarcinoma↗
PubMed1977

[Treatment of primary hyperlipoproteinemia type IIb and IV. Comparison of the lipid lowering effect of phenformin, clofibrate, and a combination of both (author's transl)].

22 outpatients with primary hyperlipoproteinemia type IIb and IV were treated in periods of eight weeks as follows: placebo; 0,15 g phenformin/day; 0,15 g phenformin + 1,5 g clofibrate/day; 1,5 g clofibrate/day; placebo. Compared to the first placeboperiode the serumtriglycerides were significantly lowered by phenformin (about 26%), by the combined treatment with phenformin + clofibrate (60%) and by clofibrate (51%) after eight weeks of treatment. The serumcholesterol was significantly lowered by phenformin (10%) and by the combined treatment with phenformin and clofibrate (14%), but not significantly by clofibrate (8%). After eight weeks of treatment with phenformin alone or in combination with clofibrate the body weight decreased significantly (1,9% or 1,4%). These changes in body weight were not related to changes in blood lipids. In conclusion, the combined treatment with 0,15 g clofibrate/day was more effective in lowering increased serum lipids than the treatment with phenformin or clofibrate alone.

Adult↗
PubMed1982

Phenformin has opposite effects on insulin and growth hormone binding to IM-9 lymphocytes.

We studied simultaneously the effect of various concentrations of phenformin on insulin and growth hormone binding to IM-9 lymphocytes, a cell type known to have receptors for both these hormones. After 24 hr preincubation with phenformin at 2 x 10(-5) M, insulin binding to IM-9 cells was increased by 80.4 +/- 10.5% over control (mean +/- SE of 10 experiments). In parallel experiments HGH binding was decreased by 43.1 +/- 2.2% (mean +/- SE). This effect of phenformin was dose-dependent for both HGH and insulin binding over the concentration range 1.5 x 10(-6) M to 5 x 10(-5) M, and was already detectable 3 hr after phenformin addition. These data indicate that phenformin has an opposite effect on insulin and growth hormone binding to IM-9 cells. Several possible mechanisms might be suggested for the decrease of HGH binding sites induced by phenformin: the simultaneous opposite effect on HGH and insulin receptors raises the possibility that some metabolic event triggered by the drug is able to induce opposite changes in the binding of these two hormones with different biological activities.

Cell Line↗
PubMed1983

Influence of oxidation polymorphism on phenformin kinetics and dynamics.

Plasma and urinary kinetics and responses of blood lactate, pyruvate, and glucose after a single 50-mg phenformin dose were investigated in eight subjects of known debrisoquin oxidation phenotype, four poor metabolizers (PM) and four extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 +/- 12.7 ng/ml; mean +/- SE) and a greater plasma AUC (779 +/- 99 ng X hr X ml-1) were reached in PM than in EM (99.8 +/- 13.7 ng/ml and 549 +/- 47 ng X hr X ml-1). Although the urinary excretion of unchanged phenformin was greater in PM between 2 and 24 hr after dosing than in EM, excretion of 4-hydroxy-phenformin could not be detected in most samples collected from PM but was present in every sample from EM. Blood lactate concentrations increased dramatically in PM but fell in EM after phenformin. There were no changes in either blood pyruvate or glucose levels. The results may help to explain lactic acidosis in patients given phenformin in the absence of other predisposing factors.

Adult↗
PubMed1979

Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics.

Glucocorticoid administration for 24 hours to phenformin-treated obese diabetics increased blood lactate and lactate/pyruvate (L/P) ratio to higher levels than those found when only one drug was given. In one of 10 subjects, a metabolic acidosis with a blood lactate of 6.2 mmol developed during simultaneous administration of the two drugs. Diabetics treated with phenformin or metformin in equipotent dosages exhibited the highest blood lactate, L/P ratio, and beta-hydroxybutyrate levels during phenformin treatment, both before and during glucocorticoid administration. Ethanol administration to biguanide-treated diabetics resulted in identical increases in blood lactate and L/P ratio during phenformin and metformin treatment. These findings are consistent with the hypothesis that phenformin has a stronger inhibitory effect of gluconeogenesis than metformin. This may be one reason why lactic acidosis is seen much more often in phenformin- than metformin-treated patients.

Aged↗
PubMed2005

Phenformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) activation of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells.

Active re-absorption of Na+ across the alveolar epithelium is essential to maintain lung fluid balance. Na+ entry at the luminal membrane is predominantly via the amiloride-sensitive Na+ channel (ENaC) down its electrochemical gradient. This gradient is generated and maintained by basolateral Na+ extrusion via Na+,K+-ATPase an energy-dependent process. Several kinases and factors that activate them are known to regulate these processes; however, the role of AMP-activated protein kinase (AMPK) in the lung is unknown. AMPK is an ultra-sensitive cellular energy sensor that monitors energy consumption and down-regulates ATP-consuming processes when activated. The biguanide phenformin has been shown to independently decrease ion transport processes, influence cellular metabolism and activate AMPK. The AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) also activates AMPK in intact cells. Western blotting revealed that both the alpha1 and alpha2 catalytic subunits of AMPK are present in Na+ transporting H441 human lung epithelial cells. Phenformin and AICAR increased AMPK activity in H441 cells in a dose-dependent fashion, stimulating the kinase maximally at 5-10 mm (P = 0.001, n = 3) and 2 mm (P < 0.005, n = 3), respectively. Both agents significantly decreased basal ion transport (measured as short circuit current) across H441 monolayers by approximately 50% compared with that of controls (P < 0.05, n = 4). Neither treatment altered the resistance of the monolayers. Phenformin and AICAR significantly reduced amiloride-sensitive transepithelial Na+ transport compared with controls (P < 0.05, n = 4). This was a result of both decreased Na+,K+-ATPase activity and amiloride-sensitive apical Na+ conductance. Transepithelial Na+ transport decreased with increasing concentrations of phenformin (0.1-10 mm) and showed a significant correlation with AMPK activity. Taken together, these results show that phenformin and AICAR suppress amiloride-sensitive Na+ transport across H441 cells via a pathway that includes activation of AMPK and inhibition of both apical Na+ entry through ENaC and basolateral Na+ extrusion via the Na+,K+-ATPase. These are the first studies to provide a cellular signalling mechanism for the action of phenformin on ion transport processes, and also the first studies showing AMPK as a regulator of Na+ absorption in the lung.

AMP-Activated Protein Kinases↗
PubMed2004

Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR.

Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPKalpha2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases.

AMP-Activated Protein Kinase Kinases↗
PubMed1975

Phenformin-induced lactic acidosis in diabetic patients.

Eighteen diabetic patients with lactic acidosis (L.A.) were analyzed for possible causal factors, metabolic changes, and efficacy of treatment. An antecedent phenformin therapy was performed in fifteen cases and was associated with renal insufficiency in ten cases and liver disease in eight cases. Tissular anoxia of primary hemodynamic or respiratory origin was absent in all cases. The severe metabolic acidosis (pH m.93 +/- 0,03; HCO3-= 6 +/- 1 MM; PaCO2 = 18 +/- 2 MM. Hg) and hyperlactatemia (14.2 +/- 0.3 mM) were associated with high lactate/pyruvate ration (70 +/- 22). High alanine levels (up to 4.6 mM) were measured in some of these patients. High beta-hydroxybutrate levels were sometimes measured (up to 7.6 mM), and substantial amounts of acetoacetate were also detected in twelve cases. Glucagon level was always increased (1,050 +/- 240 pg./ml.), and insulin/glucagon ratio was low. Cortisol (49 +/- 10 mug./100 ml.) and HGH (10.8 +/- 0.6 ng./ml.) were also elevated. Increased plasma levels of phenformin were measured in five L.A. diabetic subjects (50 +/- 5 mug./ml.) by comparison with other phenformin-treated diabetic subjects. The specificity of the assay was investigated, and phenformin metabolites were characterized by thin-layer chromatography. Por the treatment of L.A., adjunction of dialysis and furosemide improved the efficacy of early and massive sodium bicarbonate infusion. It is suggested that accumulation of phenformin via renal insufficiency plays a determinant role in causing L.A. through an impairment of lactate metabolism in the liver. An accelerated epuration of the drug may be helpful in therapy of L.A. Phenformin treatment should be avoided in case of renal and/or liver insufficiency.

Adult↗
PubMed1981

Defective hydroxylation of phenformin as a determinant of drug toxicity.

The kinetics of phenformin and its metabolite, p-hydroxyphenethylbiguanide, was studied in eight diabetic patients with varying degrees of renal impairment. Plasma and urinary phenformin and p-hydroxyphenethylbiguanide levels were determined by the multiple selected ion monitoring technique. Phenformin half-lives were unrelated to the degree of renal impairment, whereas reduced renal clearances of insulin and creatinine were significantly correlated with a prolonged half-life of the metabolite. The excretion of p-hydroxyphenethylbiguanide was quite variable (between 4.9% and 27% of total urinary drug loss), probably due to a genetic polymorphism of hepatic mechanisms for hydroxylation. A reduced formation of the metabolite was concomitant with marked increases in the amount of circulating phenformin. A positive reciprocal correlation was detected between areas under the plasma curve of phenformin and both the renal clearance of the unchanged drug and the percentage of metabolite formation. A reduced hydroxylation of phenformin seems, therefore, to be responsible for the high plasma levels of the drug previously described in toxic patients.

Aged↗
PubMed1984

The effect of phenformin on insulin-stimulated isoaminobutyric acid (AIB) transport by isolated hepatocytes.

Hepatocytes isolated from adult rat livers by collagenase perfusion were used to investigate the effect of phenformin on amino acid transport by measuring the uptake of aminoisobutyric acid (AIB). At concentrations between 0.01 and 100 micrograms/ml, phenformin hydrochloride did not affect AIB uptake, but concentrations of 500 and 1000 micrograms/ml were inhibitory. Incubating hepatocytes with insulin increased their accumulation of AIB. Inclusion of up to 100 micrograms/ml, phenformin hydrochloride during maximal and submaximal stimulation by insulin did not affect AIB uptake, but inhibition occurred with 500 and 1000 micrograms/ml. The continued presence of phenformin after addition of AIB was not required in order to produce inhibition. Furthermore, increasing the duration of exposure of hepatocytes to phenformin increased the degree of inhibition, suggesting that it is a non-competitive inhibitor. We conclude that phenformin does not enhance the sensitivity of hepatocytes to insulin and that at higher concentrations it may exert an inhibitory effect on basal and insulin stimulated aminoacid transport.

Aminoisobutyric Acids↗
PubMedDate not supplied

Comparative study of the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide or chlorpropamide.

This study was designed to compare the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide, chlorpropamide or biguanides in non-insulin-dependent diabetes. It is divided into two parts: a) in the retrospective study (473 subjects), glucose control of patients who were transferred from chlorpropamide, gliclazide, glibenclamide, glibenclamide + biguanide or metformin to the fixed combination glibenclamide-phenformin in the same tablet (2.5 mg and 25 mg, respectively) was monitored. A statistically significant decrease of blood glucose and glycosylated hemoglobin values was found under the combination of glibenclamide-phenformin contained in the same tablet in contrast to the values obtained with the treatment with glibenclamide, gliclazide, chlorpropamide, combination of glibenclamide and biguanides, metformin, and insulin. b) In the prospective study (57 subjects), the patients were transferred from chlorpropamide or gliclazide to glibenclamide for 3 months and then reallocated to the previous treatment for 3 additional months. It was found that under glibenclamide, glucose control was significantly better than under chlorpropamide or gliclazide. In conclusion, glibenclamide, a second generation sulfonylurea, and the fixed combination glibenclamide-phenformin in the same tablet are more effective compared to the other antidiabetic agents here studied and lead to a better control of type II diabetic patients. There was no increase in plasma lactic acid concentration in all patients studied before and after having received the fixed combination of glibenclamide-phenformin in the single tablet form.

Blood Glucose↗
PubMedDate not supplied

Phenformin stimulation of insulin binding to human cultured lymphocytes.

The effects of the oral hypoglycemic agent, phenformin, were studied on the binding of 125I-insulin to its receptors in IM-9 human cultured lymphocytes. Three h after the addition of 5 microgram/ml of phenformin to these cells there was detectable stimulation of 125I-insulin binding; maximal effects were seen after 18 h. A detectable effect of phenformin was seen at 1 microgram/ml and maximal effects were seen at 5 microgram/ml. These studies demonstrate therefore than phenformin increases the binding of 125I-insulin to human cultured lymphocytes, and raise the possibility that phenformin could act in vivo to regulate insulin receptors.

Cells, Cultured↗
PubMed1993

Hepatotoxic effects of ethanol and phenformin association in rats.

1. The association of ethanol and phenformin during 6 months in the Sprague-Dawley rat produces an alteration in lactate homeostasis. A basal blood lactate value of 54.13 +/- 15.43 mg/dl was found compared to 23.65 +/- 7.4 mg/dl in control rats. 2. Lactic acid levels increased to 28.8 +/- 7.42 mg/dl and 22.01 +/- 8.08 mg/dl after chronic administration of ethanol or phenformin in Sprague-Dawley rats, respectively. Nevertheless, these were not statistically significant with respect to those of control group. 3. The total hepatic collagen content after chronic administration of phenformin and ethanol was moderately elevated 7.12 +/- 1.85 mg/g of wet tissue, and statistically significant with respect to the control group, 4.77 +/- 1.17 mg/g. Collagen content values in phenformin and ethanol rats did not reveal statistically significant differences. 4. Liver showed histological degenerative changes but not any sign of fibrosis after chronic administration of ethanol and phenformin together.

Animals↗
PubMed2006

Solid phase extraction--non-aqueous capillary electrophoresis for determination of metformin, phenformin and glyburide in human plasma.

Solid phase extraction (SPE) was coupled at line to capillary electrophoresis (CE) for the determination of three basic and neutral diabetic drugs (metformin, phenformin and glyburide) in human plasma. The SPE procedure employed a C(18) cartridge to remove most of the water and proteins from the plasma sample. Analyte detectability was increased due to trace enrichment during the SPE process. Elution of metformin, phenformin and glyburide was achieved with methanol+3% acetic acid. CE analysis was performed using a non-aqueous buffer, acetonitrile+5mM ammonium acetate+5% acetic acid, which afforded rapid separation of metformin from phenformin within 3 min. Glyburide, with a migration time longer than 6 min, did not cause any interference. The present SPE-CE method, with an electrokinetic injection time of 6s and UV detection at 240 nm, was useful for monitoring down to 1 microg/mL of metformin and phenformin in human plasma. When the electrokinetic injection time was increased to 36s, the detection limits were improved to 12 ng/mL for metformin and 6 ng/mL for phenformin.

Electrophoresis, Capillary↗
PubMed1976

Can phenformin-induced lactic acidosis be prevented?

Although patients taking phenformin are more likely to develop lactic acidosis in the presence of renal, cardiovascular, or hepatic disease, criteria for safe use of the drug are not well established. Eight diabetics died of lactic acidosis in Nottingham in 1972-5 and all were taking phenformin in therapeutic doses. Six had attended the diabetic clinic within a month of their terminal illness. Two patients had appreciable renal impairment and should not have been given phenformin. Four had hypertension and minimal evidence of renal disease, while in two no predisposing factor was identified. There are so many contraindications to the use of phenformin that it is doubtful whether patients on the drug can be monitored adequately. We suggest that phenformin should be withdrawn from general use.

Acidosis↗
PubMed1975

Lactic acidosis associated with phenformin therapy. Evidence that inhibited lactate oxidation is the causative factor.

Using uniformly labeled 14C L-lactate, we have studied the turnover and oxidation of lactic acid in a patient who presented with a mild lactic acidosis while on phenformin medication. As with other cases of lactic acidosis associated with phenformin therapy, this subject had impaired renal function as evidenced by serum creatinine levels of 2 mg./100 ml. and BUNs of 40 mg./100 ml. Comparison of the rate of lactate oxidation relative to the rate of lactate turnover in this subject while on and off phenformin therapy suggests that a prime factor leading to the elevated lactate levels in this situation in impaired peripheral aerobic metabolism. Although lactate oxidation was increased in the presence of phenformin, the control studies clearly demonstrate that aerobic metabolism was not keeping pace with the increased level of anaerobic carbohydrate metabolism brought on by the drug. It is concluded that it is this imbalance in lactate metabolism that is responsible for the lactic acidosis that accompanies phenformin therapy.

Acidosis↗
PubMed1980

Phenformin increases insulin binding to human cultured breast cancer cells.

The effect of the hypoglycemic biguanide, phenformin, on the binding of insulin to MCF-7 cells, an in vitro line derived from a human breast cancer, has been investigated. Cells incubated for 24 h in the presence of 1.0 micrograms/ml of phenformin bound 62.2 +/- 8.1% (mean +/- SE) more 125I-insulin than did controls. The phenformin effect was dose-dependent over the concentration range of 0.1 micrograms/ml to 10.0 micrograms/ml. The increased binding was due to an increase in receptor number without a change in binding affinity. This demonstration of increased receptor number in response to phenformin exposure provides support for the hypothesis that one action of phenformin is to enhance tissue sensitivity to insulin.

Breast Neoplasms↗