Effects of Phenformin and Hypoglycin on Gluconeogenesis of Rat Tissues

Patrick, S. J.

doi:10.1139/o66-004

Cited by 29 publications

(13 citation statements)

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“…Consequently, it is often stated that the mechanism of the action of the biguanides is not established 26 " 28 or poorly understood. 29 The experiments in this report were carried out to improve our general understanding of the biguanides by determining whether there is a correlation between the inhibitory effects of the biguanides on oxidative processes and their effects on glucose metabolism.…”

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Metabolic Effects of the Biguanides and Possible Mechanism of Action

Jangaard¹,

Pereira²,

Pinson³

1968

Diabetes

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The relationship between the biguanide inhibition of oxidations and their effect on glucose metabolism in vitro has been investigated. We found a good correlation between the concentration of biguanide causing a halfmaximal inhibition of pyruvate oxidation (Ki) and the concentration eliciting a half-maximal stimulation (Ks) of glucose uptake in several tissues from rat, guinea pig and pigeon. Guinea pig epididymal fat pad was the most sensitive tissue tested. Gluconeogenesis by minced guinea pig liver was inhibited by the biguanides. The ability of the biguanides to inhibit gluconeogenesis correlated well with their ability to inhibit pyruvate oxidation. Inhibition of oxidations by the biguanides does not appear to be a result of a direct inhibition of the enzymes catalyzing these oxidations but seems to be secondary to a primary effect on the coupled processes of electron transport and oxidative phosphorylation. We have summarized and discussed objections to the theory that the metabolic actions of the biguanides are a result of their inhibition of oxidative processes. Our conclusion is that the inhibition of oxidations caused by the biguanides is directly related to their metabolic and hypoglycemic effects. DIABETES 77: 96-104, February, 1968. The biguanides, phenformin (phenethylbiguanide, DBI), metformin (dimethylbiguanide, Glucophage) and buformin (butylbiguanide, Silubin) are oral hypoglycemic agents used in the treatment of diabetes mellitus. Phenformin was first reported to be a hypoglycemic agent of low toxicity by Ungar, Freedman and Shapiro. 1 This observation was followed up by Tyberghein and Williams 2 and Williams et al., 3 who reported that phenformin caused an increase in glucose uptake and lactate production and a decrease in glycogen levels and oxygen uptake by isolated rat diaphragm, muscle and liver. In addition, they obtained evidence suggesting that phenformin caused a decrease in gluconeogenesis in vivo. suggested that the inhibitory effects of the biguanides on aerobic processes were related to their effects on glucose metabolism. This hypothesis received support from Kruger et al, 6 and Wick and co-workers. 7 Krall and Bradley 8 also tentatively supported this hypothesis and pointed out the similarity between the metabolic effects of phenformin and those of the guanidines. The guanidines had earlier been reported to be hypoglycemic agents, 9 ' 10 the action of which resulted from respiratory inhibition. 11 -12 Hollunger 13 localized the action of the guanidines on the electron transport chain, suggesting that they inhibit the transfer of high energy bonds to ADP, causing a secondary block of electron transport and oxygen uptake. Recent work with the biguanides has demonstrated that they too interfere with the reactions of a high energy intermediate of oxidative phosphorylation. 14 ' 15 There seems to be some site specificity involved, 10 with phenformin inhibiting the reaction of a high energy intermediate at Site II of the electron transport chain, which is associated with cytochrom...

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Metabolic Effects of the Biguanides and Possible Mechanism of Action

Jangaard¹,

Pereira²,

Pinson³

1968

Diabetes

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“…Inhibition of gluconeogenesis by biguanides has been observed in liver slices [4] and in the isolated peffused liver [5][6][7][8], although rather high concentrations of the drugs were required. Attempts to demonstrate such an effect in man by either measurement of arterial and hepatic venous substrate concentrations after a single oral or parenteral phenformin application [9,10], or by tracer studies using lactate-C TM after several days pretreatment [11,12] have not clearly confirmed the in vitro experiments.…”

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Effect of phenformin on hepatic balances of gluconeogenic substrates in man

et al. 1978

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Summary. The effect of a five day pretreatment with phenformin (3 • 50 mg daily) on hepatic metabolism was studied in six healthy volunteers. Arterial and hepatic venous concentrations of substrates and hepatic blood flow were estimated during a basal period and during a low-dose lactate infusion (0,03 mmol 9 kg -~ 9 min-1). The results have been compared with those obtained from untreated normal subjects in a previous study (16). During the baseline period arterial concentration of alanine and the hepatic venous concentration ratios of alanine: pyruvate and fi-hydroxybutyrate: acetoacetate were significantly increased with phenformin treatment, while the balances of carbon dioxide and glucose and the fractional extraction of alanine were decreased compared to the values obtained in untreated subjects. During lactate infusion mean arterial lactate concentration was significantly increased and hepatic lactate extraction was decreased compared to untreated persons under the same conditions. In the phenformin-treated group lactate infusion resulted in hepatic output of pyruvate and the hepatic glucose balance remained unchanged compared to baseline. Since the rate of hepatic blood flow was not increased during lactate infusion a significantly smaller glucose output and lactate uptake was obtained with phenformin. These findings support the present view that the hypoglycaemic effect of biguanides is due, at least in part, to inhibition of hepatic gluconeogenesis.Key words: Arterial and hepatic venous concentration of substrates, hepatic blood flow, phenformin.Besides impaired glucose absorption from the gut [1] and accelerated glucose uptake by muscle [2], reduction of hepatic gluconeogenesis has been suggested as an important mechanism explaining the hypoglycaemic effect of the biguanides [3]. Inhibition of gluconeogenesis by biguanides has been observed in liver slices [4] and in the isolated peffused liver [5][6][7][8], although rather high concentrations of the drugs were required. Attempts to demonstrate such an effect in man by either measurement of arterial and hepatic venous substrate concentrations after a single oral or parenteral phenformin application [9,10], or by tracer studies using lactate-C TM after several days pretreatment [11,12] have not clearly confirmed the in vitro experiments. It has been shown that biguanide concentrations comparable to those used in in vitro studies [13,14] can be obtained in man only after several days of pretreatment with the drug. We have therefore reinvestigated this problem measuring hepatic metabolite balances by a technique which was successfully applied earlier for study of gluconeogenesis in human liver [15,16]. Material and Methods Subjects and Pretreatment6 subjects were recruited from medical students of the Munich University School of Medicine. All were informed about the aim and the risks of the study and gave their consent. Their average age was 23.3 + 0.6 years, height 174.8 • 2.9 cm and weight 68.

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“…Experiments with phenformin (phenethylbiguanide), an agent known to inhibit gluconeogenesis in kidney cortex, 11 " 13 assisted in the clarification of these relationships. The data are consistent with a primary restricting effect of phenformin on oxidative phosphorylation.…”

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Gluconeogenesis in Renal Cortical Tubules: Effect of Phenformin

1973

Diabetes

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Studies of gluconeogenesis were carried out with isolated tubules prepared from the renal cortex of fasted rats. A study of the metabolic characteristics of this preparation upon incubation at 37° revealed a sustained respiratory rate, a constancy of ATP levels, and a linear rate of gluconeogenesis. Virtually no glucose synthesis was observed unless appropriate substrates were added; succinate and ot,-ketoglutarate were the most effective precursors. The addition of phenformin to the suspension of isolated tubules led to a decline of 0,, uptake and ATP content in the absence and in the presence of added substrate. In the presence of succinate, there was a close correlation between the ATP content and the rate of gluconeogenesis. The data indicate that the phenformin-induced inhibition of gluconeogenesis is secondary to limitation of ATP generation rather than a direct effect on the enzymatic sequence leading to new glucose formation or to limited availability of reducing equivalents. DIABETES 22:50-57, January, 1973.Two organs are capable of producing glucose in the fasting state, the liver and the kidney cortex. Although the total mass of renal cortex is considerably less than that of liver, the gluconeogenic capacity of the kidney is greater when expressed on a weight basis. 1 The pathways of gluconeogenesis in kidney cortex and liver are similar or identical. The factors controlling the rate of gluconeogenesis are for the most part unique to each organ, although fasting enhances the rate of gluconeogenesis in both liver 2 and kidney. 3 On the other hand, acidosis 4 and parathyroid hormone 5 stimulate only renal cortical gluconeogenesis. Alcohol, 6 -7 glucagon, 8 and insulin 9 -10 influence hepatic, but not renal, cortical gluconeogenesis.In the present study with isolated renal cortical tubules, attention has been directed to the metabolic

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Effects of Phenformin and Hypoglycin on Gluconeogenesis of Rat Tissues

Cited by 29 publications

References 2 publications

Metabolic Effects of the Biguanides and Possible Mechanism of Action

Metabolic Effects of the Biguanides and Possible Mechanism of Action

Effect of phenformin on hepatic balances of gluconeogenic substrates in man

Gluconeogenesis in Renal Cortical Tubules: Effect of Phenformin

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