Metabolic Effects of Phenethylbiguanide in Normal Subjects and in Diabetic Patients

Fajans, Stefan S.; Moorhouse, John A.; Doorenbos, H; Louis, Lawrence H.; Conn, Jerome W.

doi:10.2337/diab.9.3.194

Cited by 60 publications

(18 citation statements)

References 4 publications

(7 reference statements)

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“…It seems noteworthy that in spite of the reduction of basal hepatic glucose output, the arterial glucose concentration was not significantly different from that in untreated persons. This finding is in line with the present view that biguanides lower blood sugar levels in diabetics but not in healthy subjects [32]. This phenomenon may be explained by our recent observation that, in contrast to the effect in diabetic subjects [2], glucose uptake by muscle in the forearm of healthy volunteers was significantly reduced by phenformin under identical conditions [33].…”

Section: Discussionsupporting

confidence: 75%

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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Section: Discussionsupporting

confidence: 75%

Effect of phenformin on hepatic balances of gluconeogenic substrates in man

et al. 1978

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“…Die Mittelwerte der %Vachstumshormonspiegel, die insgesamt unter 5 ng/ml blieben, liel3en insbesondere in Previous studies of the effects of biguanides on glucose tolerance and insulin secretion have yielded conflicting results. Whereas several authors (Pomeranze et al (1957), Abramson and Arky (1967)) observed an improved oral glucose tolerance in humans upon administration of biguanides, other workers (Fajans et al (1960), Schilling (1959), Gutsche (1960)) failed to substantiate these reports. Studies of Czyzyk and Lawecki (1966) with diabetic patients indicated that biguanides may improve oral glucose tolerance without, however, affecting intravenous glucose tolerance (cf.…”

Section: Die Wirkung Yon Dimethylbiguanid Auf Glucosetoleranz Serumimentioning

confidence: 70%

The effect of dimethylbiguanide on glucose tolerance, serum insulin and growth hormone in obese patients

1972

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“…The acidosis secondary to this drug appears to be dose-dependent. 9 High serum levels may be achieved in patients with either hepatic or renal dysfunc¬ tion since phenformin is metabolized by the liver and is excreted along with its metabolites by the kidney.'" Once high serum levels are attained, lactic acidosis results, because phenformin inhibits cellular oxidative mechanisms and forces glucose to be metabolized through anaerobic glycolysis."'…”

Section: Commentmentioning

confidence: 99%