Effect of phenformin on hepatic balances of gluconeogenic substrates in man

Abstract

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.

Lactic Acidosis Revisited

“…Dietze and his colleagues 70 have for the first time clearly showed in man receiving phenformin in therapeutic doses that net splanchnic clearance of lactate and production of glucose are re-LACTIC ACIDOSIS REVISITED duced during lactate infusion (up to blood lactate concentrations of 1.74 mmol/L). The work of Arieff and his colleagues 17 in dogs showed that extrahepatic splanchnic lactate production was increased and hepatic uptake reduced in the presence of phenformin.…”