Gluconeogenesis in Renal Cortical Tubules: Effect of Phenformin

Abstract

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

Renal Response to Acid Load after Phenformin

“…The three main theories favour an enhanced peripheral glucose utilization, a decreased glucose absorption, and an inhibition of gluconeogenesis (Searle et al, 1966;Alleyne and Scullard, 1969;Alleyne et al, 1971;Gordon and de Hartog, 1973). The decrease in kidney gluconeogenesis is intimately related to the ammonia production, at least in rats.…”

“…Though phenformin has been in use for years there is no agreement yet on its mode of action. Gordon and de Hartog (1973) showed that the oxidative phosphorylation and the adenosine triphosphate production in the renal cortex of rats was depressed by the drug. Aber et al (1966), Alleyne and Scullard (1969), and Alleyne et al (1971) showed a reduction of the renal glyconeogenesis and of the renal ammonium production to an acid load in rats.…”