Ketone bodies activate gluconeogenesis in isolated rabbit renal cortical tubules incubated in the presence of amino acids and glycerol.

Abstract

In isolated rabbit renal kidney-cortex tubules 2 mM glycerol, which is a poor gluconeogenic substrate, does not induce glucose formation in the presence of alanine, while it activates gluconeogenesis on substitution of alanine by aspartate, glutamate or proline. The addition of either 5 mM 3-hydroxybutyrate or 5 mM acetoacetate to renal tubules incubated with alanine + glycerol causes a marked induction of glucose production associated with inhibition of glutamine synthesis. In contrast, the rate of the latter process is not altered by ketones in the presence of glycerol and either aspartate, glutamine or proline despite the stimulation of glucose formation. Acceleration of gluconeogenesis by ketone bodies in the presence of amino acids and glycerol is probably due to (i) stimulation of pyruvate carboxylase activity, (ii) activation of malate-aspartate shuttle as concluded from elevated intracellular levels of malate, aspartate and glutamate, as well as (iii) diminished supply of ammonium for glutamine synthesis from alanine resulting from a decrease in glutamate dehydrogenase activity.

Acetate stimulates flux through the tricarboxylic acid cycle in rabbit renal proximal tubules synthesizing glutamine from alanine: a 13C NMR study

“…In the rabbit nephron, the functional unit of the kidney, glutamine synthetase activity has been localized in the glomerulus, the entire proximal tubule and the distal straight tubule [4]. In agreement with the latter findings, suspensions of rabbit proximal tubules have been shown to synthesize glutamine at high rates from a variety of precursors including alanine [6,7], aspartate [6][7][8], glutamate [9] and glucose plus ammonia [10].…”

“…The rate of glutamine synthesis from 5 mM alanine found in our study was approx. 1.8-fold greater than that found by Lietz et al [7]. This is probably because our tubules utilized alanine at a rate that was more than twice that found in the other laboratory [24].…”

“…It is known that the rabbit kidney, which produces an alkaline urine [2], contains a high activity of glutamine synthetase [1][2][3] located in the proximal tubule [4] and does not readily use glutamine as substrate [10,27] because its glutaminase activity is low [2]. Accordingly, in the rabbit, the urinary excretion of ammonium ions is low and the high rate of renal glutamine synthesis known to occur in itro [1,[7][8][9][10][11] seems to be an important process that detoxifies the great quantities of ammonia produced by the very active glutamate dehydrogenase reaction in this organ. The rabbit renal proximal tubule also has a high capacity to metabolize acetate [9] (Table 1), the most concentrated volatile fatty acid in the rabbit blood [12].…”

“…We have recently demonstrated that the rate of glutamine synthesis along the proximal tubule from both alanine and aspartate is regulated in a segment-and substrate concentration-dependent manner [11]. Lietz and Bryla [8] and Lietz et al [7] have also studied the influence of glycerol, lactate and ketone bodies, which are potentially important substrates for rabbit proximal tubules, on glutamine synthesis from alanine and aspartate. They found that these compounds might either stimulate or inhibit glutamine synthesis from these two amino acids.…”

Cellular and Molecular Mechanisms of Metformin Action

“…As described in the preceding sections, glycerol turnover is increased in individuals with T2D due to insulin resistance and inflammation in WAT, which in turn leads to increased contributions of glycerol to gluconeogenesis by a substrate-push mechanism ( 111 , 114 , 115 ). There is also evidence to suggest that metformin can alter redox balance even when rates of the glycerophosphate shuttle do not exceed that of the malate-aspartate shuttle ( 160-162 ).…”