A possible mechanism for the anti-ketogenic action of alanine in the rat

Abstract

1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10mug/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70+/-11% decrease in [3-hydroxybutyrate] and a 58+/-9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72+/-9% decrease in the rate of production of ketone bodies and a 57+/-8% decrease in disappearance rate as assessed by [3-(14)C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia, hypoglycaemia and post-hypoglycaemic hyperglycaemia

“…Although NEFA may suppress glucagon secretion [30], whether this was the case in the present studies cannot be established. However, the results of the present studies are concordant with earlier data indicating that the formation of ketone bodies is reduced by the elevation of plasma alanine, as shown in rats [31,32] and man [33]. These studies point towards a clear anti-ketogenic effect of alanine in the setting of a reciprocal relationship between alanine and ketone bodies (alanine-ketone body cycle) [33,34].…”

Concentration of free oxaloacetate in the mitochondrial compartment of isolated liver cells

“…Thus, on the basis of the data shown in Tables 1 and 2, 25-30% of the increase in ketone-body production seen at elevated fatty acid supply could be explained by the decrease in acetyl-CoA utilization by citrate synthase. These results provide a quantitative basis for the estimation of the role of oxaloacetate availability in the regulation of ketonebody production, qualitatively documented by several earlier studies (Lehninger, 1946;Breusch, 1948;Wieland, 1968;Lopes-Cardozo & Van den Bergh, 1972;Lopes-Cardozo, 1978;Blackshear et al, 1975;Nosadini et al, 1980;Demaugre et al, 1982). In connection with our previous measurements of mitochondrial [3-hydroxybutyrate]/…”

Regulation of Ketogenesis

“…The flux of acetyl-CoA into the citric acid cycle and in the 3-hydroxymethylglutaryl-CoA cycle is mainly determined by the concentration of free oxaloacetate [9,10] which in turn is influenced by changes in the redox states of the mitochondrial pyridine nucleotides [ll] or by N 6 , 0 Zdibutyryladenosine 3',5'-monophosphate [12]. Unequivocally these metabolic events render the disposition of acetyl-CoA for ketone body production.…”