Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients.
Normal subjects, fasted 60 h, and patients with insulin-dependent diabetes mellitus (IDDM), withdrawn from insulin and fasted overnight, were given phenylacetate orally and intravenously infused with [3-14C]lactate and 13C-bicarbonate. Rates of hepatic gluconeogenesis relative to Krebs cycle rates were estimated from the 14C distribution in glutamate from urinary phenylacetylglutamine. Assuming the 13C enrichment of breath CO2 was that of the CO2 fixed by pyruvate, the enrichment to be expected in blood glucose, if all hepatic glucose production had been by gluconeogenesis, was then estimated. That estimate was compared with the actual enrichment in blood glucose, yielding the fraction of glucose production due to gluconeogenesis. Relative rates were similar in the 60-h fasted healthy subjects and the diabetic patients. Conversion of oxaloacetate to phosphoenolpyruvate was two to eight times Krebs cycle flux and decarboxylation of pyruvate to acetyl-CoA, oxidized in the cycle, was less than one-30th the fixation by pyruvate of CO2. Thus, in estimating the contribution of a gluconeogenic substrate to glucose production by measuring the incorporation of label from the labelled substrate into glucose, dilution of label at the level of oxaloacetate is relatively small. Pyruvate cycling was as much as one-half the rate of conversion of pyruvate to oxaloacetate. Glucose and glutamate carbons were derived from oxaloacetate formed by similar pathways if not from a common pool. In the 60-h fasted subjects, over 80% of glucose production was via gluconeogenesis. In the diabetic subjects the percentages averaged about 45%.
Landau
B R
BR
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4951, USA.
Chandramouli
V
V
Schumann
W C
WC
Ekberg
K
K
Kumaran
K
K
Kalhan
S C
SC
Wahren
J
J
D000328:Adult; D001639:Bicarbonates / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D002952:Citric Acid Cycle; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005215:Fasting; D005260:Female; D005943:Gluconeogenesis; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000031:analogs & derivatives / Q000652:urine; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D011865:Radioisotope Dilution Technique; D012016:Reference Values; D014508:Urea / Q000652:urine
D001639:Bicarbonates; D001786:Blood Glucose; D002250:Carbon Radioisotopes; D007773:Lactates; D005973:Glutamine; D018698:Glutamic Acid; D014508:Urea; C003089:phenylacetylglutamine