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Normal subjects, fasted 60 h, and patients with insulin-dependent diab etes mellitus (IDDM), withdrawn from insulin and fasted overnight, wer e given phenylacetate orally and intravenously infused with [3-C-14]la ctate and C-13-bicarbonate. Rates of hepatic gluconeogenesis relative to Krebs cycle rates were estimated from the C-14 distribution in glut amate from urinary phenylacetylglutamine. Assuming the C-13 enrichment of breath CO2 was that of the CO2 fixed by pyruvate, the enrichment t o be expected in blood glucose, if all hepatic glucose production had been by gluconeogenesis, was then estimated. That estimate was compare d with the actual enrichment in blood glucose, yielding the fraction o f glucose production due to gluconeogenesis. Relative rates were simil ar in the 60-h fasted healthy subjects and the diabetic patients. Conv ersion of oxaloacetate to phosphoenolpyruvate was two to eight times K rebs cycle flux and decarboxylation of pyruvate to acetyl-CoA, oxidize d 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 l abelled substrate into glucose, dilution of label at the level of oxal oacetate is relatively small. Pyruvate cycling was as much as one-half the rate of conversion of pyruvate to oxaloacetate. Glucose and gluta mate 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 genesis. In the diabetic subjects the percentages averaged abo ut 45 %.