Fasted state net glucose synthesis from hepatic GP

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Under these conditions, hepatic G6P is assumed to be entirely derived from gluconeogenesis and glycogenolysis activities and to be the sole source of plasma glucose synthesis, as shown in Figure 8.3. Because of extensive G6P-F6P exchange, position 2 is assumed to be enriched to the same level as body water and therefore it represents all G6P sources. Meanwhile, position 5 enrichment reflects the total gluconeogenic contribution. On this basis, the ratio of position 5 to position 2 enrichment (H5/H2) of plasma glucose provides an estimate of the percent contribution of gluconeogenesis to hepatic glucose production (equation 1), with the glycogenolysis contribution obtained by difference (equation 2). The difference between

Figure 8.3 Metabolic Model for the Sources of Hepatic Glucose Output During Fasting Also shown is a 2H NMR spectrum of a MAG derivative prepared from plasma glucose of a heart failure patient with new-onset diabetes. The number above each signal represents the glucose position where the signal originated. The ratio of position 5 to position 2 (H5/H2) and position 6S to position 2 (H6S/H2) enrichments as determined from the relative areas of the NMR signals are also shown. Applying these data to equations 1-4 gives the following estimates of flux contributions to fasting glucose production: 7% from glycogenolysis, 67% from PEP and 26% from glycerol.

Figure 8.3 Metabolic Model for the Sources of Hepatic Glucose Output During Fasting Also shown is a 2H NMR spectrum of a MAG derivative prepared from plasma glucose of a heart failure patient with new-onset diabetes. The number above each signal represents the glucose position where the signal originated. The ratio of position 5 to position 2 (H5/H2) and position 6S to position 2 (H6S/H2) enrichments as determined from the relative areas of the NMR signals are also shown. Applying these data to equations 1-4 gives the following estimates of flux contributions to fasting glucose production: 7% from glycogenolysis, 67% from PEP and 26% from glycerol.

position 5 and position 6 enrichments (H5 and H6) reflects the contributions of glycerol to the gluconeogenic fraction. The contribution of glycerol and PEP gluconeogenesis to fasting glucose production can thus be calculated according to equations 3 and 4.

1) Percentage of glucose derived by glycogenolysis = [1-(H5/H2)] x 100

2) Percentage of glucose derived by total gluconeogenesis = (H5/H2) x 100

3) Fraction of glucose derived by glycerol gluconeogenesis = [(H5 - H6)/H2] x 100

4) Fraction of glucose derived by PEP gluconeogenesis = (H6/H2) x 100

Since all flux parameters are based on relative rather than absolute glucose 2H-enrichment values, they can be obtained before plasma glucose and body water have reached isotopic steady state. These equations do not account for the effects of transaldolase exchange and will therefore give overestimates of gluconeogenic flux in the presence of transaldolase activity. (For example, after overnight fasting H5/H2 is typically 0.50, hence the estimated contribution of gluconeogenesis to glucose production is 50 % and that of glycogenolysis is 50 %. Assume that 20 % of G6P molecules also underwent transaldolase exchange and let x be the real percentage of glucose molecules formed by glycogenolysis with 100-x being the percentage formed by gluconeogenesis. Then, 100-x% would be enriched at position 5 by gluconeogenesis and 0.2x % would be enriched at position 5by transaldolase exchange. Thus, H5/H2 = 0.5 = (100-x + 0.2x)/100. Solving for x gives 62.5% - the real contribution of glycogenolysis. The real contribution of gluconeogenesis is therefore 37.5%. From the NMR spectrum shown in Figure 8.3, the lower intensity of the position 3 signal relative to

Nmr Spectra Paracetamol

Figure 8.4 Metabolic Scheme Representing Hepatic Glycogen Synthesis During Feeding Also shown is a 2H NMR spectrum of a MAG derivative prepared from Paracetamol glucuronide of a healthy subject that had ingested 2H2O and Paracetamol some hours before a morning breakfast meal. The number above each signal represents the glucuronide position where the signal originated. The ratio of position 5 to position 2 (H5/H2) enrichments as determined from the relative areas of the NMR signals and the enrichment of position 2 relative to body water (H2/body water) are also shown. Applying these data to equations 5-7 gives the following estimates of UDP-glucose flux contributions: 33% from galactose, 33 % from gluconeogenesis and 34 % from direct pathway metabolism of glucose.

Figure 8.4 Metabolic Scheme Representing Hepatic Glycogen Synthesis During Feeding Also shown is a 2H NMR spectrum of a MAG derivative prepared from Paracetamol glucuronide of a healthy subject that had ingested 2H2O and Paracetamol some hours before a morning breakfast meal. The number above each signal represents the glucuronide position where the signal originated. The ratio of position 5 to position 2 (H5/H2) enrichments as determined from the relative areas of the NMR signals and the enrichment of position 2 relative to body water (H2/body water) are also shown. Applying these data to equations 5-7 gives the following estimates of UDP-glucose flux contributions: 33% from galactose, 33 % from gluconeogenesis and 34 % from direct pathway metabolism of glucose.

those of positions 4 and 5 reflects a reduced enrichment in position 3 relative to positions 4 and 5, which is consistent with transaldolase activity.

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