Fructose-6-Phosphate Cycling and the Pentose Cycle in Hyperthyroidism

Abstract

Hepatic fructose-6-phosphate (fructose-6-P) cycling and pentose cycle activity were quantified in hyperthyroid patients. A measure of the fructose-6-P cycle was the incorporation of 14C, on administering [3-3H,6-14C]galactose, into carbon 1 of blood glucose and the 3H/14C ratio in blood glucose. The measure of the pentose cycle was the randomization of 14C to carbon 1 of blood glucose on administering [2-14C]galactose. [2-3H]Galactose was also administered, so the 3H/14C ratio in blood glucose measured the extent of equilibration of glucose-6-P with fructose-6-P. Patients given [3-3H,6-14C]galactose were restudied when euthyroid. Of the 14C from [3-3H,6-14C]galactose, 7.7-9.5% was in carbon 1 of glucose in both states. 3H/14C ratios were also the same in both states. Fructose-6-P cycling was estimated to be 13 +/- 1% the rate of glucose turnover in the euthyroid and 15 +/- 1% that in the hyperthyroid state. The pentose cycle contributed about 2% to glucose utilization, similar to previous estimates in healthy humans. As in healthy individuals, about 25% of 3H was retained in the conversion of [2-3H]glucose-6-P to glucose. Thus, the fractions of glucose turnover participating in hepatic fructose-6-P and pentose cycling are similar in hyperthyroid and healthy subjects. As a result, augmented fructose-6-P cycling does not substantially contribute to increased hepatic oxygen consumption in hyperthyroidism.

Contributions of gluconeogenesis to glucose production in the fasted state.

“…At 8% the corrected values would remain essentially unchanged, e.g., at 14 h [(51 ϩ 4)/104]100 ϭ 53%. No significant cycling between glucose-6-P and triose-P after an overnight fast was found in one study (24), but was estimated to be 13% of glucose-6-P conversion to glucose in another study (31). Glucosyl units of glycogen converted to glucose-6-P in the process of glycogenolysis and experiencing that cycling, as well as fructose-6-P formed from glycogen and subjected to the transaldolase exchange reaction (7), would be included in the fraction of glucose formed by gluconeogenesis.…”

Contribution to Postprandial Hyperglycemia and Effect on Initial Splanchnic Glucose Clearance of Hepatic Glucose Cycling in Glucose-Intolerant or NIDDM Patients

“…In contrast to these studies, we saw no evidence of a transient increase in postprandial hepatic glucose cycling in previous studies in which we used a systemic infusion of [3-3 H]-and [2-3 H]glucose to measure glucose turnover (20). However, our ability to quantitate hepatic glucose cycling was limited in those experiments, because [3-3 H]glucose can be detritiated either during fructose/fructose-6-phosphate cycling or via the pentose phosphate shunt (42,43), and we are unsure about the purity of the isotopes used in that study (44). similar to those used in these experiments have shown that intravenous infusion of glucagon increases hepatic glucose cycling (32,33).…”

Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors

“…13 C NMR analysis of both GBM and CCRCC brain metastases revealed 13 C-13 C coupling in glutamate and GABA, suggesting that glucose was metabolized to acetyl-CoA and further oxidized in the Krebs cycle. Although [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]-labeled glucose is a suboptimal tracer for assessing Krebs cycle intermediates, as only 50% of acetyl-CoA becomes 13 C labeled, the presence of multiplets in glutamate and GABA nevertheless denotes the presence of Krebs cycle activity. This observation suggests that malignant brain tumors, growing in the microenvironment of the brain, rely on oxidative metabolism in addition to glycolysis and increased production of lactate, the latter being characteristic of the Warburg effect (2).…”

“…All carbon tracer methods probing the pathway rely on the detection of the effects of this characteristic decarboxylation reaction in downstream metabolites, particularly lactate. Traditionally, 14 C-enriched glucose was used in rodent and human experiments (3)(4)(5), but more recent studies have extensively evaluated the use of [2-13 C]glucose or [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]glucose with the detection of lactate by either 13 C NMR spectroscopy (6)(7)(8)(9) or mass spectrometry (10). Together, these studies indicate that the flux of glucose through the PPP is active in a variety of tissues, and that it is increased in cancer (11) or after brain injury (12).…”

“…To minimize non-physiological metabolic changes in the cell, we developed an orthotopic mouse model of human brain tumors that provides a good approximation of the cell's native microenvironment. Using this model, we analyzed the relative activity of the PPP and compared it with glycolysis in orthotopic glioblastoma (GBM) and orthotopic clear cell renal cell carcinoma (CCRCC) brain metastasis in situ by infusion of [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]glucose, followed by microdissection and analysis of the tissue extract by 13 C NMR spectroscopy. The distribution of 13 C in lactate was used to assess the flux through the PPP relative to glycolysis, essentially as described by others (10,12,15).…”