Measurement of Fractional Whole-Body Gluconeogenesis in Humans From Blood Samples Using 2H Nuclear Magnetic Resonance Spectroscopy

Kunert, Olaf; Stingl, Harald; Rosian, E; Krššák, Martin; Bernroider, Elisabeth; Seebacher, W; Zangger, Klaus; Stæhr, Peter; Chandramouli, Visvanathan; Landau, Bernard R.; Nowotny, Peter; Waldhäusl, W.; Haslinger, Ernst; Roden, Michael

doi:10.2337/diabetes.52.10.2475

Cited by 35 publications

(63 citation statements)

References 31 publications

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“…Other MAG 2 H-signals corresponding to positions 3, 4, and 5 of glucuronide were less intense, indicating dilution of 2 Henrichment at these sites by G6P derived from unlabeled hepatic glycogen. The intensity of signal 5 relative to signal 2 corresponds to the 2 H-enrichment ratio of positions 5 and 2 (G5/G2) and provides an estimate of the relative contribution of gluconeogenesis and glycogenolysis to G6P synthesis (10,19). While the mean G5/G2 was significantly higher for the type 1 diabetic group compared with healthy control subjects, the ranges (0.52-0.70 for type 1 diabetic and 0.49 -0.61 for healthy control subjects) overlapped considerably.…”

Section: Resultsmentioning

confidence: 99%

“…In healthy subjects who were given 2 H 2 O and fasted overnight, the plasma glucose hydrogen 5-to-hydrogen 2 enrichment ratio (H5/H2) increased by ϳ10% between the 12th and 14th hour of fasting (22). In another 2 H 2 O study, plasma glucose H5/H2 increased by 14% in healthy subjects and 13% for type 2 diabetes patients from the 14th to the 16th hour of fasting (10). Direct and indirect pathway contributions to glycogen synthesis also change over the initial few hours after feeding (4,7).…”

Section: Discussionmentioning

confidence: 97%

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Noninvasive Analysis of Hepatic Glycogen Kinetics Before and After Breakfast with Deuterated Water and Acetaminophen

et al. 2006

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The contributions of hepatic glycogenolysis to fasting glucose production and direct pathway to hepatic glycogen synthesis were quantified in eight type 1 diabetic patients and nine healthy control subjects by ingestion of 2 H 2 O and acetaminophen before breakfast followed by analysis of urinary water and acetaminophen glucuronide. After overnight fasting, enrichment of glucuronide position 5 relative to body water (G5/body water) was significantly higher in type 1 diabetic patients compared with control subjects, indicating a reduced contribution of glycogenolysis to glucose production (38 ؎ 3 vs. 46 ؎ 2%). Following breakfast, G5/body water was significantly higher in type 1 diabetic patients, indicating a smaller direct pathway contribution to glycogen synthesis (47 ؎ 2 vs. 59 ؎ 2%). Glucuronide hydrogen 2 enrichment (G2) was equivalent to body water during fasting (G2/body water 0.94 ؎ 0.03 and 1.02 ؎ 0.06 for control and type 1 diabetic subjects, respectively) but was significantly lower after breakfast (G2/body water 0.78 ؎ 0.03 and 0.82 ؎ 0.05 for control and type 1 diabetic subjects, respectively). The reduced postprandial G2 levels reflect incomplete glucose-6-phosphate-fructose-6-phosphate exchange or glycogen synthesis from dietary galactose. Unlike current measurements of human hepatic glycogen metabolism, the 2 H 2 O/acetaminophen assay does not require specialized on-site clinical equipment or personnel. Diabetes

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Noninvasive Analysis of Hepatic Glycogen Kinetics Before and After Breakfast with Deuterated Water and Acetaminophen

et al. 2006

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“…All participants gave informed written consent to the protocol, which was approved by our institutional ethics board. They ingested a liquid meal (60% carbohydrate, 20% protein, 20% fat) at 18.30 hours [26] and fasted overnight.…”

Section: Protocolmentioning

confidence: 99%

Changes in hepatic glycogen cycling during a glucose load in healthy humans

et al. 2005

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Aims/hypothesis: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested 2 H 2 O (5 ml/kg body water) and were infused with [5-3 H] glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of 2 H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the 3 H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results: Glucose infusion rates increased (p<0.01) to ∼50 μmol kg −1 min −1 . Plasma insulin and the insulin : glucagon ratio rose ∼3.6-and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2-4 h, 54±6%; 4-6 h, 59±5%; 6-8 h, 63±4%) and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2-4 h) to 4±3% (4-6 h) and 1±3% (6-8 h). Conclusions/interpretation: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.

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“…Together with glucose tracer methodology, this is important for understanding the progression of type 2 diabetes and for evaluating the effects of various therapeutic strategies (viz., medications) intended to mitigate excessive hepatic glucose production by inhibiting gluconeogenesis. Therefore, validation of tracer-derived gluconeogenesis measurements is possible in principle, for example, by comparison with gluconeogenic fluxes obtained by subtraction of real-time glycogenolysis and EGP (18,23,24), a measurement that is insensitive to TA activity. However, outside of a few specialized clinical research centers, this approach is not available, and in many cases it does not provide reliable estimates of gluconeogenesis under clamp conditions.…”

Section: Discussionmentioning

confidence: 99%

Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes

Rajpal

Dube

Carvalho

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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13 C]acetate during a separate visit in a subset of ND (n ϭ 7) subjects. Ratio of 13 C3/ 13 C4 obtained following either tracer was Ͻ1.0 at baseline and during clamp, indicating that TPI exchange was essentially complete and did not contribute to asymmetric glucose enrichment. Uncorrected and corrected rates of gluconeogenesis were no different (P ϭ not significant) in T2DM vs. ND both at baseline and during clamp. TA correction resulted in equivalent estimates of corrected gluconeogenesis in T2DM and ND that were ϳ25-35% lower than uncorrected gluconeogenesis both at baseline and during the clamp. The asymmetric enrichment of glucose from 13 C-gluconeogenic tracers is attributable to TA exchange and can be utilized to correct for TA exchange. In conclusion, TA exchange does not differ between T2DM and ND under fasting or hyperglycemic clamp conditions, and the 2 H2O method continues to provide an accurate estimation of gluconeogenesis. gluconeogenesis; deuterated water; transaldolase; triose phosphate isomerase AFTER AN OVERNIGHT FAST, plasma glucose is not symmetrically labeled from gluconeogenic carbon tracers such as [U-13 C] glycerol (21) and [3-14 C]lactate (25). Exchange of fructose 6-phosphate and triose phosphate mediated by transaldolase has been implicated by us (3, 7, 9) and others (12) in overestimation of rates of gluconeogenesis, utilizing the deuterated water method. In this method, glucose derived from glycogenolysis (GGL) via glucose 6-phosphate (G6P) source can become labeled in carbons 4, 5, and 6 from either a carbonlabeled gluconeogenic precursor or deuterated water independent of gluconeogenesis. This results in an overestimation of the gluconeogenic fraction and a corresponding underestimation of the glycogenolytic contribution to endogenous glucose production. This exchange is particularly important in the study of type 2 diabetes mellitus (T2DM) since it mimics the characteristic shift toward increased hepatic gluconeogenic activity during the progression of this disease. With a few exceptions (14), stable isotope tracer studies indicate an increased fractional gluconeogenesis in overnight-fasted T2DM subjects compared with healthy nondiabetic (ND) controls (6,10,15,16,28). Transaldolase (TA) exchange activity has been implicated in both ND and T2DM subjects from the depletion of position 5 relative to position 3 label following metabolism of [3, H 2 ]galactose to glucose (7). However, it is not known whether transaldolase exchange activity is different between ND and T2DM under conditions of fasting and hyperglycemia (frequently seen with meals). This study was undertaken to compare TA exchange reaction in ND and T2DM subjects using [1-13 C]acetate infusion under conditions of fasting and during a hyperglycemic moderate-dose insulin clamp to determine whether or not TA exchange activity explains differences in glucose enrichment from gluconeogenic substrates between ND and T2DM subjects.We have demonstrated that TA activity occurs in healthy humans based on a higher enrichment of gluco...

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Measurement of Fractional Whole-Body Gluconeogenesis in Humans From Blood Samples Using 2H Nuclear Magnetic Resonance Spectroscopy

Cited by 35 publications

References 31 publications

Noninvasive Analysis of Hepatic Glycogen Kinetics Before and After Breakfast with Deuterated Water and Acetaminophen

Noninvasive Analysis of Hepatic Glycogen Kinetics Before and After Breakfast with Deuterated Water and Acetaminophen

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes

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