scholarly journals The realiability of rates of glucose appearance in vivo calculated from constant tracer infusions

1978 ◽  
Vol 172 (3) ◽  
pp. 407-416 ◽  
Author(s):  
J R Allsop ◽  
R R Wolfe ◽  
J F Burke
Keyword(s):  
Specific Radioactivity ◽  
Glucose Production ◽  
Volume Of Distribution ◽  
Endogenous Glucose Production ◽  
Single Step ◽  
Actual Rate ◽  
Steady State Rate ◽  
Isotope Technique ◽  
State Rate

The rate of appearance of unlabelled glucose was calculated from tracer data and compared with the actual rate of infusion of unlabelled glucose into a anaesthetized dog with all sources of endogenous glucose production surgically removed. The mean steady-state rate of appearance of unlabelled glucose calculated from the equilibrium specific radioactivity was insignificantly higher (0.3%) than the actual rate of infusion of unlabelled glucose (n = 6). During non-steady states, a time-variable volume of distribution of glucose (V) was necessary to predict the rate of appearance of unlabelled glucose correctly from the pool-dependent equation described by Steele [(1959) Ann. N.Y. Acad. Sci. 82, 420–430]. Rapid fluctuations in the rate of appearance of glucose could be predicted reasonably well by using a fixed value of V for 40ml/kg, but by using larger fixed values for V (100–160ml/kg) the rates were inaccurate. The pool-dependent two-radiactive-isotope technique described by Issekutz, Issekutz & Elahi [(1974) Can. J. Physiol. Pharmacol. 52, 215–224] predicted single-step increases in the rate of infusion of glucose reasonably accurately, but the Steele (1959) equation was better at predicting sequential changes in the rate of infusion of unlabelled glucose.

The reliability of rates of glucose appearance in vivo calculated from single tracer injections

1979 ◽  
Vol 57 (11) ◽  
pp. 1267-1274 ◽  
Author(s):  
John R. Allsop ◽  
Robert R. Wolfe ◽  
Joseph J. DiStephano III ◽  
John F. Burke
Keyword(s):  
Plasma Glucose ◽  
Infusion Rate ◽  
Specific Radioactivity ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Constant Infusion ◽  
Glucose Turnover ◽  
Time Curve ◽  
The Mean

The rate of appearance of unlabelled glucose was calculated from changes in plasma glucose specific radioactivity after a single intravenous injection of labelled glucose and compared with the actual constant infusion rate of unlabelled glucose into an anaesthetized dog with all sources of endogenous glucose production surgically removed. The mean steady-state rate of appearance of unlabelled glucose calculated from the area under the specific radioactivity versus time curve was 7% higher than the actual infusion rate (n = 4), but the difference was not statistically significant. The variability in the rate calculated in this manner was, however, greater than the variability we have reported with rates determined from a primed constant infusion of tracer. Using 15- to 60- or 60- to 120-min specific radioactivity data the mean rate of appearance of glucose, calculated on the assumption of a one-pool model for glucose turnover in vivo, was approximately 60% higher than the actual infusion rate. The results also indicate that it is possible to construct multi-pool models, but it is difficult to equate specific physiological events with the individual terms of the multi-exponential equation which describes the changes in plasma glucose specific radioactivity.

scholarly journals Growth hormone signaling and action in obese versus lean human subjects

2019 ◽  
Vol 316 (2) ◽  
pp. E333-E344 ◽  
Author(s):  
Morten Lyng Høgild ◽  
Ann Mosegaard Bak ◽  
Steen Bønløkke Pedersen ◽  
Jørgen Rungby ◽  
Jan Frystyk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Human Subjects ◽  
Glucose Production ◽  
Relative Increase ◽  
Antagonistic Effect ◽  
Endogenous Glucose Production ◽  
Metabolic Adaptation ◽  
Igf I

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, −66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

Experimental validation of measurements of glucose turnover in nonsteady state.

1978 ◽  
Vol 234 (1) ◽  
pp. E84 ◽  
Author(s):  
J Radziuk ◽  
K H Norwich ◽  
M Vranic
Keyword(s):  
Dispersion Model ◽  
Glucose Production ◽  
Compartment Model ◽  
Sole Source ◽  
Volume Of Distribution ◽  
Endogenous Glucose Production ◽  
The Body ◽  
Glucose Turnover ◽  
Turnover Rates ◽  
Nonsteady State

The aim of the present experiments is to validate, in conscious dogs, the tracer infusion methods of measuring nonsteady turnover rates. This was done in nine experiments performed in four normal dogs by infusing isotopically labeled glucose (2-3H, 6-3H, 1-14C) and monitoring the concentrations of both the labeled and unlabeled substances. The validation is based on the observation that a high exogenous infusion of glucose will suppress endogenous glucose production and become the sole source of glucose in the body. By infusing glucose at a high, time-varying rate, calculating its rate of appearance, (Ra) and comparing it to the infused rate, the method can be verified. The calculations were based on: a) a single-compartment model with a modified volume of distribution; b) a two-compartment model; and c) a generalized dispersion model. The absolute values of the areas of the deviations of the calculated from the infused curves were found to be, respectively, 9.5, 8.4, and 7.8 percent of the total area under the infused curve. It was concluded that the tracer infusion method can reliably measure Ra of glucose when it is changing rapidly, and the system is out of steady state.

scholarly journals Glucagon sensitivity and clearance in type 1 diabetes: insights from in vivo and in silico experiments

2015 ◽  
Vol 309 (5) ◽  
pp. E474-E486 ◽  
Author(s):  
Ling Hinshaw ◽  
Ashwini Mallad ◽  
Chiara Dalla Man ◽  
Rita Basu ◽  
Claudio Cobelli ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Silico ◽  
Artificial Pancreas ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Action Model ◽  
The Difference ◽  
Hormone Control

Glucagon use in artificial pancreas for type 1 diabetes (T1D) is being explored for prevention and rescue from hypoglycemia. However, the relationship between glucagon stimulation of endogenous glucose production (EGP) viz., hepatic glucagon sensitivity, and prevailing glucose concentrations has not been examined. To test the hypothesis that glucagon sensitivity is increased at hypoglycemia vs. euglycemia, we studied 29 subjects with T1D randomized to a hypoglycemia or euglycemia clamp. Each subject was studied at three glucagon doses at euglycemia or hypoglycemia, with EGP measured by isotope dilution technique. The peak EGP increments and the integrated EGP response increased with increasing glucagon dose during euglycemia and hypoglycemia. However, the difference in dose response based on glycemia was not significant despite higher catecholamine concentrations in the hypoglycemia group. Knowledge of glucagon's effects on EGP was used to develop an in silico glucagon action model. The model-derived output fitted the obtained data at both euglycemia and hypoglycemia for all glucagon doses tested. Glucagon clearance did not differ between glucagon doses studied in both groups. Therefore, the glucagon controller of a dual hormone control system may not need to adjust glucagon sensitivity, and hence glucagon dosing, based on glucose concentrations during euglycemia and hypoglycemia.

Novel Double-Isotope Technique for Enzymatic Assay of Catecholamines, Permitting High Precision, Sensitivity and Plasma Sample Capacity

1981 ◽  
Vol 61 (5) ◽  
pp. 591-598 ◽  
Author(s):  
M. J. Brown ◽  
D. A. Jenner
Keyword(s):  
Plasma Sample ◽  
Specific Radioactivity ◽  
High Specific Radioactivity ◽  
Coefficients Of Variation ◽  
Isotope Technique ◽  
Noradrenaline And Adrenaline ◽  
Radioenzymatic Assays ◽  
Double Isotope ◽  
Catecholamine Concentration

1. A novel use of a double-isotope method is described which allows radioenzymatic assays to combine precision and sensitivity. 2. In the catechol O-methyltransferase assay separate portions of each plasma sample are incubated with either S-[3H]- or S-[14C]-adenosyl-l-methionine. Standards of noradrenaline and adrenaline are added to the latter portions and are thus converted into standards of [14C]metadrenalines. These are added to the 3H-labelled portions after the incubation, where they function as tracers. 3. The final recovery of 14C radioactivity corrects for (a) the efficiency of methylation in the plasma sample concerned and (b) the recovery of metadrenalines during the extraction procedures. 4. The 3H/14C ratio is constant in each assay for a given catecholamine concentration and is determined for samples to which standards of noradrenaline and adrenaline are added to the 3H- (as well as the I4C-) labelled portions before the initial incubation. 5. The sensitivity of the assay is increased by using high specific radioactivity S-[3H]adenosyl-l-methionine (60-85 Ci/mmol), and low backgrounds are maintained by catecholamine depletion in vivo in the rats used for enzyme preparation. 6. Both catecholamines (1.5 pg/ml; 10 pmol/l) may be detected; the coefficients of variation are 3.0 and 3.2% for noradrenaline and adrenaline respectively (intra-assay) and 4.6 and 5.0% (inter-assay).

scholarly journals Mass spectrometry-based microassay of 2H and 13C plasma glucose labeling to quantify liver metabolic fluxes in vivo

2015 ◽  
Vol 309 (2) ◽  
pp. E191-E203 ◽  
Author(s):  
Clinton M. Hasenour ◽  
Martha L. Wall ◽  
D. Emerson Ridley ◽  
Curtis C. Hughey ◽  
Freyja D. James ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Glucose ◽  
Ad Hoc ◽  
Citrate Synthase ◽  
Physiological Stress ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose

Mouse models designed to examine hepatic metabolism are critical to diabetes and obesity research. Thus, a microscale method to quantitatively assess hepatic glucose and intermediary metabolism in conscious, unrestrained mice was developed. [13C3]propionate, [2H2]water, and [6,6-2H2]glucose isotopes were delivered intravenously in short- (9 h) and long-term-fasted (19 h) C57BL/6J mice. GC-MS and mass isotopomer distribution (MID) analysis were performed on three 40-μl arterial plasma glucose samples obtained during the euglycemic isotopic steady state. Model-based regression of hepatic glucose and citric acid cycle (CAC)-related fluxes was performed using a comprehensive isotopomer model to track carbon and hydrogen atom transitions through the network and thereby simulate the MIDs of measured fragment ions. Glucose-6-phosphate production from glycogen diminished, and endogenous glucose production was exclusively gluconeogenic with prolonged fasting. Gluconeogenic flux from phospho enolpyruvate (PEP) remained stable, whereas that from glycerol modestly increased from short- to long-term fasting. CAC flux [i.e., citrate synthase ( V CS)] was reduced with long-term fasting. Interestingly, anaplerosis and cataplerosis increased with fast duration; accordingly, pyruvate carboxylation and the conversion of oxaloacetate to PEP were severalfold higher than V CS in long-term fasted mice. This method utilizes state-of-the-art in vivo methodology and comprehensive isotopomer modeling to quantify hepatic glucose and intermediary fluxes during physiological stress in mice. The small plasma requirements permit serial sampling without stress and the affirmation of steady-state glucose kinetics. Furthermore, the approach can accommodate a broad range of modeling assumptions, isotope tracers, and measurement inputs without the need to introduce ad hoc mathematical approximations.

Estimation of glucose production during exercise with a one-compartment variable-volume model

1992 ◽  
Vol 72 (6) ◽  
pp. 2501-2509 ◽  
Author(s):  
D. T. Finegood ◽  
P. D. Miles ◽  
H. L. Lickley ◽  
M. Vranic
Keyword(s):  
Specific Activity ◽  
Glucose Production ◽  
Compartment Model ◽  
Accurate Estimate ◽  
Endogenous Glucose Production ◽  
Single Step ◽  
Regression Method ◽  
Variable Volume ◽  
Volume Model ◽  
Fixed Volume

A variable-volume one-compartment model of glucose kinetics and step increases in the rate of tracer infusion were examined for estimation of endogenous glucose production (Ra) during moderate exercise in dogs. A primed infusion of D-[3–3H]glucose was left constant or increased 1.5-, 2-, 3-, 4-, or 5-fold at the onset of a 60-min period of exercise. Application of a regression method, in which Ra and the effective distribution volume were estimated over time, revealed dynamic changes in Ra that were not evident during the constant tracer infusion with a fixed-volume model. Application of the fixed-volume model to studies performed with a two- or three-fold step increase in tracer resulted in the lowest sum-of-squares difference from the regression method. Our results demonstrate that application of a variable-volume model can be achieved during exercise by enrichment of the plasma specific activity through step increases in the rate of tracer infusion and application of a regression method. Alternately, estimates of Ra with a fixed-volume model can be improved by enrichment of the plasma specific activity through a single step increase in the rate of tracer infusion. Our results suggest that when endogenous Ra is changing rapidly, such as at the onset of exercise, these methods will provide a more accurate estimate of Ra than the standard fixed-volume model and constant tracer infusion.

scholarly journals Effects of Somatostatin and Glucagon on the Utilization of [2_14C] Propionate in Glucose Production in Vivo in Sheep

1980 ◽  
Vol 33 (4) ◽  
pp. 457 ◽  
Author(s):  
Ronald P Brockman ◽  
Cindy Greer
Keyword(s):  
Continuous Infusion ◽  
Plasma Glucose ◽  
Control Period ◽  
Specific Radioactivity ◽  
Glucose Production ◽  
Irreversible Loss ◽  
Selective Effect ◽  
Glycogenolytic Effect ◽  
Glucose Synthesis

This study examined the effects of hypoglucagonaemia and hyperglucagonaemia on the incorporation of 14C from [2-14C]propionate into plasma glucose of sheep in vivo. The sheep were adult ewes fed a maintenance diet of lucerne pellets delivered in equal aliquots hourly. The irreversible loss of glucose was determined by the continuous infusion of [6-3H]glucose. During the control period (the hour immediately preceding infusion of hormones) 63 �2 % of the propionate was converted to glucose, accounting for 30�2 % of glucose production. Glucagon deficiency, induced by infusion of somatostatin (100 J1g/h), did not affect gluconeogenesis and the irreversible loss of glucose significantly. However, glucagon infusion at 11 �5 �O� 6 J1g/h significantly increased the irreversible loss of glucose, with the greatest increase occurring in the first 15 min of infusion. The 14C specific radioactivity of glucose and the fraction of glucose derived from propionate decreased significantly during glucagon infusion. The data are consistent with glucagon having a marked glycogenolytic effect initially, but little or no selective effect in promoting the utilization of propionate for glucose synthesis in vivo in sheep.

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