scholarly journals A Convenient LC-MS Method for Assessment of Glucose Kinetics In Vivo with d-[13C6]Glucose as a Tracer

2009 ◽  
Vol 55 (3) ◽  
pp. 527-532 ◽  
Author(s):  
Haoyue Zhang ◽  
Robert D Stevens ◽  
Sarah P Young ◽  
Richard Surwit ◽  
Anastasia Georgiades ◽  
...  
Keyword(s):  
Solid Phase ◽  
Low Cost ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Ionization Mass ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Novel Approach ◽  
Glucose Derivative

Abstract Background: The isotope-labeled intravenous glucose tolerance test (IVGTT) combined with computer modeling is widely used to derive parameters related to glucose metabolism in vivo. Most of these methods involve use of either 2H2-labeled or 13C1-labeled d-glucose as a tracer with GC-MS to measure the isotope enrichment. These methods are challenging, both technologically and economically. We have developed a novel approach that is suitable for labeled-IVGTT studies involving a large cohort of individuals. Methods: The tracer, d-[13C6]glucose, is a low-cost alternative with the significant advantage that the sixth isotope of natural glucose has virtually zero natural abundance, which facilitates isotopomer analysis with <1% labeled glucose in the infusate. After deproteinization of plasma samples collected at various times, glucose is converted to a stable derivative, purified by solid-phase extraction (SPE), and analyzed by HPLC–electrospray ionization mass spectrometry to accumulate the isotope-abundance data for the A+2, A+3, and A+6 ions of the glucose derivative. A 2-pool modeling program was used to derive standard kinetic parameters. Results: With labeled-IVGTT data from 10 healthy male individuals, the values for insulin sensitivity, glucose effectiveness, and the plasma clearance rate estimated with the 2-pool minimal model compared well with values obtained via traditional methods. Conclusions: The relative simplicity and robustness of the new method permit the preparation and analysis of up to 48 samples/day, a throughput equivalent to 2 complete IVGTT experiments, and this method is readily adaptable to existing 96 well–format purification and analytical systems.

scholarly journals The hot IVGTT two-compartment minimal model: indexes  of glucose effectiveness and insulin sensitivity

1997 ◽  
Vol 273 (5) ◽  
pp. E1024-E1032 ◽  
Author(s):  
Paolo Vicini ◽  
Andrea Caumo ◽  
Claudio Cobelli
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Glucose Production ◽  
Normal Subjects ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Distribution Volume ◽  
Intravenous Glucose ◽  
Glucose Effectiveness

A two-compartment minimal model (2CMM) has been proposed [A. Caumo and C. Cobelli. Am. J. Physiol. 264 ( Endocrinol. Metab. 27): E829–E841, 1993] to describe intravenous glucose tolerance test (IVGTT) labeled (hereafter hot) glucose kinetics. This model, at variance with the one-compartment minimal model (1CMM), allows the estimation of a plausible profile of glucose production. The aim of this study is to show that the 2CMM also allows the assessment of insulin sensitivity ([Formula: see text]), glucose effectiveness ([Formula: see text]), and plasma clearance rate (PCR). The 2CMM was identified on stable-isotope IVGTTs performed in normal subjects ( n = 14). Results were (means ± SE) [Formula: see text] = 0.85 ± 0.14 ml ⋅ kg−1 ⋅ min−1, PCR = 2.02 ± 0.14 ml ⋅ kg−1 ⋅ min−1, and [Formula: see text] = 13.83 ± 2.54 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml. The 1CMM was also identified; glucose effectiveness and insulin sensitivity indexes were [Formula: see text]V = 1.36 ± 0.08 ml ⋅ kg−1 ⋅ min−1and [Formula: see text] V = 12.98 ± 2.21 × 10−2ml ⋅ kg−1 ⋅ min−1 ⋅ μU−1 ⋅ ml, respectively, where V is the 1CMM glucose distribution volume.[Formula: see text]V was lower than PCR and higher than [Formula: see text] and did not correlate with either [ r = 0.45 (NS) and r = 0.50 (NS), respectively], whereas [Formula: see text]V was not different from and was correlated with[Formula: see text]( r = 0.95; P < 0.001).[Formula: see text] compares well ( r = 0.78; P < 0.001) with PCR normalized by the 2CMM total glucose distribution volume. In conclusion, the 2CMM is a powerful tool to assess glucose metabolism in vivo.

Influence of mild exercise at the lactate threshold on glucose effectiveness

1999 ◽  
Vol 87 (6) ◽  
pp. 2305-2310 ◽  
Author(s):  
Makoto Sakamoto ◽  
Yasuki Higaki ◽  
Yuichiro Nishida ◽  
Akira Kiyonaga ◽  
Munehiro Shindo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Lactate Threshold ◽  
Lactate Production ◽  
Area Under The Curve ◽  
Young Male ◽  
Threshold Level ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
Glucose Effectiveness

The effect of a single bout of mild exercise on glucose effectiveness (SG) and insulin sensitivity (SI) was studied in six young male subjects by using a minimal model. An intravenous glucose tolerance test was performed under two conditions as follows: 1) 25 min after a bout of exercise on a cycle ergometer at the lactate threshold level for 60 min (Ex) and 2) without any prior exercise (Con). Leg blood flow (LBF) was also measured by strain-gauge plethysmography simultaneously with blood sampling. SI did not significantly change after exercise (18.1 ± 1.5 vs. 17.7 ± 1.9 × 10−5 min/pM), whereas SG significantly increased (0.016 ± 0.002 vs. 0.025 ± 0.002 min−1, P < 0.01). The increased blood flow after exercise remained high during the time period for measurement of the glucose disappearance constant and may be a determinant of SG. The incremental lactate area under the curve until insulin loading was also significantly higher in Ex than in Con (2.6 ± 0.9 vs. −3.5 ± 1.5 mM/min, P < 0.05). These results suggest that increased SG after mild exercise may be due, at least in part, to increased LBF and lactate production under a hyperglycemic state.

Effects of a single bout of exercise on glucose effectiveness

1996 ◽  
Vol 80 (3) ◽  
pp. 754-759 ◽  
Author(s):  
Y. Higaki ◽  
T. Kagawa ◽  
J. Fujitani ◽  
A. Kiyonaga ◽  
M. Shindo ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Exercise Bout ◽  
Threshold Level ◽  
Tolerance Test ◽  
Cycle Ergometer ◽  
Intravenous Glucose Tolerance Test ◽  
Exhaustive Exercise ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Single Bout

The effects of a single bout of exercise on glucose effectiveness (SG) and insulin sensitivity (SI) in 22 sedentary subjects were estimated with a minimal model approach. The intravenous glucose tolerance test (IVGTT) was performed 1) 11 h after an exercise bout on a cycle ergometer at the lactate threshold level (mild exercise) for 60 min, 2) 11 h after an exercise bout at the 4 mM lactate level (hard exercise) for 36 +/- 1 min, 3) 11 h after an exhaustive-exercise bout (exhaustive exercise) for 96 +/- 7 min, or 4) without any prior exercise (control). Only the exhaustive exercise increased the glucose disappearance constant (2.69 +/- 0.28 vs. 2.05 +/- 0.13%/min; P < 0.05) and SI (15.0 +/- 2.0 vs. 10.3 +/- 0.9 x 10(-5) min/pM: P < 0.05) in comparison with the control condition. The SG and SG at zero insulin (GEZI) were not affected by any exercise condition. However, a marked individual difference in GEZI emerged after the exhaustive exercise and could be divided into two subgroups: one decreased in GEZI (0.014 +/- 0.001 vs. 0.007 +/- 0.001 min-1) and the other increased in GEZI (0.014 +/- 0.001 vs. 0.021 +/- 0.003 min-1). The former subgroup was accompanied by elevated levels of plasma creatine kinase (100 +/- 16 vs. 598 +/- 315 IU/l; P < 0.05) and myoglobin (Mb; 46 +/- 4 vs. 126 +/- 47 ng/ml; P < 0.05), whereas the latter subgroup showed no significant change in creatinine kinase (99 +/- 10 vs. 128 +/- 9 IU/l; P = 0.05) and Mb (50 +/- 7 vs. 51 +/- 4 ng/ml; P = 0.05). In both subgroups, SI was similarly increased after the exhaustive exercise. These results thus suggest that a single bout of exercise that results in muscle damage or changes in muscle permeability, as reflected in the increased creatine kinase and Mb levels, decreases GEZI, whereas exhaustive exercise without such alterations increases GEZI.

Intravenous glucose tolerance test—derived glucose effectiveness in strength-trained humans

Metabolism ◽  
1998 ◽  
Vol 47 (7) ◽  
pp. 874-877 ◽  
Author(s):  
Junzo Fujitani ◽  
Yasuki Higaki ◽  
Toshiko Kagawa ◽  
Makoto Sakamoto ◽  
Akira Kiyonaga ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Intravenous Glucose Tolerance

Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice

2002 ◽  
Vol 283 (4) ◽  
pp. E738-E744 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Control Diet ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
High Fat ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Time Points

This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at 1 wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness (SG) and disposition index (DI), i.e., insulin sensitivity (SI) times early or total insulin secretion. Glucose disappearance (KG) and SI were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced SI, as judged by normal DI50 min. In contrast, early (10 min) insulin secretion was not sufficiently increased; DI10 min was reduced after 1, 3, and 10 mo. SG was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding.

Muscarinic stimulation maintains in vivo insulin secretion in response to glucose after prolonged hyperglycemia

1995 ◽  
Vol 268 (2) ◽  
pp. R475-R479 ◽  
Author(s):  
B. Balkan ◽  
B. E. Dunning
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Insulin Response ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
General Mechanism ◽  
Intravenous Glucose ◽  
Intravenous Glucose Tolerance

Prolonged hyperglycemia impairs the in vitro insulin release by islets of Langerhans in response to glucose but exaggerates the in vivo insulin response. We hypothesized that this discrepancy results from increased vagal stimulation of the islets. Conscious chronically cannulated rats were infused with glucose (15 mg/min) or saline for 48 h. Three hours thereafter, an intravenous glucose tolerance test was performed with or without prior injection of atropine (0.2 mg). Atropine markedly (> 70%) reduced the insulin response in glucose-infused, but not in saline-infused, rats. Glucose-infused rats displayed basal hypoglycemia but normal glucose excursions during an intravenous glucose tolerance test. It is concluded that prolonged hyperglycemia produces exaggerated muscarinic activation of the beta-cells that will persist > or = 3 h after the termination of the glucose infusion and normalizes in vivo insulin secretion. It is possible that increased parasympathetic activation of the pancreas might constitute a general mechanism to maintain insulin output when the demand for insulin exceeds the inherent beta-cell responsiveness.

scholarly journals Minimal model SGoverestimation and SIunderestimation: improved accuracy by a Bayesian two-compartment model

1999 ◽  
Vol 277 (3) ◽  
pp. E481-E488 ◽  
Author(s):  
Claudio Cobelli ◽  
Andrea Caumo ◽  
Matteo Omenetto
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Compartment Model ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Glucose Kinetics ◽  
Intravenous Glucose ◽  
Glucose Effectiveness ◽  
Normal Humans ◽  
Improved Accuracy

The intravenous glucose tolerance test (IVGTT) single-compartment minimal model (1CMM) method has recently been shown to overestimate glucose effectiveness and underestimate insulin sensitivity. Undermodeling, i.e., use of single- instead of two-compartment description of glucose kinetics, has been advocated to explain these limitations. We describe a new two-compartment minimal model (2CMM) into which we incorporate certain available knowledge on glucose kinetics. 2CMM is numerically identified using a Bayesian approach. Twenty-two standard IVGTT (0.30 g/kg) in normal humans were analyzed. In six subjects, the clamp-based index of insulin sensitivity ([Formula: see text]) was also measured. 2CMM glucose effectiveness ([Formula: see text]) and insulin sensitivity ([Formula: see text]) were, respectively, 60% lower ( P < 0.0001) and 35% higher ( P < 0.0001) than the corresponding 1CMM [Formula: see text] and[Formula: see text] indexes: 2.81 ± 0.29 (SE) vs.[Formula: see text] = 4.27 ± 0.33 ml ⋅ min−1 ⋅ kg−1and [Formula: see text] = 11.67 ± 1.71 vs.[Formula: see text] = 8.68 ± 1.62 102ml ⋅ min−1 ⋅ kg−1per μU/ml. [Formula: see text] was not different from[Formula: see text] = 12.61 ± 2.13 102ml ⋅ min−1 ⋅ kg−1per μU/ml (nonsignificant), whereas [Formula: see text]was 60% lower ( P < 0.02). In conclusion, a new 2CMM has been presented that improves the accuracy of glucose effectiveness and insulin sensitivity estimates of the classic 1CMM from a standard IVGTT in normal humans.

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