TY - JOUR
T1 - Advantages of dynamic "closed loop" stable isotope flux phenotyping over static "open loop" clamps in detecting silent genetic and dietary phenotypes
AU - Vaitheesvaran, Bhavapriya
AU - Chueh, Fu Yu
AU - Xu, Jun
AU - Trujillo, Chuck
AU - Saad, M. F.
AU - Lee, W. N.P.
AU - McGuinness, Owen P.
AU - Kurland, Irwin J.
N1 - Funding Information:
Acknowledgements This work was supported by grants from National Institutes of Health Grant (R01 DK58132-07) (to I.J.K.), UCLA Center of Excellence in Pancreatic disease (P01 AT003960, W.N.P.L.), Harbor-UCLA GCRC Mass Spectrometry Core (M01 RR00425, W.N.P.L.), the Vanderbilt Mouse Metabolic Phenotyping Center (DK 59637) and (R21 DK 064877, O.P.M.).
PY - 2010/6
Y1 - 2010/6
N2 - In vivo insulin sensitivity can be assessed using "open loop" clamp or "closed loop" methods. Open loop clamp methods are static, and fix plasma glucose independently from plasma insulin. Closed loop methods are dynamic, and assess glucose disposal in response to a stable isotope labeled glucose tolerance test. Using PPARα-/- mice, open and closed loop assessments of insulin sensitivity/glucose disposal were compared. Indirect calorimetry done for the assessment of diurnal substrate utilization/metabolic flexibility showed that chow fed PPARα-/- mice had increased glucose utilization during the light (starved) cycle. Euglycemic clamps showed no differences in insulin stimulated glucose disposal, whether for chow or high fat diets, but did show differences in basal glucose clearance for chow fed PPARα-/- versus SV129J-wt mice. In contrast, the dynamic stable isotope labeled glucose tolerance tests reveal enhanced glucose disposal for PPARα-/- versus SV129J-wt, for chow and high fat diets. Area under the curve for plasma labeled and unlabeled glucose for PPARα-/- was ≈1.7-fold lower, P < 0.01 during the stable isotope labeled glucose tolerance test for both diets. Area under the curve for plasma insulin was 5-fold less for the chow fed SV129J-wt (P < 0.01) but showed no difference on a high fat diet (0.30 ± 0.1 for SV129J-wt vs. 0.13 ± 0.10 for PPARα-/-, P = 0.28). This study demonstrates that dynamic stable isotope labeled glucose tolerance test can assess "silent" metabolic phenotypes, not detectable by the static, "open loop", euglycemic or hyperglycemic clamps. Both open loop and closed loop methods may describe different aspects of metabolic inflexibility and insulin sensitivity.
AB - In vivo insulin sensitivity can be assessed using "open loop" clamp or "closed loop" methods. Open loop clamp methods are static, and fix plasma glucose independently from plasma insulin. Closed loop methods are dynamic, and assess glucose disposal in response to a stable isotope labeled glucose tolerance test. Using PPARα-/- mice, open and closed loop assessments of insulin sensitivity/glucose disposal were compared. Indirect calorimetry done for the assessment of diurnal substrate utilization/metabolic flexibility showed that chow fed PPARα-/- mice had increased glucose utilization during the light (starved) cycle. Euglycemic clamps showed no differences in insulin stimulated glucose disposal, whether for chow or high fat diets, but did show differences in basal glucose clearance for chow fed PPARα-/- versus SV129J-wt mice. In contrast, the dynamic stable isotope labeled glucose tolerance tests reveal enhanced glucose disposal for PPARα-/- versus SV129J-wt, for chow and high fat diets. Area under the curve for plasma labeled and unlabeled glucose for PPARα-/- was ≈1.7-fold lower, P < 0.01 during the stable isotope labeled glucose tolerance test for both diets. Area under the curve for plasma insulin was 5-fold less for the chow fed SV129J-wt (P < 0.01) but showed no difference on a high fat diet (0.30 ± 0.1 for SV129J-wt vs. 0.13 ± 0.10 for PPARα-/-, P = 0.28). This study demonstrates that dynamic stable isotope labeled glucose tolerance test can assess "silent" metabolic phenotypes, not detectable by the static, "open loop", euglycemic or hyperglycemic clamps. Both open loop and closed loop methods may describe different aspects of metabolic inflexibility and insulin sensitivity.
KW - Metabolic flexibility
KW - Orphan nuclear receptor action
KW - Stable isotope flux phenotyping
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U2 - 10.1007/s11306-009-0190-2
DO - 10.1007/s11306-009-0190-2
M3 - Article
AN - SCOPUS:77952094371
SN - 1573-3882
VL - 6
SP - 180
EP - 190
JO - Metabolomics
JF - Metabolomics
IS - 2
ER -