Advantages of dynamic "closed loop" stable isotope flux phenotyping over static "open loop" clamps in detecting silent genetic and dietary phenotypes

Bhavapriya Vaitheesvaran, Fu Yu Chueh, Jun Xu, Chuck Trujillo, M. F. Saad, W. N P Lee, Owen P. McGuinness, Irwin J. Kurland

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)180-190
Number of pages11
JournalMetabolomics
Volume6
Issue number2
DOIs
StatePublished - Jun 2010

Fingerprint

Clamping devices
Isotopes
Peroxisome Proliferator-Activated Receptors
Fluxes
Phenotype
Glucose
Glucose Tolerance Test
High Fat Diet
Insulin
Nutrition
Insulin Resistance
Area Under Curve
Plasmas
Fats
Indirect Calorimetry
Glucose Clamp Technique
Photoperiod
Calorimetry
Diet

Keywords

  • Metabolic flexibility
  • Orphan nuclear receptor action
  • Stable isotope flux phenotyping

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Advantages of dynamic "closed loop" stable isotope flux phenotyping over static "open loop" clamps in detecting silent genetic and dietary phenotypes. / Vaitheesvaran, Bhavapriya; Chueh, Fu Yu; Xu, Jun; Trujillo, Chuck; Saad, M. F.; Lee, W. N P; McGuinness, Owen P.; Kurland, Irwin J.

In: Metabolomics, Vol. 6, No. 2, 06.2010, p. 180-190.

Research output: Contribution to journalArticle

Vaitheesvaran, Bhavapriya ; Chueh, Fu Yu ; Xu, Jun ; Trujillo, Chuck ; Saad, M. F. ; Lee, W. N P ; McGuinness, Owen P. ; Kurland, Irwin J. / Advantages of dynamic "closed loop" stable isotope flux phenotyping over static "open loop" clamps in detecting silent genetic and dietary phenotypes. In: Metabolomics. 2010 ; Vol. 6, No. 2. pp. 180-190.
@article{bb2e0b985385402894d7b666934356a8,
title = "Advantages of dynamic {"}closed loop{"} stable isotope flux phenotyping over static {"}open loop{"} clamps in detecting silent genetic and dietary phenotypes",
abstract = "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.",
keywords = "Metabolic flexibility, Orphan nuclear receptor action, Stable isotope flux phenotyping",
author = "Bhavapriya Vaitheesvaran and Chueh, {Fu Yu} and Jun Xu and Chuck Trujillo and Saad, {M. F.} and Lee, {W. N P} and McGuinness, {Owen P.} and Kurland, {Irwin J.}",
year = "2010",
month = "6",
doi = "10.1007/s11306-009-0190-2",
language = "English (US)",
volume = "6",
pages = "180--190",
journal = "Metabolomics",
issn = "1573-3882",
publisher = "Springer New York",
number = "2",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=77952094371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952094371&partnerID=8YFLogxK

U2 - 10.1007/s11306-009-0190-2

DO - 10.1007/s11306-009-0190-2

M3 - Article

AN - SCOPUS:77952094371

VL - 6

SP - 180

EP - 190

JO - Metabolomics

JF - Metabolomics

SN - 1573-3882

IS - 2

ER -