TY - JOUR
T1 - Metabolomics Identifies Distinctive Metabolite Signatures for Measures of Glucose Homeostasis
T2 - The Insulin Resistance Atherosclerosis Family Study (IRAS-FS)
AU - Palmer, Nicholette D.
AU - Okut, Hayrettin
AU - Hsu, Fang Chi
AU - Ng, Maggie C.Y.
AU - Chen, Yii Der Ida
AU - Goodarzi, Mark O.
AU - Taylor, Kent D.
AU - Norris, Jill M.
AU - Lorenzo, Carlos
AU - Rotter, Jerome I.
AU - Bergman, Richard N.
AU - Langefeld, Carl D.
AU - Wagenknecht, Lynne E.
AU - Bowden, Donald W.
N1 - Publisher Copyright:
Copyright © 2018 Endocrine Society.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Context: Metabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes. Objective: Survey metabolites associated with dynamic and basal measures of glucose homeostasis. Design: Analysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study. Setting: Community based. Participants: One thousand one hundred eleven Mexican Americans. Main Outcome: Dynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and b-cell function. Results: Insulin sensitivity was associated with 99 metabolites (P < 6.82 x 10-5) explaining 28%of the variance (R2 adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 3 10-18 to 1.70 3 10-5, R2 adj = 8.1%) and phospholipids (P = 3.51 x 10-17 to 3.00 x 10-5, R2 adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.493 10-23 to 4.14x 10-7, R2 adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 3 10-16). Homeostatic model assessment of b-cell function had significant signatures from the urea cycle (P = 9.64 x 10-14 to 7.27 x 10-6, R2 adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 x 10-13 to 6.70 x 10-5, R2 adj = 10%) and LCFAs (P = 9.06 x10-15 to 3.93 x10-7, R2 adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55x10-12 to 5.81x10-6; R2 adj = 3.8%) beyond that of its component measures. Conclusions: Metabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.
AB - Context: Metabolomics provides a biochemical fingerprint that, when coupled with clinical phenotypes, can provide insight into physiological processes. Objective: Survey metabolites associated with dynamic and basal measures of glucose homeostasis. Design: Analysis of 733 plasma metabolites from the Insulin Resistance Atherosclerosis Family Study. Setting: Community based. Participants: One thousand one hundred eleven Mexican Americans. Main Outcome: Dynamic measures were obtained from the frequently sampled intravenous glucose tolerance test and included insulin sensitivity and acute insulin response to glucose. Basal measures included homeostatic model assessment of insulin resistance and b-cell function. Results: Insulin sensitivity was associated with 99 metabolites (P < 6.82 x 10-5) explaining 28%of the variance (R2 adj) beyond 28% by body mass index. Beyond branched chain amino acids (BCAAs; P = 1.85 3 10-18 to 1.70 3 10-5, R2 adj = 8.1%) and phospholipids (P = 3.51 x 10-17 to 3.00 x 10-5, R2 adj = 14%), novel signatures of long-chain fatty acids (LCFAs; P = 4.493 10-23 to 4.14x 10-7, R2 adj = 11%) were observed. Conditional analysis suggested that BCAA and LCFA signatures were independent. LCFAs were not associated with homeostatic model assessment of insulin resistance (P > 0.024). Acute insulin response to glucose was associated with six metabolites; glucose had the strongest association (P = 5.68 3 10-16). Homeostatic model assessment of b-cell function had significant signatures from the urea cycle (P = 9.64 x 10-14 to 7.27 x 10-6, R2 adj = 11%). Novel associations of polyunsaturated fatty acids (P = 2.58 x 10-13 to 6.70 x 10-5, R2 adj = 10%) and LCFAs (P = 9.06 x10-15 to 3.93 x10-7, R2 adj = 10%) were observed with glucose effectiveness. Assessment of the hyperbolic relationship between insulin sensitivity and secretion through the disposition index revealed a distinctive signature of polyunsaturated fatty acids (P = 1.55x10-12 to 5.81x10-6; R2 adj = 3.8%) beyond that of its component measures. Conclusions: Metabolomics reveals distinct signatures that differentiate dynamic and basal measures of glucose homeostasis and further identifies new metabolite classes associated with dynamic measures, providing expanded insight into the metabolic basis of insulin resistance.
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U2 - 10.1210/jc.2017-02203
DO - 10.1210/jc.2017-02203
M3 - Article
C2 - 29546329
AN - SCOPUS:85047178202
SN - 0021-972X
VL - 103
SP - 1877
EP - 1888
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -