Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index
Abstract
:1. Introduction
2. Methods
2.1. Materials and Specimen Collection
2.2. The Insulin Resistance Atherosclerosis Study (IRAS)
2.3. Acquisition of NMR Spectra
2.4. Quantification of Ketone Bodies by Signal Deconvolution Analysis
2.5. Determination of LP-IR Scores and GlycA Levels
2.6. Assay Performance Testing
2.7. Method Comparison
2.8. Comparison of Specimen Collection Tubes and Stability Testing
2.9. Reference Interval Studies
2.10. Statistical Analyses
3. Results
3.1. Ketone Body Assay Development and Performance Characteristics
3.2. Cross-Sectional Analysis of Ketone Bodies in a Cohort of Subjects with Metabolic Disease
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
AcAc | acetoacetate |
β-HB | β-hydroxybutyrate |
BMI | body mass index |
CLSI | Clinical and Laboratory Standards Institute |
CV% | coefficient of variation |
FFAs | free fatty acids |
GC | gas chromatography |
HOMA-IR | Homeostatic Model Assessment of Insulin Resistance |
IRAS | Insulin Resistance Atherosclerosis Study |
LC/MS/MS | liquid chromatography coupled to tandem mass spectrometry |
LOAs | limits of agreement |
LOB | limit of blank |
LOD | limit of detection |
LOQ | limit of quantitation |
NMR | nuclear magnetic resonance spectroscopy |
ppm | parts per million |
T2DM | type 2 diabetes mellitus |
TG | triglycerides |
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β-hydroxybutyrate (µM) | Acetoacetate (µM) | Acetone (µM) | |||||
---|---|---|---|---|---|---|---|
Low | Medium | High | Low | High | Low | High | |
Within-laba | |||||||
Mean | 129.5 | 219.0 | 1188.9 | 127.1 | 182.9 | 106.5 | 187.9 |
SD | 12.0 | 12.9 | 27.5 | 9.8 | 11.2 | 9.7 | 12.4 |
CV (%) | 9.3 | 5.9 | 2.3 | 7.7 | 6.1 | 9.1 | 6.6 |
Within-runb | |||||||
Mean | 127.5 | 214.8 | 1168.2 | 127.0 | 180.3 | 105.2 | 178.2 |
SD | 10.8 | 12.5 | 15.6 | 9.1 | 5.6 | 6.4 | 6.8 |
CV (%) | 8.5 | 5.8 | 1.3 | 7.1 | 3.1 | 6.1 | 3.8 |
Percentile | Total Ketone Bodies (µM) | β-hydroxybutyrate (µM) | Acetoacetate (µM) | Acetone (µM) |
---|---|---|---|---|
0% | <65.0 | <45.0 | <26.3 | <19.7 |
2.5% | 88.8 | 48.6 | <26.3 | <19.7 |
25.0% | 136.9 | 88.8 | <26.3 | <19.7 |
50.0% | 174.1 | 111.3 | 35.7 | 26.8 |
75.0% | 235.8 | 154.1 | 49.7 | 37.8 |
97.5% | 623.2 | 396.4 | 120.0 | 78.6 |
100% | 1130 | 714.7 | 279.8 | 271.8 |
Characteristics | Non-Diabetic Subjects (n = 825) | T2DM Subjects (n = 373) | p-Value |
---|---|---|---|
Age (years) | 55 ± 8 | 57 ± 8 | <0.0001 |
Sex, men (%) | 467 (57) | 194 (52) | 0.14 |
Race | |||
Non-Hispanic white (%) | 334 (40) | 128 (34) | 0.04 |
Hispanic (%) | 272 (33) | 119 (32) | 0.72 |
African American (%) | 219 (27) | 126 (34) | 0.01 |
SBP (mmHg) | 122 ± 17 | 129 ± 18 | <0.0001 |
DBP (mmHg) | 78 ± 9 | 78 ± 9.9 | 0.42 |
BMI (kg/m2) | 28.4 ± 5.6 | 31.5 ± 5.6 | <0.0001 |
Waist circumference (cm) | 90 ± 13 | 99 ± 12 | <0.0001 |
Fasting glucose (mmol/L) | 5.5 ± 0.6 | 9.7 ± 3.2 | <0.0001 |
2 Hour glucose (mmol/L) | 6.9 ± 1.9 | 17.7 ± 4.8 | <0.0001 |
Fasting FFAs (mmol/L) | 0.47 ± 0.19 | 0.60 ± 0.23 | <0.0001 |
Total cholesterol (mmol/L) | 5.44 ± 1.11 | 5.51 ± 1.12 | 0.33 |
HDL-C (mmol/L) | 1.21 ± 0.39 | 1.05 ± 0.30 | <0.0001 |
Triglycerides (mmol/L) | 1.24 (0.88–1.81) | 1.77 (1.19–2.46) | <0.0001 |
GlycA (µM) | 346 ± 70 | 373 ± 71 | <0.0001 |
LP-IR score (0–100) | 50 ± 21 | 62 ± 18 | <0.0001 |
Total ketone bodies (µM) | 142 (98–208) | 182 (116–269) | <0.0001 |
β-hydroxybutyrate (µM) | 100 (67–154) | 131 (79–193) | <0.0001 |
Acetoacetate (µM) | 26 (13–44) | 32 (15–52) | 0.011 |
Acetone (µM) | 15 (8–24) | 18 (10–30) | 0.0004 |
Total KB | β-HB | AcAc | Acetone | |||||
---|---|---|---|---|---|---|---|---|
r | p-Value | r | p-Value | r | p-Value | r | p-Value | |
Age | 0.057 | 0.050 | 0.057 | 0.048 | 0.028 | 0.328 | 0.004 | 0.884 |
Sex (men/women) | 0.161 | <0.0001 | 0.210 | <0.0001 | 0.014 | 0.624 | −0.028 | 0.337 |
Glucose | 0.162 | <0.0001 | 0.137 | <0.0001 | 0.139 | <0.0001 | 0.137 | <0.0001 |
FFAs | 0.294 | <0.0001 | 0.306 | <0.0001 | 0.155 | <0.0001 | 0.176 | <0.0001 |
TG | −0.078 | 0.007 | −0.099 | 0.0007 | −0.178 | 0.541 | 0.047 | 0.104 |
LP-IR score | −0.134 | <0.0001 | −0.157 | <0.0001 | −0.063 | 0.028 | −0.000 | 0.990 |
T2DM (yes/no) | 0.152 | <0.0001 | 0.145 | <0.0001 | 0.087 | 0.003 | 0.115 | <0.0001 |
Total KB | β-HB | AcAc | Acetone | |||||
---|---|---|---|---|---|---|---|---|
β | p-Value | β | p-Value | β | p-Value | β | p-Value | |
Age | −0.036 | 0.188 | −0.030 | 0.273 | −0.020 | 0.494 | −0.073 | 0.011 |
Sex (men/women) | 0.013 | 0.820 | 0.064 | 0.265 | −0.079 | 0.191 | −0.136 | 0.026 |
FFAs | 0.326 | <0.0001 | 0.336 | <0.0001 | 0.215 | <0.0001 | 0.199 | <0.0001 |
TG | −0.132 | <0.0001 | −0.168 | <0.0001 | −0.035 | 0.301 | 0.019 | 0.581 |
LP-IR score | −0.115 | 0.0005 | −0.108 | 0.0009 | −0.110 | 0.001 | −0.072 | 0.037 |
T2DM (yes/no) | 0.231 | 0.0003 | 0.240 | 0.0001 | 0.131 | 0.049 | 0.168 | 0.012 |
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Garcia, E.; Shalaurova, I.; Matyus, S.P.; Oskardmay, D.N.; Otvos, J.D.; Dullaart, R.P.F.; Connelly, M.A. Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index. J. Clin. Med. 2020, 9, 321. https://doi.org/10.3390/jcm9020321
Garcia E, Shalaurova I, Matyus SP, Oskardmay DN, Otvos JD, Dullaart RPF, Connelly MA. Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index. Journal of Clinical Medicine. 2020; 9(2):321. https://doi.org/10.3390/jcm9020321
Chicago/Turabian StyleGarcia, Erwin, Irina Shalaurova, Steven P. Matyus, David N. Oskardmay, James D. Otvos, Robin P.F. Dullaart, and Margery A. Connelly. 2020. "Ketone Bodies Are Mildly Elevated in Subjects with Type 2 Diabetes Mellitus and Are Inversely Associated with Insulin Resistance as Measured by the Lipoprotein Insulin Resistance Index" Journal of Clinical Medicine 9, no. 2: 321. https://doi.org/10.3390/jcm9020321