Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity
Open accessAbstract
Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin‐stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4‐h insulin‐stimulated euglycemic clamp. In obesity and T2DM, long‐chain AcylCNs were similarly significantly increased in the fasted state; free‐CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short‐ and medium‐chain AcylCNs, both saturated and hydroxy, as well as increased C 4‐dicarboxylcarnitine (C 4 DC–CN) that correlated with an index of poor glycemic control (HbA 1c; r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long‐chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
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Similar abnormalities in acylcarnitine accumulation and incomplete β-oxidation occur in humans with obesity or type 2 diabetes and in primary human skeletal myocytes from obese compared to lean subjects.
“Similar abnormalities in acylcarnitine accumulation and incomplete β-oxidation have been identified in humans with obesity or type 2 diabetes (Adams et al., 2009; Huffman et al., 2009; Mihalik et al., 2010) and in primary human skeletal myocytes derived from obese compared to lean subjects (Bell et al., 2010; Kovalik et al., 2011).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Mihalik et al., 2010
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- Authors
- Mihalik, S. J., Goodpaster, B. H., Kelley, D. E., Chace, D. H., Vockley, J., Toledo, F. G. S., & DeLany, J. P.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- DeLany, James P.
- Venue
- Obesity
- Publisher
- Wiley
- Published
- 2010-09
- Volume
- 18
- Issue
- 9
- Pages
- 1695-1700
- ISSN
- 1930-7381 (ISSN-L)
- 1930-739X
- PMC
- PMC3984458
- OpenAlex
- W1963756943
- Cited by
- 653
- References
- 23
- Citations by year
- 2026: 28 · 2025: 53 · 2024: 34 · 2023: 57 · 2022: 59 · 2021: 61 · 2020: 58 · 2019: 45 · 2018: 51 · 2017: 37 · 2016: 45 · 2015: 33 · 2014: 40 · 2013: 16 · 2012: 21
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Obesity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000005, 5p30dk046204-15)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-462, DK-49200-08, R01DK078775, R01DK049200, DK78755, R01DK054936, P30-DK046204)
- National Center for Research Resources (M01RR000056, 5 M01 RR00056, UL1RR024153)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- acylcarnitines, fatty acid oxidation, type 2 diabetes, insulin resistance, glucolipotoxicity, HbA1c, fatty acid oxidation disorders, plasma biomarkers
- MeSH terms
- Adult, Carnitine, Diabetes Mellitus, Type 2, Fasting, Glycated Hemoglobin, Humans, Insulin, Middle Aged, Obesity, Oxidation-Reduction, Glucose Clamp Technique, Biomarkers, Body Mass Index, Glucose Intolerance, Lipid Metabolism, Tandem Mass Spectrometry
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