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Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients
Open accessAbstract
Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type 2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes. To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using 13C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive control subjects underwent 13C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13C label into C4 glutamate during a [2-13C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by 30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g−1 · min−1, P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g−1 · min−1). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial oxidative phosphorylation.
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“Lean normal-glucose-tolerant (NGT), insulin-resistant offspring of T2DM parents have a 30–40% decrease in metabolic flux through the tricarboxylic acid cycle [104] and oxidative phosphorylation [31] in skeletal muscle under basal conditions.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [104]
In the citing paper
“This hypothesis is supported by in vivo reports that the incorporation of 13 C-acetate into glutamate and mitochondrial phosphorylation was approximately 30% lower in muscle of insulin-resistant versus lean individuals (81,83).”
From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [83]
In the citing paper
“These data and the evidence indicating multiple mitochondrial abnormalities in type 2 diabetic and insulin-resistant individuals ([3](#r3), [25](#r25), [36](#r36), [37](#r37), [40](#r40), [42](#r42), [43](#r43), [48](#r48), [59](#r59)) led to the hypothesis that lower mitochondrial capacity is associated with reduced resting lipid oxidation and therefore increased muscle lipid accumulation.”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [3]
In the citing paper
“Furthermore, the mitochondrial capacity to oxidize acetyl-CoA coming from glucose is conserved in insulin-resistant subjects even if mitochondrial defects have been reported in those individuals ([3](#r3), [25](#r25), [36](#r36), [37](#r37), [40](#r40), [42](#r42), [43](#r43), [48](#r48), [59](#r59)).”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [3]
In the citing paper
“For example, rates of mitochondrial OXPHOS in offspring of type 2 diabetic subjects, as assessed by 31 P spectroscopy, are reduced by 30% in the fasting state (117), and TCA cycle flux, modeled using rates of 4-13 C-glutamate enrichment during infusion of 13 C-acetate, is reduced by 30% (118).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [118]
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Metadata
- Authors
- Befroy, D. E., Petersen, K. F., Dufour, S., Mason, G. F., de Graaf, R. A., Rothman, D. L., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2007-05-01
- Volume
- 56
- Issue
- 5
- Pages
- 1376-1381
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2995532
- OpenAlex
- W2152386173
- Cited by
- 453
- References
- 34
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 13 · 2023: 17 · 2022: 14 · 2021: 21 · 2020: 22 · 2019: 14 · 2018: 18 · 2017: 19 · 2016: 24 · 2015: 19 · 2014: 28 · 2013: 34 · 2012: 36
- FWCI
- 15.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R56AG023686, R01AG023686)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK049230, P30DK045735, P01DK068229)
- National Center for Research Resources (M01RR000125)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- insulin resistance, type 2 diabetes, offspring of diabetic patients, skeletal muscle, fatty acid oxidation, intramyocellular lipid, oxidative phosphorylation, 13C NMR, glutamate, mitochondrial dysfunction
- MeSH terms
- Adult, Carbon Isotopes, Citric Acid Cycle, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Humans, Insulin Resistance, Kinetics, Life Style, Male, Mitochondria, Muscle, Models, Biological, Nuclear Family, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Body Mass Index
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