Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle.
Abstract
To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.
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Increments in mitochondrial transcripts were positively related to insulin-mediated glucose disposal, supporting that muscle mitochondria are mediators of insulin action to increase glucose utilization.
“Interestingly, increments in mitochondrial transcripts were positively related to those of insulin-mediated glucose disposal (29), supporting the hypothesis that muscle mitochondria are mediators of insulin action to increase glucose utilization.”
From Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction (2011) · cites this paper as [29]
Hyperinsulinemia in the high-physiological range increased transcript levels of complex I and complex IV subunits of the respiratory chain.
“Hyperinsulinemia in the high–physiological range increased transcript levels of complex I and complex IV subunits of the respiratory chain (28).”
From Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction (2011) · cites this paper as [28]
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- Authors
- Huang, X., Eriksson, K. F., Vaag, A., Lehtovirta, M., Hansson, M., Laurila, E., Kanninen, T., Olesen, B. T., Kurucz, I., Koranyi, L., & Groop, L.
- Affiliations
- Lund University (SE)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-08-01
- Volume
- 48
- Issue
- 8
- Pages
- 1508-1514
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2151584333
- Cited by
- 60
- References
- 15
- Citations by year
- 2020: 1 · 2019: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 4
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- RUCforsk (Roskilde University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- insulin regulation, mitochondrial gene expression, skeletal muscle, type 2 diabetes, insulin resistance, glucose uptake, cytochrome c oxidase subunit I, monozygotic twins, impaired glucose tolerance, glucose flux
- MeSH terms
- Aged, Diabetes Mellitus, Type 2, Diseases in Twins, Female, Gene Expression Regulation, Glucose, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Mitochondria, Reference Values, Twins, Monozygotic, DNA, Complementary, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction
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