Paradoxical changes in muscle gene expression in insulin-resistant subjects after sustained reduction in plasma free
Mandeep Bajaj1, Rafael Medina-Navarro, Swangjit Suraamornkul
1School of Life Sciences, Arizona State University, P.O. Box 874501, Tempe, AZ 85287-4501, USA.
Abstract:
Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclear-encoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 +/- 0.041 to 0.252 +/- 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 +/- 0.46 to 6.31 +/- 0.55 mg . kg(-1) . min(-1) (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 +/- 1.9 to 4.54 +/- 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1-and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III alpha-subunits (82- and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-beta1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear-encoded mitochondrial genes do not always correlate with changes in insulin sensitivity.
Insights
Reducing lipid levels in insulin-resistant individuals improved glucose uptake but did not reverse all molecular changes. Muscle gene expression shifts suggest complex responses to lipid reduction, not always correlating with insulin sensitivity improvements.
Area of Science:
- Metabolic diseases
- Molecular biology
- Exercise physiology
Background:
- Lipid oversupply contributes to skeletal muscle insulin resistance.
- It reduces mitochondrial gene expression and increases extracellular matrix remodeling.
- Understanding if lipid reduction reverses these changes is crucial for type 2 diabetes research.
Purpose of the Study:
- To investigate the effects of decreased plasma lipid content on insulin resistance markers in skeletal muscle.
- To determine if reducing free fatty acids reverses molecular abnormalities in insulin-resistant individuals.
Main Methods:
- Used euglycemic clamps and muscle biopsies in insulin-resistant subjects with a family history of type 2 diabetes.
- Administered acipimox to suppress plasma free fatty acids.
- Analyzed changes in glucose disposal, intramuscular fatty acyl CoA, and gene expression.
Main Results:
- Acipimox significantly reduced free fatty acids and increased glucose disposal.
- Intramuscular fatty acyl CoA levels decreased markedly.
- Paradoxically, expression of PGC-1 and nuclear-encoded mitochondrial genes decreased, while collagen and growth factor expression increased.
Conclusions:
- Reduced lipid supply does not fully reverse molecular changes in skeletal muscle associated with lipid oversupply.
- Changes in nuclear-encoded mitochondrial gene expression may not consistently correlate with insulin sensitivity.
- These findings highlight the complexity of metabolic adaptations in insulin resistance.
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