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Substrate competition and insulin action in animal models
R Vettor1, A M Lombardi, R Fabris
1Department of Medical and Surgical Sciences, University of Padova, Italy. rvettor@ux1.unipd.it
Summary
Obesity-related increases in free fatty acids (FFA) and lactate impair insulin sensitivity by reducing glucose uptake and GLUT4 expression in muscles. This suggests a synergistic role for FFA and lactate in metabolic dysfunction.
Area of Science:
- Metabolic research
- Obesity studies
- Molecular endocrinology
Background:
- Elevated plasma free fatty acids (FFA) and lactate are common in obesity.
- These metabolic alterations are implicated in impaired insulin action.
- The precise molecular mechanisms underlying this insulin resistance remain unclear.
Purpose of the Study:
- To investigate the impact of elevated FFA and lactate on insulin-dependent glucose uptake.
- To explore the effects on glucose transporter type 4 (GLUT4) gene and protein expression.
- To elucidate the molecular mechanisms of insulin resistance in obesity.
Main Methods:
- Chronic infusion of Intralipid plus heparin in rats to elevate FFA.
- Induction of chronic hyperlactatemia in rats.
- Measurement of insulin-dependent glucose uptake in muscular tissue.
- Assessment of GLUT4 gene (mRNA) and protein expression.
Main Results:
- Chronic Intralipid/heparin infusion decreased insulin-dependent glucose uptake and GLUT4 gene expression in rat muscle.
- Chronic hyperlactatemia reduced muscle glucose uptake and decreased GLUT4 mRNA and protein levels.
- FFA and lactate appear to act synergistically in reducing insulin sensitivity.
Conclusions:
- Elevated plasma FFA and lactate contribute to insulin resistance in obesity.
- Reduced glucose uptake and GLUT4 expression in muscle are key consequences.
- Visceral fat-derived FFA and lactate overproduction play a synergistic role in metabolic dysfunction.