Updating the effects of fatty acids on skeletal muscle

We hypothesized that FFA-induced insulin resistance is closely related to disruption of the inner mitochondrial membrane potential and reduced mitochondrial gene expression.

In the present study, we demonstrate that short-term lipid infusion significantly reduces inner mitochondrial membrane potential in healthy NGT subjects.

Physiological elevation of plasma FFA for 48 h down-regulates multiple genes involved in mitochondrial biogenesis (16).

updating the effects of fatty acids on skeletal muscle-51updating the effects of fatty acids on skeletal muscle-63updating the effects of fatty acids on skeletal muscle-61

Intramyocellular accumulation of toxic FFA metabolites, fatty acyl-coenzyme A, diacylglycerol, and ceramides, has been shown to impair insulin signal transduction, glucose transport/phosphorylation, and glycogen synthesis (4–6).

Because skeletal muscle accounts for the majority (70–80%) of insulin-mediated glucose uptake in the postprandial state (7), skeletal muscle has been the focus of insulin resistance.

It also remains to be established whether the elevated plasma FFA concentration seen in T2DM is the cause or consequence of mitochondrial dysfunction.

A recent study demonstrated that short-term plasma FFA elevation impaired insulin-stimulated ATP synthesis in skeletal muscle of healthy subjects (17).

Eleven healthy volunteers (eight males, three females; age = 32 ± 2 yr; body mass index = 24.4 ± 1 kg/m 21 ± 1.3) without family history of diabetes participated in the study.

Fasting plasma glucose (92 ± 2 mg/dl), glycosylated hemoglobin (5.2 ± 0.1%), fasting plasma insulin (5 ± 1 μU/ml), and plasma total, low-density lipoprotein, and high-density lipoprotein cholesterol levels were normal in all subjects.

Vastus lateralis muscle biopsies were performed at baseline and after 6 h lipid or saline infusion.

Inner mitochondrial membrane potential (Ψ Insulin resistance is a key metabolic defect in type 2 diabetes mellitus (T2DM) and precedes the onset of overt hyperglycemia by decades (1, 2).

Studies in humans and rodents consistently have demonstrated that experimental elevation in free fatty acids (FFA) in healthy subjects reduces insulin-stimulated glucose uptake in a dose-dependent manner (3).

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