Acylcarnitines: potential implications for skeletal muscle insulin resistance

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Research

Background:

• Insulin resistance is associated with altered fatty acid metabolism and increased acylcarnitine levels in tissues like skeletal muscle.
• The precise role of acylcarnitines in mediating muscle insulin resistance versus merely reflecting metabolic dysregulation remains unclear.

Purpose of the Study:

• To investigate if acylcarnitines can directly induce insulin resistance in muscle cells.
• To elucidate the relationship between incomplete fatty acid oxidation, acylcarnitine accumulation, oxidative stress, inflammation, and insulin resistance.

Main Methods:

• Treatment of differentiated C2C12, primary mouse, and human myotubes with specific acylcarnitines (C4:0, C14:0, C16:0) or palmitate.
• Assessment of insulin response via Akt phosphorylation and glucose uptake.
• Evaluation of oxidative stress markers and proinflammatory cytokines.
• Intervention with mildronate (carnitine acyltransferase inhibitor) and antioxidants.

Main Results:

• Acylcarnitine treatment (C4:0, C14:0, C16:0) reduced insulin response by 20-30% in myotubes.
• Mildronate mitigated palmitate-induced insulin resistance and decreased acylcarnitine secretion.
• Acylcarnitines significantly elevated oxidative stress (2-3 fold) but did not affect proinflammatory cytokines.
• Antioxidant treatment reversed acylcarnitine-induced oxidative stress and insulin resistance.

Conclusions:

• Incomplete fatty acid beta-oxidation leads to acylcarnitine buildup in muscle.
• Acylcarnitines contribute to muscle insulin resistance, at least partly, through inducing oxidative stress.
• These findings highlight a potential mechanism linking metabolic disturbances to insulin resistance development.