Metabolic Mechanisms of Insulin Resistance and Fatty Acid Dynamics

Insulin resistance arises when insulin-sensitive tissues—principally adipose, skeletal muscle and liver—fail to respond appropriately to insulin’s signals to promote glucose uptake and to suppress hepatic glucose production. A central driver of this process is dysregulated fatty acid dynamics, in which elevated lipolysis in adipose depots increases circulating free fatty acids (FFAs). Excess FFAs impair insulin signalling through serine phosphorylation of insulin receptor substrate proteins and by promoting lipid accumulation in non-adipose tissues, a phenomenon known as ectopic lipid deposition. In parallel, chronic overexposure to FFAs induces mitochondrial dysfunction, endoplasmic reticulum stress and low-grade inflammation, further exacerbating insulin unresponsiveness. Lipogenesis, the insulin-stimulated synthesis of triglycerides from glucose and FFAs, becomes blunted in insulin-resistant states, leading to impaired lipid storage capacity in adipocytes and diversion of lipids towards harmful pathways. The net result is a vicious cycle in which defective lipid handling perpetuates insulin resistance, contributing to the pathogenesis of metabolic syndrome, type 2 diabetes and associated cardiovascular complications. Understanding the interplay between adipose tissue function, FFA flux and intracellular signalling networks is essential for the development of targeted therapies that restore insulin sensitivity and normalise lipid homeostasis.

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Metabolic Mechanisms of Insulin Resistance and Fatty Acid Dynamics publication trend

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Technical terms

Insulin resistance: Reduced responsiveness of target tissues to the actions of insulin, particularly glucose uptake and lipogenesis.

Lipolysis: The enzymatic breakdown of triglycerides stored in adipocytes into free fatty acids and glycerol.

Lipogenesis: The metabolic pathway by which acetyl-CoA and NADPH are used to synthesise fatty acids and triglycerides.

Free fatty acids (FFAs): Non-esterified fatty acids released into the circulation by adipose tissue lipolysis.

Adipose tissue: Specialized connective tissue for energy storage in the form of triglycerides and an endocrine organ regulating systemic metabolism.

Ectopic lipid deposition: Accumulation of lipids in non-adipose tissues such as liver, muscle or pancreas, impairing cellular function.

References

1. Insulin resistance in adipocytes: Novel insights into the pathophysiology of metabolic syndrome. Clinical Nutrition (2023).
2. Fat Depots, Free Fatty Acids, and Dyslipidemia. Nutrients (2013).
3. Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects. Journal of Lipid Research (2011).