Insulin Action and Resistance in Obesity and Metabolic Disorders

Insulin orchestrates the disposal of circulating nutrients by promoting glucose uptake, lipid synthesis and protein anabolism in responsive tissues. In skeletal muscle and adipose tissue, insulin binding to its receptor triggers a cascade of tyrosine kinase signalling that culminates in translocation of glucose transporters to the cell surface and activation of lipid-synthesising enzymes. In the liver, insulin suppresses gluconeogenesis while promoting glycogen and triglyceride storage. Obesity and related metabolic disorders disrupt this finely tuned system at multiple levels. Chronic nutrient excess and adipose inflammation provoke serine phosphorylation of insulin receptor substrates, attenuating downstream signalling and diminishing glucose uptake. Lipotoxic intermediates generated in over-expanded adipocytes further impair insulin receptor function and provoke ectopic lipid deposition in liver and muscle. Genetic and environmental factors converge to exacerbate these defects, giving rise to a spectrum of insulin-resistant phenotypes that underpin type 2 diabetes, non-alcoholic fatty liver disease and cardiovascular complications. Understanding the cellular and molecular bases of impaired insulin action in obesity is crucial to designing interventions that restore metabolic flexibility and prevent long-term sequelae.

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Insulin Action and Resistance in Obesity and Metabolic Disorders publication trend

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Technical terms

Insulin resistance: A state in which target tissues respond inadequately to physiological insulin concentrations, leading to impaired glucose disposal and compensatory hyperinsulinaemia.

Insulin receptor: A transmembrane tyrosine kinase that binds insulin at the cell surface and initiates intracellular signalling pathways essential for metabolic regulation.

Glucose transporter (GLUT4): An insulin-responsive membrane protein that facilitates facilitated diffusion of glucose into muscle and adipose cells upon translocation to the plasma membrane.

Lipogenesis: The enzymatic conversion of acetyl-CoA into fatty acids and triglycerides, a process stimulated by insulin in adipocytes and hepatocytes.

Hypercaloric diet: A nutritional regimen providing calories in excess of energetic needs, often high in fat or simple sugars, used experimentally to induce obesity and metabolic derangements.

References

1. Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats. Nutrients (2019).
2. Mechanism of insulin resistance in adipocytes of rats fed a high-fat diet.. Journal of Lipid Research (1979).
3. Evidence that translocation of the glucose transport activity is the major mechanism of insulin action on glucose transport in fat cells.. Journal of Biological Chemistry (1982).