Inflammation and Metabolic Dysregulation in Insulin Resistance

Insulin resistance arises when cells in metabolic organs such as liver, muscle and adipose tissue fail to respond adequately to circulating insulin, leading to impaired glucose uptake and altered lipid handling. Chronic low-grade inflammation and nutrient overload intersect to drive a complex web of metabolic dysregulation. Excessive nutrient intake promotes adipocyte hypertrophy, hypoxia and cell stress, which in turn stimulate immune cell recruitment and cytokine secretion. These inflammatory mediators disrupt insulin signalling cascades at multiple levels, from receptor activation through downstream kinases, and promote lipid accumulation in non-adipose tissues. The resulting multi-organ insulin resistance underpins the development of type 2 diabetes, cardiovascular disease and other metabolic disorders. Recent advances in systems-level analysis, immune profiling and redox biology have begun to unravel the interplay of signalling networks, immune cell phenotypes and organ-specific contributions, opening new avenues for targeted therapies that restore metabolic homeostasis.

Research from Nature Portfolio

Global phosphoproteomic profiling of adipocytes and adipose tissue has revealed extensive rewiring of insulin-responsive signalling networks in insulin-resistant states. Across diverse insulin-desensitising insults, both the magnitude of canonical phosphorylation events and the emergence of novel, resistance-specific phosphosites were observed. Subnetwork analysis identified non-canonical regulators such as MARK2 and MARK3, while dysregulation of glycogen synthase kinase 3 (GSK3) emerged as a common driver. Functional studies showed that pharmacological inhibition of GSK3 partially restores insulin-stimulated glucose uptake in cells and tissue explants. These findings characterise insulin resistance as a multi-nodal signalling defect and highlight kinase-targeted approaches for therapeutic intervention.

Inflammation and Metabolic Dysregulation in Insulin Resistance publication trend

The graph below shows the total number of articles in inflammation and metabolic dysregulation in insulin resistance across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin resistance: A reduced capacity of cells to respond to insulin, resulting in diminished glucose uptake and perturbed lipid metabolism.

Inflammation: A protective biological reaction to injury or stress involving immune cell activation and mediator release, which becomes harmful when chronically sustained.

Cytokines: Soluble proteins secreted by immune cells that coordinate inflammatory responses and can interfere with insulin signalling.

Phosphoproteomics: A high-throughput technique for mapping protein phosphorylation across the proteome to elucidate signalling network alterations.

Mitochondrial oxidative stress: An imbalance caused by excessive reactive oxygen species generation within mitochondria, impairing cellular functions including glucose transport.

Adipocytes: Fat-storing cells in adipose tissue that regulate energy balance and, when dysregulated, contribute to inflammatory and metabolic disturbances.

References

1. Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance. Nature Communications (2023).
2. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Frontiers in Physiology (2020).
3. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy (2022).
4. Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation. Journal of Biological Chemistry (2018).