Insulin resistance induced by obesity: Mechanisms, metabolic implications and therapeutic approaches

Figures

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  Fig. 1. Schematic representation of insulin signalling pathway. Insulin binds to the insulin receptor, leading to activation of IRS-1 and PI3K. PI3K catalyzes the conversion of PIP2 to PIP3, which activates PDK1. PDK1, together with mTORC2, phosphorylates and activates Akt. Activated Akt promotes GLUT4 translocation to the plasma membrane, enhancing glucose uptake, and inhibits GSK-3, thereby stimulating glycogen synthase activity and glycogen synthesis. IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent kinase 1; mTORC2, mechanistic target of rapamycin complex 2; Akt, protein kinase B; GLUT4, glucose transporter 4; GSK-3, glycogen synthase kinase-3. Illustration created using Canva (https://www.canva.com)

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  Fig. 2. Comparison of adipokine levels between normal individuals and individuals with obesity. In normal individuals, adipose tissue is characterized by a higher proportion of anti-inflammatory M2 macrophages and a lower proportion of pro-inflammatory M1 macrophages, resulting in reduced secretion of pro-inflammatory adipokines such as TNF-α, IL-6, leptin, and resistin, along with increased secretion of anti-inflammatory adipokines including adiponectin, adipsin, and omentin-1. In contrast, individuals with obesity exhibit adipose tissue dysfunction characterized by increased M1 macrophage infiltration, reduced M2 macrophage numbers, elevated levels of pro-inflammatory adipokines, and decreased production of anti-inflammatory adipokines, contributing to chronic low-grade inflammation and insulin resistance. TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6. Illustration created using Canva (https://www.canva.com)

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  Fig. 3. The Nuclear Factor-kappa B (NF-κB) pathway in developing insulin resistance. Inflammatory stimuli including TNF-α, ROS, ER stress, FFAs, and hypoxia activate the IKK complex, resulting in activation of NF-κB signalling. NF-κB induces the expression of pro-inflammatory cytokines such as TNF-α and IL-6, as well as SOCS1 and SOCS3. These mediators impair IRS-1 signalling through IKKβ- and JNK-dependent pathways. Disruption of IRS-1 signalling reduces PI3K and Akt activity, leading to decreased GLUT4 translocation, reduced glucose uptake, impaired glycogen synthesis due to dysregulation of GSK-3 activity, and ultimately the progression of insulin resistance. TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species; ER stress, endoplasmic reticulum stress; FFAs, free fatty acids; IKK, IκB kinase; NF-κB, nuclear factor-kappa B; IL-6, interleukin-6; IKKβ, inhibitory kappa B kinase beta; JNK, c-Jun N-terminal kinase; SOCS1, suppressor of cytokine signalling 1; SOCS3, suppressor of cytokine signalling 3; IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; GLUT4, glucose transporter 4; GSK-3, glycogen synthase kinase-3; GS, glycogen…

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  Fig. 4. Schematic representation of Therapeutic methods for obesity-induced insulin resistance. Therapeutic approaches for obesity-induced insulin resistance are broadly categorized into natural products, pharmacological interventions, and lifestyle modifications. Natural products include polyphenols such as resveratrol, curcumin, and EGCG, as well as traditional herbal extracts, such as berberine and bitter melon, which exert antioxidant, anti-inflammatory, and insulin-sensitizing effects. Pharmacological treatments include insulin-sensitizing agents, anti-inflammatory drugs, GLP-1 receptor agonists, and SGLT2 inhibitors. Lifestyle interventions such as adherence to a Mediterranean diet, calorie restriction, and regular physical activity play a critical role in improving metabolic homeostasis and insulin sensitivity. EGCG, epigallocatechin gallate; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2. Illustration created using Canva (https://www.canva.com)