Journal of Clinical & Experimental Nephrology

Hepatic Insulin Resistance in Type 2 Diabetes: Mechanisms and Therapeutic Insights

Type 2 Diabetes Mellitus (T2DM) is a long-lasting metabolic condition characterized by ongoing hyperglycemia resulting from insulin resistance and deficient insulin secretion. In addition to its systemic consequences, T2DM makes individuals vulnerable to liver-related issues, such as Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). The interaction of disturbed insulin signaling, inflammation, oxidative stress and ectopic fat accumulation in the liver creates a complicated network of pathophysiology that aggravates the progression of the disease and complications. This review explores the mechanisms that underlie hepatic insulin resistance and the therapeutic possibilities offered by bioactive compounds, especially flavonoids. In normal hepatocytes, insulin attaches to its receptor, triggering a signaling cascade that Activates Protein Kinase B (Akt). Akt manages glucose uptake and energy metabolism, thus ensuring metabolic equilibrium. However, in T2DM, insulin resistance hinders this pathway, decreasing Akt phosphorylation and resulting in hyperglycemia. Chronic low-grade inflammation, referred to as meta-inflammation, is a defining feature of T2DM. Excessive generation of reactive pro-oxidant species results in oxidative stress, which disrupts insulin signaling by lowering tyrosine phosphorylation in insulin receptor substrates and Akt. Oxidative stress additionally activates Nuclear factor-κB (NF-κB), creating a destructive cycle of inflammation and insulin resistance.

Author(s): Liam Noah

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