Hepatic Insulin Resistance Mechanisms in Metabolic Disorders

Hepatic insulin resistance arises when the liver fails to respond adequately to insulin, disrupting the balance between glucose production and lipid metabolism. Under normal conditions, insulin binding to its receptor triggers phosphorylation cascades involving insulin receptor substrates and the PI3K–Akt pathway, suppressing gluconeogenesis and promoting glycogen synthesis. In metabolic disorders such as obesity, non-alcoholic fatty liver disease and type 2 diabetes, excess fatty acids and lipid intermediates accumulate within hepatocytes, activating novel protein kinase C (PKC) isoforms—particularly PKCε—which interfere with insulin receptor substrate phosphorylation. Pro-inflammatory mediators, including the NLRP3 inflammasome, and organelle stress responses—especially endoplasmic reticulum stress and aberrant mitochondrial redox states—further attenuate insulin signalling and promote hepatic steatosis. Ceramides and other sphingolipids exacerbate this dysfunction through lipotoxic effects and cross-talk with stress kinases such as JNK. These intersecting pathways not only drive hyperglycaemia and dyslipidaemia but also underpin progression to steatohepatitis and fibrosis. A deeper mechanistic understanding supports the development of targeted therapies—from nuclear receptor modulators and lipid-lowering agents to mitochondrial uncouplers—aimed at restoring hepatic insulin sensitivity and averting systemic metabolic decline.

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Hepatic Insulin Resistance Mechanisms in Metabolic Disorders publication trend

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

Technical terms

Hepatic insulin resistance: A state in which liver cells fail to respond properly to insulin, leading to impaired suppression of glucose production and altered lipid metabolism.

Protein kinase C epsilon (PKCε): An isoform of protein kinase C activated by diacylglycerol, which disrupts insulin receptor substrate phosphorylation in hepatocytes.

NLRP3 inflammasome: A multiprotein complex in the innate immune system that, when activated in hepatocytes, promotes inflammation and impairs insulin signalling.

Mitochondrial reductive stress: An imbalance in mitochondrial redox reactions, characterised by excessive reducing equivalents that compromise cellular metabolism and insulin action.

Gluconeogenesis: The metabolic pathway by which the liver generates glucose from non-carbohydrate precursors, normally suppressed by insulin signalling.

References

1. Hepatocyte NLRP3 interacts with PKCε to drive hepatic insulin resistance and steatosis. Science Bulletin (2023).
2. Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease. Trends in Pharmacological Sciences (2024).