Hepatic Metabolism and Insulin Resistance

The liver serves as a central hub in whole‐body energy homeostasis by coordinating uptake, storage and release of nutrients. In the fed state, insulin promotes hepatic glucose uptake and glycogen synthesis, suppresses gluconeogenesis and stimulates de novo lipogenesis. During fasting, counter‐regulatory hormones drive glycogenolysis and gluconeogenesis to maintain blood glucose. Insulin resistance in the liver manifests as impaired suppression of glucose production despite continued or exaggerated lipogenesis, leading to hyperglycaemia, hepatic steatosis and systemic metabolic dysfunction. Key drivers include chronic inflammation, oxidative stress and dysregulated signalling through insulin receptor substrates and downstream kinases. A deeper mechanistic understanding of these pathways is critical for developing targeted therapies to alleviate type 2 diabetes and nonalcoholic fatty liver disease.

Research from Nature Portfolio

Recent studies have developed a human induced pluripotent stem cell (iPSC)-based co-culture model in which hepatocytes exposed to pro-inflammatory macrophages recapitulate insulin-resistant glucose output. Tumour necrosis factor α and interleukin-1β were identified as principal mediators acting via NF-κB and JNK to impair insulin signalling, and combined neutralisation of both cytokines restored hepatocyte insulin sensitivity more effectively than single interventions. Another investigation revealed that the WD40 repeat-containing protein WDR6 drives persistent de novo lipogenesis under insulin-resistant conditions by promoting dephosphorylation of protein phosphatase 1 β (PPP1CB) and enhancing fatty acid synthase gene transcription via DNA-dependent protein kinase and USF1. A small natural compound was shown to disrupt WDR6–PPP1CB interaction and to attenuate hepatic lipid accumulation, highlighting a novel therapeutic target. Studies of zonal distribution of insulin receptor substrates further explain how periportal and perivenous hepatocytes diverge in their response to hyperinsulinaemia, underpinning ‘selective insulin resistance.’

Hepatic Metabolism and Insulin Resistance publication trend

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

Technical terms

Gluconeogenesis: Synthesis of glucose from non-carbohydrate precursors, chiefly in the liver, to maintain blood glucose during fasting.

De novo lipogenesis: Pathway by which acetyl-CoA is converted into fatty acids in hepatocytes, typically activated by insulin.

Selective insulin resistance: Phenomenon in which insulin fails to suppress hepatic gluconeogenesis yet continues to drive lipogenesis.

Hyperinsulinaemia: Chronically elevated plasma insulin levels often accompanying insulin resistance and obesity.

Induced pluripotent stem cell (iPSC): Somatic cell reprogrammed to a pluripotent state, used to model human hepatocyte function in vitro.

References

1. Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages. Nature Communications (2023).
2. Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice. Nature Metabolism (2023).
3. Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity. Nature Communications (2016).
4. Unraveling the Regulation of Hepatic Gluconeogenesis. Frontiers in Endocrinology (2019).
5. Liver glucose metabolism in humans. Bioscience Reports (2016).
6. The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways*. Journal of Biological Chemistry (2010).