ArticleInternational journal of obesity (2005)2018
Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.
Article in International journal of obesity (2005), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 112 citations in OpenAlex.
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- Identification of shared biomarkers in obesity and non-alcoholic fatty liver disease: a comprehensive analysis of Mendelian randomization and transcriptomic data.Frontiers in nutrition · 2026Article
- Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.Nature communications · 2025Article
- Molecular mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD): functional analysis of glucose and fructose metabolism pathways.Clinical science (London, England : 1979) · 2025Review
- The pathophysiological link between type 1 diabetes and MASLD: insights into insulin resistance and liver dysfunction.Journal of endocrinological investigation · 2025Review
- Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications.Diabetes & metabolism journal · 2025Review
- Role of amino acids in the regulation of hepatic gluconeogenesis and lipogenesis in metabolic dysfunctionassociated steatotic liver disease.Clinical and molecular hepatology · 2025Review
- Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.Cell metabolism · 2025Article
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- Differences in Fatty Acid Metabolism between MCDD and HFD Induced Metabolic Dysfunction-associated Fatty Liver Disease Model Mice.Biological procedures online · 2025Article
- Puerarin Targets HIF-1α to Modulate Hypoxia-Related Sphingolipid Metabolism in Diabetic Hepatopathy via the SPTLC2/Ceramide Pathway.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Physiological and pathophysiological actions of insulin in the liver.Endocrine journal · 2025Review
- Therapeutic Potential ofFood science & nutrition · 2025Article
- A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.Cell reports. Medicine · 2024Article
- Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis.Cell reports. Medicine · 2024Article
- VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway.Journal of translational medicine · 2024Article
- A metabolic dysfunction-associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system.Communications biology · 2024Article
- Article
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND/
objectiveInsulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/
methodsWe examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data.
resultsIn NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression.
conclusionThese analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.
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