Get started
Work

Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans

Year: 2024
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR, defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. DESIGN: Cross-sectional study in men and women across a range of adiposity. METHODS: Medication-free participants (n = 177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. RESULTS: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. CONCLUSIONS: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF, and these pathways should be considered for therapeutic targeting.
DOI: 10.1093/ejendo/lvae123
Authors: Felix A Westcott, Shilpa R Nagarajan, Sion A Parry, Dragana Savic, Charlotte J Green, Thomas Marjot, Elspeth Johnson, Thomas Cornfield, Ferenc E Mózes, Paige O’Rourke, Jessica Mendall, David Dearlove, Barbara Fielding, Kieran Smith, Jeremy W Tomlinson, Leanne Hodson
Institutions: University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Aston University, University of Surrey, National Institute for Health and Care Research, Oxford University Hospitals NHS Trust
Language: English
Subfield: Epidemiology
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $4,316
Funders: National Institute for Health and Care Research, British Heart Foundation, University of Oxford, Novo Nordisk, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council, NIHR Oxford Biomedical Research Centre
Awards: Compartmentalisation of liver lipid flux determines atherogenic lipoprotein production and liver fat accumulation: the relevance of dietary macronutrient composition, The effect of fructose on human hepatocyte-adipocyte cellular crosstalk and metabolic health, G2497959486, Research Excellence (round 3), G4613715315, Heterogeneity in hepatic synthesis pathways may influence the development of non-alcoholic fatty liver disease (NAFLD) and atherogenic dyslipidaemia: studies in humans using in vivo and in vitro approaches, The effect of a high fat vs high sugar diet on liver fat accumulation and metabolism, Dissecting the steroid metabolome in the pathogenesis and treatment of metabolic liver disease, G7740023122, G7952107051, G8050594159, An investigation of intra-hepatic fatty acid partitioning and its regulation in man: relevance to the production of atherogenic lipoproteins
OpenAlex ID: W4403011742
FWCI: 0.781
Cites: 58
Cited by: 3
Related to: 10