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Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic\u2013euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By design, the lipid overload\u2010induced hepatic (50%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and peripheral insulin resistance (73%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal\u2009=\u20090.22\u2009mM, Insulin\u2009=\u20090.07\u2009mM; Lipid: Basal\u2009=\u20090.78\u2009mM, Insulin\u2009=\u20090.51\u2009mM; 2\u2010way ANOVA: Lipid <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, Insulin <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, Interaction <jats:italic>p<\/jats:italic>\u2009=\u20090.07). In the saline control condition, ketones did not correlate with hepatic or peripheral insulin sensitivity. Conversely, in the lipid condition, ketones were positively correlated with hepatic insulin sensitivity (<jats:italic>r<\/jats:italic>\u2009=\u20090.59, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), but inversely related to peripheral insulin sensitivity (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.64, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Hyperlipidemia increased plasma inflammatory markers, but did not impact skeletal muscle inflammatory gene expression. Gene expression related to ketone and fatty acid metabolism in skeletal muscle increased in response to hyperlipidemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This work provides important insight into the role of ketones in human health and suggests that ketone body metabolism is altered at the onset of lipid\u2010induced insulin resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14054","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T07:50:27Z","timestamp":1697442627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Ketogenic propensity is differentially related to lipid\u2010induced hepatic and peripheral insulin resistance"],"prefix":"10.1111","volume":"239","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6826-7762","authenticated-orcid":false,"given":"J. 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