Ketogenic propensity is differentially related to lipid‐induced hepatic and peripheral insulin resistance.

Aim: Determine the ketogenic response (β‐hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans. Methods: In total, nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m2) received either a 12 h overnight lipid infusion or saline in a randomized, crossover design. Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic–euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation. Results: By design, the lipid overload‐induced hepatic (50%, p < 0.001) and peripheral insulin resistance (73%, p < 0.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal = 0.78 mM, Insulin = 0.51 mM; 2‐way ANOVA: Lipid p < 0.001, Insulin p < 0.001, Interaction p = 0.07). 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 (r = 0.59, p < 0.01), but inversely related to peripheral insulin sensitivity (r = −0.64, p < 0.01). 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. Conclusion: 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‐induced insulin resistance. [ABSTRACT FROM AUTHOR]

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