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

Abstract

AimDetermine the ketogenic response (β‐hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans.MethodsIn 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.ResultsBy 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.ConclusionThis 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.

Unraveling the complex connection between ketone bodies and insulin resistance

“…Lipoprotein lipase is crucial for the lipolysis of fatty acids from circulating lipoproteins, and heparin prevents the uptake of lipids in adipose tissue, ensuring the availability of ketogenic-free fatty acids to the liver. 7 Additionally, this study 6 did not quantify ketone body turnover, specifically the rates of hepatic ketogenesis (rate of appearance) and extrahepatic ketolysis (rate of disappearance). 2 While a static plasma βOHB concentration often reflects hepatic ketogenesis rates, whether hepatic ketogenesis or extrahepatic disposal are dynamically regulated is important to understand in pathophysiological states such as insulin resistance.…”

“…3,4 Understanding the intricate relationship between ketogenesis and insulin resistance may be crucial for maintaining wellness and is likely to be guided by distinct molecular signals than those driving impaired suppression of glucose production in insulin resistance. 5 A recent study contributed by Mey et al 6 seeks to determine the interplay between ketone bodies and lipidinduced insulin resistance in human participants. Acute insulin resistance was provoked via a 12 h overnight intravenous lipid infusion in a randomized crossover design, and hepatic and peripheral tissue insulin sensitivity were quantified by hyperinsulinemic-euglycemic clamps, focusing on understanding whether the propensity of the liver to generate ketones protects against insulin resistance.…”

“…A recent study contributed by Mey et al 6 . seeks to determine the interplay between ketone bodies and lipid‐induced insulin resistance in human participants.…”

“…Limitations of this study design leave opportunity for the development of additional insights. First, the lipid infusion protocol 6 did not include heparin, an anticoagulant that also liberates lipoprotein lipase from adipose into the circulation. Lipoprotein lipase is crucial for the lipolysis of fatty acids from circulating lipoproteins, and heparin prevents the uptake of lipids in adipose tissue, ensuring the availability of ketogenic‐free fatty acids to the liver 7 .…”