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Extracellular vesicles (EVs) mediate endocrine and metabolic signalling. EV responses to shifts in substrate utilisation, from euketonaemia to hypoketonaemia, remain poorly understood. Chronic hyperinsulinaemia suppresses ketogenesis, causing hypoketonaemia; however, its impact on EV profiles in metabolically healthy individuals has not been characterised. We investigated the effects of hypoketonaemia on EV profiles in the KetoSAge cohort, examining associations between EV concentration, mean size, and modal size and metabolic–endocrine biomarkers. Ten lean (BMI, 20.52 ± 1.39 kg/m2), healthy premenopausal women (mean age, 32.30 ± 8.97 years) maintaining euketonaemia (mean 3.9 ± 2.3 years) completed a three-phase crossover trial, comprising 21 days each of: euketonaemia (baseline), induced-hypoketonaemia, and return-to-euketonaemia. No statistically significant phase-level differences in EV concentration or size parameters were detected. Linear mixed-effects analyses identified nominally significant associations between EV concentration and adiponectin, free T3, bilirubin, luteinising hormone, and epidermal growth factor, between EV mean size and HDL-cholesterol and between EV modal size and insulin, HOMA-IR, beta-hydroxybutyrate, GKI, thyroid hormones, ALT, AST, IL-6 and oestrogen (all unadjusted p < 0.05). However, none of these associations remained statistically significant after false discovery rate correction (FDR < 0.10). Hypoketonaemia via insulin-compensated euglycaemia revealed coordinated EV–biomarker relationships across metabolic–endocrine, hepatic and inflammatory pathways. Although exploratory, these findings suggest that EV profiles may reflect an insulin-responsive signalling network linked to the systemic bioenergetic state, highlighting their potential as early indicators of metabolic–endocrine adaptation.
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“In a landmark study, women who had been in ketosis for years paused it for 21 days, leading to quick rises in insulin and leptin that fully reversed once ketosis resumed, demonstrating both flexibility and resilience of metabolic regulation. Her research also highlights how hormonal cycles and GLP-1 responses shape women's experiences with ketosis, and how self-selected, individualized dietary approaches yield better adherence and outcomes than rigid controlled diets.”
“Consistent with the information presented in our paper are the findings from the recent KetoSAge trial showing that the presence of a safe, elevated level of ketone bodies in the blood (euketonaemia) was associated with improved insulin sensitivity, liver function, and reduced pro-inflammatory and growth-related biomarkers. On the other hand, higher GKI values indicated excessive insulin release, with worsening biomarker profiles despite seemingly normal glucose ranges.”
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Cooper et al. (2026) studied this question.
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