Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1β, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1β, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.