Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans

Purpose Fibroblast growth factor (FGF) 21 is a circulating hormone with metabolic regulatory importance. In mice, FGF21 increases in response to a ketogenic diet and fasting. In humans, a similar increase is only observed after prolonged starvation. We aim to study the acute effects of ketone bodies on circulating FGF21 levels in humans. Methods Participants from three randomized, placebo-controlled crossover studies, with increased endogenous or exogenous ketone bodies, were included. Study 1: patients with type 1 diabetes (T1D) (n = 9) were investigated after a) insulin deprivation and lipopolysaccharide (LPS) injection and b) insulin-controlled euglycemia. Study 2: patients with T1D (n = 9) were investigated after a) total insulin deprivation for 9 hours and b) insulin-controlled euglycemia. Study 3: Healthy adults (n = 9) were examined during a) 3-hydroxybutyrate (OHB) infusion and b) saline infusion. Plasma FGF21 was measured with immunoassay in serial samples. Results Circulating OHB levels were significantly increased to 1.3, 1.5, and 5.5 mmol/l in the three studies, but no correlations with FGF21 levels were found. Also, no correlations between FGF21, insulin, or glucagon were found. Insulin deprivation and LPS injection resulted in increased plasma FGF21 levels at t = 120 min (p= .005) which normalized at t = 240 min. Conclusion We found no correlation between circulating FGF21 levels and levels of ketone bodies. This suggests that it is not ketosisper sewhich controls FGF21 production, but instead a rather more complex regulatory mechanism.

Automated summary

This study found no significant correlation between circulating FGF21 levels and levels of ketone bodies, insulin, or glucagon. The results suggest that the production of FGF21 is not solely controlled by ketosis itself, but rather by a more complex regulatory mechanism.