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

ABSTRACT

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 ketosis per se which controls FGF21 production, but instead a rather more complex regulatory mechanism.

Trial registration

clinicaltrials.gov ID number: Study 1: NCT02157155 (5/6-2014), study 2: NCT02077348 (4/3-2014), and study 3: NCT02357550 (6/2-2015)

KEYWORDS:

• Fibroblast Growth Factor 21
• ketone Bodies
• insulin
• 3-hydroxybutyrate
• lipopolysaccharide
• inflammation

Acknowledgments

We would like to thank Lisa Buus, The Medical Research Laboratory, Institute of Clinical Medicine, Aarhus University, for invaluable technical assistance.

Disclosure Of Interest

The authors report no conflict of interest.

Additional information

Funding

This work was supported by The Danish Council for Strategic Research under grant no. 0603-00479; and the Steno Diabetes Center Aarhus (SDCA) which is partially funded by an unrestricted donation from the Novo Nordisk Foundation.