Do exogenous ketones affect insulin secretion? Original paper

Although exogenous ketones are sometimes used to induce ketosis, it's unclear how they might affect hormones related to nutrient digestion.

This open-label nonrandomized crossover trial assessed whether oral ingestion of the ketone 3-hydroxybutyrate (3-OHB) stimulated insulin, gut hormone secretion, gut motility, or appetite as compared to intravenous 3-OHB. The investigators collected blood samples from 8 healthy male participants on two occasions at least 48 hours apart. At the first visit, they repeated the blood sample after participants consumed 36 grams of a 3-OHB salt. At the second visit, they collected blood samples after intravenous delivery of the 3-OHB salt to assess whether the effects were due to gastrointestinal factors. Immediately after 3-OHB administration in both conditions, the participants consumed 1,500 mg of acetaminophen to evaluate gastric emptying.

The primary outcome was the difference in insulin area under the curve (AUC; a measure of systemic exposure) at 180 minutes after 3-OHB administration. The secondary outcomes were the AUCs of C-peptide (a measure of insulin production) and gut hormones (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, cholecystokinen (CCK), and gastrin) after ketone ingestion as well as gastric emptying, appetite, and ad libitum food intake, all assessed at 180 minutes.

Oral consumption of 3-OHB led to a higher AUC for insulin, C-peptide, gastrin, and CCK than intravenous administration. There were no differences in other gut hormones, appetite, or ad libitum food intake between conditions.

Serum levels of acetaminophen were delayed in the oral 3-OHB condition compared to the intravenous condition, suggesting that oral 3-OHB slowed gastric emptying.

The authors concluded that oral (but not intravenous) 3-OHB stimulated CCK release, C-peptide and insulin and slowed gastric emptying. Although more research is needed given the current study's small sample size, these results highlight a notable potential difference between exogenous and endogenously produced ketones.