Exogenous D-β-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis

Background: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose-lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L-alanine blood levels. In this study, we sought to determine whether supplementation with L-alanine would attenuate the glucose-lowering effect of exogenous ketosis using a ketone ester (KE). Methods: This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of D-beta-hydroxybutyrate (beta HB) in the form of a KE drink (Delta G(R)) on two separate visits. During one of the visits, participants additionally ingested 2 g of L-alanine to see whether L-alanine supplementation would attenuate the glucose-lowering effect of the KE drink. Blood L-alanine, L-glutamine, glucose, beta HB, free fatty acids (FFA), lactate and C-peptide were measured for 120 min after ingestion of the KE, with or without L-alanine. Findings: The KE drinks elevated blood beta HB concentrations from negligible levels to 4.52 +/- 1.23 mmol/L, lowered glucose from 4.97 +/- SD 0.39 to 3.77 +/- SD 0.40 mmol/L, and lowered and L-alanine from 0.56 +/- SD 0.88 to 0.41 +/- SD 0.91 mmol/L. L-alanine in the KE drink elevated blood L-Alanine by 0.68 +/- SD 0.15 mmol/L, but had no significant effect on blood beta HB, L-glutamine, FFA, lactate, nor C-peptide concentrations. By contrast, L-alanine supplementation significantly attenuated the ketosis-induced drop in glucose from 28% +/- SD 8% to 16% +/- SD 7% (p < .01). Conclusions: The glucose-lowering effect of acutely elevated beta HB is partially due to beta HB decreasing L-alanine availability as a substrate for gluconeogenesis.

Automated summary

The study showed that acutely elevated beta HB can lower blood glucose by decreasing the availability of L-alanine as a substrate for gluconeogenesis.