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-β-hydroxybutyrate (βHB) in the form of a KE drink (ΔG ) 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, βHB, 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 βHB 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 βHB, 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 βHB is partially due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.