Exogenous D-β-Hydroxybutyrate Lowers Blood Glucose by Decreasing the Availability of L-Alaninefor Gluconeogenesis

Abstract

BackgroundInterventions that acutely increase blood ketone concentrations simultaneously lower blood glucose levels, although the explanation for this phenomenon is unknown. The hypoglycaemic effect of acute ketosis is greater in people with type 2 diabetes (T2D) in whom gluconeogenesis contributes significantly to hyperglycaemia. L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D. As infusion of ketones lower circulating L-alanine blood levels, we sought to determine whether supplementation with L-alanine would attenuate the hypoglycaemic effect of an exogenous ketone ester (KE) supplement.MethodsThis crossover study involved 10 healthy human volunteers who fasted for 24 hours 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 if L-alanine supplementation would attenuate the hypoglycaemic effect of the KE drink. Blood L-alanine, L-glutamine, glucose, βHB, free fatty acids (FFA), lactate, and C-peptide were measured every fifteen minutes for 120 minutes after ingestion of the KE, with or without L-alanine.FindingsThe KE drinks elevated blood βHB concentrations from negligible levels to 4.5 ± 1.24 mmol/L, lowered glucose from 4.97 to 3.77 ± 0.4 mmol/L, and lowered and L-alanine from 0.56 to 0.41 ± 0.9 mmol/L. L-alanine in the KE drink elevated blood L-Alanine to 0.68 ± 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% to 16% (p<0.001).ConclusionsThe hypoglycaemic effect of acutely elevated βHB is partially due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.