Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts

• Published in: Clinical nutrition ESPEN 2023-04, Vol.54, p.277-287
• Main Authors: Buga, Alex, Kackley, Madison L., Crabtree, Christopher D., Bedell, Teryn N., Robinson, Bradley T., Stoner, Justen T., Decker, Drew D., Hyde, Parker N., LaFountain, Rich A., Brownlow, Milene L., O'Connor, Annalouise, Krishnan, Deepa, McElroy, Craig A., Kraemer, William J., Volek, Jeff S.
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid; Adult; Beta-hydroxybutyrate; Diet, Ketogenic; Fasting; Glucose; Humans; Insulin; Ketogenic diet; Ketone Bodies; Ketone salts; Ketones; Ketosis; Low-fat diet; Salts; Weight loss
• ISSN: 2405-4577; 2405-4577
• DOI: 10.1016/j.clnesp.2023.01.030

Single doses of exogenous ketone salts (KS) transiently increase circulating beta-hydroxybutyrate (BHB) (∼1 mM; 1–2 h) regardless of starting levels of ketosis; however, no studies have explored how sustained use of KS influences measures of ketonemia and glycemia. To determine the response to a hypocaloric, well-formulated ketogenic diet (KD), with and without the inclusion of two daily racemic KS doses (6 g R-BHB + 6 g S-BHB per serving) on 1) daily fasting capillary R-BHB and glucose (R-BHB/GLUfast), 2) bi-weekly 13 h diurnal BHB and glucose (R-BHB/GLUdiur), 3) three-hours post–KS ingestion kinetics (R-BHBKS), and 4) bi-weekly fasting plasma enantiomer-specific BHB (R/S-BHBplasma). Non-diabetic adults with overweight and obesity were randomized to receive a precisely measured hypocaloric KD (∼75 %en of maintenance) for six weeks, supplemented twice-daily with KS or placebo (PL). A non-randomized comparison group was provided an isonitrogenous/isoenergetic low-fat diet (LFD). All meals were provided to subjects. Capillary blood was collected daily to measure R-BHB/GLUfast and hourly for R-BHB/GLUdiur. Plasma was collected to measure R/S-BHBplasma, insulin, fasting glucose, and insulin resistance (HOMA-IR). Total AUC was calculated using the trapezoidal method. Mean R-BHBfast increased significantly during KD + PL (1.0 mM BHB), an effect enhanced 26% during KD + KS. GLUfast AUC was −6% lower during KD + KS versus LFD. Mean R-BHBdiur increased 40% in KD + KS versus KD + PL, whereas GLUdiur decreased 13% during both KDs versus LFD. R-BHBKS peaked (Δ: ∼1 mM) 1 h after the morning KS dose, but not following the afternoon dose. Both R/S-BHBplasma increased during KD independent of KS inclusion. R-BHBplasma was 50-times greater compared to S-BHBplasma, and the KS augmented S-BHBplasma 50% more than PL. Fasting insulin and HOMA-IR decreased after 14 days independent of diet. A hypocaloric KD was effective at reducing diurnal glucose compared to a LFD independent of weight loss, but twice-daily racemic KS ingestion during KD augmented ketonemia, both as R- and S-BHB, and decreased mean fasting glucose beyond a KD alone. The hypoglycemic effects of KD in combination with exogenous ketones merit further investigation.