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

doi:10.21203/rs.3.rs-355173/v1

Download PDF

Research Article

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

https://doi.org/10.21203/rs.3.rs-355173/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this older preprint version

Read the latest preprint version →

Background

Interventions 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 their hyperglycaemia. One gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D is L-alanine. Infusion of ketones lowers circulating L-alanine blood levels, so here we sought to determine whether supplementation with L-alanine would attenuate the hypoglycaemic effect of a ketone ester (KE) drink.

Methods

This crossover study involved two separate visits for 10 healthy human volunteers who fasted for 24 hours prior to the ingestion of 25 g of d-β-hydroxybutyrate (βHB) monoester (ΔG^®). During one of the visits participants ingested 2 g of L-alanine. Blood L-alanine, L-glutamine, glucose, βHB, free fatty acids (FFA), lactate, and C-peptide were measured.

Findings

The KE drinks elevated blood βHB concentrations from negligible to 4.5 ± 1.24 mM/l, and lowered both glucose, from 4.97 to 3.77 ± 0.4 mM/l, and L-alanine from 0.56 to 0.41 ± 0.9 mM/l. L-alanine in the KE drink elevated blood L-Alanine to 0.56 ± mM/l, but had no significant effect on blood βHB, L-glutamine, FFA, lactate, or C-peptide concentrations. Preventing the KE-induced decrease in L-alanine by supplementing it significantly attenuated the glucose drop from mean 28% to 16% (p<0.001). (Illustrated in Figure 1).

Conclusions

The hypoglycaemic effect of acutely elevated βHB is, at least partially, due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.

Physiology

Endocrinology & Metabolism

Alanine

D-β-hydroxybutyrate

Diabetes

Exogenous Ketosis

Gluconeogenesis

Hyperglycaemia

Hypoglycaemia

Ketone Bodies

In the fed state, the human brain relies almost exclusively on glucose as an energy source. However, dietary carbohydrates are not always available, so glucose can be derived from through gluconeogenesis. But gluconeogenesis alone is not compatible with human life as it requires the catabolism of lean muscle tissue and, thus, even relatively short periods without carbohydrate would lead to severe muscle wasting and death. Ketone bodies, primarily d-β-hydroxybutyrate (βHB), are derived from fat stores to provide an alternative fuel substrate for the brain. Not only does βHB supplant glucose as a brain fuel substrate, but it inhibits gluconeogenesis and, thus, spares lean muscle tissue¹.

In type 2 diabetes (T2D), excessive gluconeogenesis underlies hyperglycemia². Because βHB inhibits gluconeogenesis³, it may be useful in managing hyperglycemia and ketogenic diets successfully reverse T2D^4,5. Carbohydrate restriction certainly plays a role in glycaemic control, it is also true that, in both animals and humans, exogenous infusion of βHB decreases blood glucose^6–9. Therefore, the development of exogenous ketones for human consumption has inspired interest in exogenous ketosis as a potential treatment for this T2D¹⁰, especially because the hypoglycemic effect of ketosis is larger in people living with T2D than in healthy controls¹¹. However, no mechanism describing this difference has been elucidated.

Gluconeogenesis is main hyperglycaemic mechanism in people living with T2D^2,12. Ketosis preserves gluconeogenic muscle tissue¹³ and ketones limit the secretion of L-alanine, a gluconeogenic substrate, by muscle cells^11,14. Thus, it is plausible that ketones decrease blood glucose (and do so to a greater extent in those with T2D) by reducing L-alanine availability for gluconeogenesis. This study sought to test this hypothesis by investigating whether L-alanine supplementation attenuates hypoglycaemic effect of exogenously induced ketosis.

I) Ethics

This study was pre-registered at ISRCTN16169021 and received Ethics approval by the East of England - Cambridge South Research Ethics Committee on February 18^th, 2019 (Reference 18/EE/0115). All participants were older than 18 years old and signed an informed consent form approved by the same Research Ethics Committee.

This study was conducted in accordance with the guidelines set forth by the International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki regarding the treatment of human subjects in a study³².

II) Statistical analysis

Sample size was calculated to detect a blood glucose difference of at least 0.9 mM between groups with a statistical power of 80% and an alpha probability of 0.05. Therefore, six participants per group were needed. To achieve a sex and age balanced cohort and to allow for dropouts, a total of 10 participants were recruited and all completed the study. Sample size calculations were performed using G*Power version 3.1³¹.

All statistical tests and analysis were performed using Excel^®(Microsoft, United States). Data, presented as means ± standard deviations (SD), were analysed using One-way repeated measurements ANOVA and adjusted with Bonferroni’s correction for multiple comparisons. Differences were considered significant at p < 0.05. Since baseline blood concentrations of L-Alanine and L-Glutamine have large interpersonal variations due to body composition, comparisons were made using change from baseline.

III) Materials and procedures

Participants fasted for 24 hours. At each visit, participants drank a mix 25 ml of the ΔG^®ketone monoester, (R)-3- hydroxy butyl (R)-3-hydroxybutyrate (TdeltaS Ltd., United Kingdom), diluted in 25 ml water.

After ingestion, the βHB monoester bond is cleaved by esterases in the gut wall, yielding βHB and butanediol in equal amounts. Both are absorbed into the portal circulation and the latter is taken up by the liver, where it is converted into βHB by alcohol dehydrogenase (ADH). βHB leaves hepatocytes via monocarboxylate transporters. Pharmacokinetic studies have shown that, in the fasted and resting states, the βHB monoester can induce ketoses for 3–4 h, with a peak at ∼1 h that is dose-dependent³³.

On their second visit, to match skeletal muscle release of L-alanine per two hours², participants drank 2g of L-alanine (Hard Eight Nutrition LLC, United States) in water.

Blood samples were collected through a venous cannula at baseline and every 15 minutes for two hours. Glucose, βHB, lactate and free fatty acids were assayed using a commercial semi-automated bench-top analyser (ABX Pentra, Montpellier, France). L-alanine, L-glutamine and human C-peptide were measured using kits (by Abcam, United Kingdom: ab83394, ab145659 and ab178641 respectively).

Participants’ anthropometric characteristics

Five healthy males and five healthy females aged 40 years old (+/- 16) were enrolled. Ingestion of the ΔG^® ketone monoester drink was well-tolerated by all participants and none presented symptomatic hypoglycaemia. All participants were healthy, not overweight, and included five women and five men. Their mean age was 40 years old (SD = 16 years) and their mean BMI: 23.2 kg/m2 (SD = 2.4). Table 1 summarises anthropometric characteristics of our participants.

Table 1. Participant characteristics

Sex	5 (F), 5 (M)
Age (years)	40 (16)
Height (cm)	176 (15)
Weight (kg)	73 (18)
BMI (kg/m²)	23.2 (2.4)

Data are expressed as mean (Standard deviation).

Blood L-alanine, L-glutamine and glucose concentration changes after inducing acute ketosis without and with L-alanine supplementation.

In the absence of L-alanine supplementation, inducing acute ketosis with the ΔG^® ketone monoester raised blood βHB concentration to 4.5 mM/l ± 1.24mM/l and L-glutamine by 9% ± 4% (absolute change from 1.099 to 1.223 mM/l ± 0.045 mM/l). By contrast, exogenous ketosis lowered blood L-alanine by 26% ± 9.3% (absolute change from 0.563 to 0.4409 mM/l ± 0.053 mM/l) and blood glucose by 28% ± 8% (absolute change from 4.97 to 3.77 mM/l ± 0.4 mM/l). Compared to baseline, changes in βHB, glucose, and alanine, but not glutamine, were significantly different (p < 0.05).

In the presence of L-alanine supplementation, inducing ketosis raised blood βHB concentration to 4.6 ± 1.35 mM/l and L-glutamine by 10% ± 6% (absolute change from 1.12 to 1.26 ± 0.05 mM/l). As expected, L-alanine supplementation led to a net increase in L-alanine by 16% (absolute change from 0.543 to 0.682 μmol/L ± 0.051 mM/l), thus maintaining L-alanine availability for gluconeogenesis. Correspondingly, blood glucose decreased by a lesser amount, only by 17% ± 5% (absolute change from 5.01 to 4.03 mM/l ± 0.3 mM/l). Again, changes in βHB, glucose and L-alanine, but not L-glutamine, were significant (p<0.05). These results are described in detail in Table 2 and illustrated in Figure 2.

Table 2. Blood L-alanine, L-glutamine and glucose concentration changes after inducing acute ketosis with and without L-alanine supplementation

a) Absolute changes	Timepoint	βHB (mM/l)	βHB + A (mM/l)	Glucose (mM/l)	Glucose + A (mM/l)	Glutamine (mM/l)	Glutamine + A (mM/l)	Alanine (mM/l)	Alanine + A (mM/l)
	0	0.6	0.5	4.97	5.01	1.099	1.120	0.563	0.543
	15	3.4	3.2	4.52	4.64	1.120	1.130	0.492	0.579
	30	3.9	4.0	4.11	4.31	1.143	1.170	0.432	0.635
	45	3.8	4.3	3.77	4.03	1.187	1.210	0.409	0.682
	60	4.3	4.7	3.79	4.07	1.223	1.260	0.417	0.641
	75	4.5	4.6	3.91	4.15	1.211	1.190	0.444	0.599
	90	4.1	4.2	3.99	4.37	1.190	1.210	0.492	0.557
	120	3.7	3.6	4.1	4.51	1.130	1.120	0.515	0.541
b) Relative changes from BL (%)	Timepoint	βHB	βHB	Glucose	Glucose + A	Glutamine	Glutamine + A	Alanine	Alanine + A
	0	0	0	0	0	0	0	0	0
	15	566.7	627.5	-9	-4	7	5	-26	10
	30	650.0	778.4	-18	-13	9	10	-24	13
	45	633.3	843.1	-28	-17	7	9	-25	11
	60	716.7	921.6	-24	-16	6	4	-25	16
	75	750.0	892.2	-24	-12	4	1	-24	12
	90	683.3	825.5	-22	-10	0	5	-13	8
	120	616.7	705.9	-19	-9	4	10	-11	5

Data are expressed as means from n=10.

All measurements were performed by triplicate.

L-alanine supplementation attenuated the hypoglycaemic effect of acute ketosis.

The magnitude of the hypoglycaemic effect of exogenous ketosis was significantly smaller when L-alanine was supplemented, as compared to when it was not, at 45 and 60 min after ΔG^® administration (p<0.001). Glucose levels were consistently higher, relative to baseline, at all timepoints when L-alanine was supplemented as compared to when it was not (Figure 3).

L-Alanine supplementation did not impact changes in blood lactate, free fatty acids (FFA) and C-peptide during acute ketosis.

Blood lactate, FFA and C-peptide concentrations were similar at all timepoints after inducing ketosis with ΔG^®regardless of L-alanine supplementation (illustrated in Figure 4).

These data demonstrate that a decrease in L-alanine availability contributes to the hypoglycaemic effect of acute ketosis. The magnitude of the effect suggests that βHB-mediated decrease in L-alanine levels is a major contributor to this phenomenon; however, it is also evident that the hypoglycaemic effect of ketosis is a result of multiple mechanisms.

Pyruvate in disguise

During prolonged fasting, L-alanine blood levels decrease more so than those of any other amino acid, largely because of hepatic uptake of L-alanine to fuel gluconeogenesis. This phenomenon prompted the discovery of the glucose-alanine cycle, in which pyruvate is transformed into L-alanine via transamination in skeletal muscle. L-alanine (pyruvate in disguise) is released to the bloodstream, taken up by the liver, and transformed back into pyruvate to fuel gluconeogenesis¹⁵. Thus, any reduction in intramuscular pyruvate would result in lower L-alanine levels in the blood and less gluconeogenesis.

Ketone oxidation decreases intramuscular pyruvate via two mechanisms. First, ketone oxidation reduces glycolysis in skeletal muscles¹⁴ and, therefore, decreases pyruvate production. Second, ketone body oxidation increases Acetyl CoA levels¹⁶. Acetyl CoA is an allosteric activator of pyruvate carboxylase, thus, driving the conversion of pyruvate to oxaloacetate¹⁷. In addition to decreasing pyruvate for transamination into L-alanine, ketosis also directly decreases L-alanine production by reducing skeletal muscle protein degradation¹³.

Furthermore, in the liver, L-alanine supports gluconeogenesis. L-alanine allosterically inhibits the liver isozyme of pyruvate kinase, the enzyme responsible for the last step of glycolysis¹⁸. Thus, L-alanine restriction would favour glycolysis over gluconeogenesis L-alanine is also a potent glucagon secretion agonist¹⁹, and glucagon stimulates gluconeogenesis. Again, L-alanine restriction is predicted to downregulate gluconeogenesis in the liver.

These links between ketone metabolism and gluconeogenesis resonate with the evolutionary function of ketosis: to spare gluconeogenic muscle tissue.

The hypoglycaemic effect of ketone body oxidation is likely pleiotropic.

Exogenously induced ketosis can stimulate insulin secretion^20,21; however, the insulin change is not large enough to account for the entire hypoglycaemic effect. There is also evidence that it is not an increase in glucose clearance from the blood, but rather a decrease in glucose secretion into the blood that accounts for most of the hypoglycaemic effect of ketosis³. Furthermore, ketone salt infusions in patients with type 1 diabetes who were off insulin demonstrate that acute ketosis still lowers blood glucose, even in the absence of insulin¹¹.

The hypoglycaemic effect is not restricted to the fasting state. Inducing acute ketosis lowers the postprandial glycaemic curve after a dextrose challenge without inducing significant differences in insulin secretion²². One of the proposed mechanisms is that βHB-mediated inhibition of lipolysis²³ depletes the blood supply of fatty acids, driving an increase in glucose uptake. However, this has not been observed after the ingestion of niacin, which also blocks lipolysis and has no effect on gluconeogenesis²⁴. Moreover, while inhibiting lipolysis would restrict the amount of glycerol available to fuel gluconeogenesis, in the fasting human, L-alanine and lactate, not glycerol, are the main relative contributors to liver gluconeogenesis²⁵. Figure 5 summarises the mechanisms whereby exogenously induced acute ketosis lowers blood glucose concentration.

Limitations of this study

First, the relative of L-alanine to gluconeogenesis varies depending on whether a person is in the fed or fasted state^26,27. Participants in this study were all fasted, and this was necessary for control purposes. Future studies may choose to investigate the same question in postprandial participants. Second, the contribution of a ketone ester liver-specific effect cannot be ruled out.

However, the liver cannot oxidise ketone bodies²⁸ and, while the hepatic conversion of butanediol derived from ketone ester into βHB would alter hepatocyte NAD/NADH balance (which could impact endogenous glucose production), studies comparing the ingestion of equimolar quantities of ketone salts and ketone esters (that lack a butanediol component) demonstrate hypoglycaemic effects of similar magnitudes⁹.

Future Directions

These data demonstrate, in healthy humans, that a reduction in L-alanine availability to fuel gluconeogenesis is a major contributor to the hypoglycaemic effects of acute ketosis. Because gluconeogenesis is pathologically elevated during insulin resistance, and gluconeogenesis is a major contributor to poor glycaemic control in T2D, future studies will investigate the potential for exogenous ketosis to manage hyperglycaemia in T2D.

ACKNOWLEDGMENTS

The authors thank Vicky Ball for her diligent support. Adrian Soto-Mota thanks the Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) and the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (FUNSAED, Mexico) for their financial support.

AUTHOR CONTRIBUTIONS

All authors contributed significantly to the design, execution, analysis and reporting of this study.

DECLARATION OF INTERESTS

The intellectual property covering the uses of ketone bodies and ketone esters are owned by BTG Plc, Oxford University Innovation Ltd and the US National Institutes of Health. Professor Kieran Clarke, as an inventor, will receive a share of the royalties under the terms prescribed by each institution. Professor Clarke is a director of TdeltaS Ltd, a company spun out of the University of Oxford to develop products based on the science of ketone bodies in human nutrition. The other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.

Cahill, G.F., and George, F.C. (2006). Fuel Metabolism in Starvation. Annu. Rev. Nutr. 26, 1–22.
Consoli, A., Nurjhan, N., Reilly, J.J., Bier, D.M., and Gerich, J.E. (1990). Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabilism. J. Clin. Invest. 86, 2038–2045.
Beylot, M., Chassard, D., Chambrier, C., Guiraud, M., Odeon, M., Beaufrere, B., And Bouletreau, P. (1994). Metabolic effects of a D-β-hydroxybutyrate infusion in septic patients. Crit. Care Med. 22, 1091–1098.
Hallberg, S.J., McKenzie, A.L., Williams, P.T., Bhanpuri, N.H., Peters, A.L., Campbell, W.W., Hazbun, T.L., Volk, B.M., McCarter, J.P., Phinney, S.D., et al. (2018). Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther. 9, 583–612.
Lim, E.L., Hollingsworth, K.G., Aribisala, B.S., Chen, M.J., Mathers, J.C., and Taylor, R. (2011). Reversal of type 2 diabetes: Normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54, 2506–2514.
Nakatani, T., Yasuda, K., Ozawa, K., and Tobe, T. (1984). Changes in Blood Glucose Levels in Relation to Blood Ketone Body Ratio following Hypertonic Glucose Infusion in 70% Hepatectomized Rabbits. Eur. Surg. Res. 16, 303–311.
Felts, P.W., Crofford, B., and Park, C.R. (1964). Effect of Infused Ketone Bodies on Glucose Utilization in the Dog.
Muller, M.J., Paschen, U., and Seitz, H.J. (1984). Effect of ketone bodies on glucose production and utilization in the miniature pig. J. Clin. Invest. 74, 249–261.
Stubbs, B.J., Cox, P.J., Evans, R.D., Santer, P., Miller, J.J., Faull, O.K., Magor-Elliott, S., Hiyama, S., Stirling, M., and Clarke, K. (2017). On the metabolism of exogenous ketones in humans. Front. Physiol. 8, 848.
Soto-Mota, A., Norwitz, N.G., and Clarke, K. (2020). Why a D-β-hydroxybutyrate monoester? Biochem. Soc. Trans. 48, 51–59.
Sherwin, R.S., Hendler, R.G., and Felig, P. (1976). Effect of diabetes mellitus and insulin on the turnover and metabolic response to ketones in man. Diabetes 25, 776–784.
Magnusson, I., Rothman, D.L., Katz, L.D., Shulman, R.G., and Shulman, G.I. (1992). Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 90, 1323–1327.
Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, A.J., Stubbs, B., West, J., McLure, S.W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 24, 256–268.
Wu, G., and Thompson, J.R. (1988). The effect of ketone bodies on alanine and glutamine metabolism in isolated skeletal muscle from the fasted chick. Biochem. J. 255, 139–144.
Felig, P., Pozefsk, T., Marlis, E., and Cahill, G.F. (1970). Alanine: Key Role in Gluconeogenesis. Science (80-. ). 167, 1003–1004.
Sato, K., Kashiwaya, Y., Keon, C.A., Tsuchiya, N., King, M.T., Radda, G.K., Chance, B., Clarke, K., and Veech, R.L. (1995). Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9, 651–658.
Jitrapakdee, S., Maurice, M.S., Rayment, I., Cleland, W.W., Wallace, C., and Attwood, P. V (2008). Structure, Mechanism and Regulation of Pyruvate Carboxylase. Biochem J 413, 369–387.
Van Veelen, C.W.M., Rijksen, G., Vlug, A.M.C., and Staal, G.E.J. (1981). Correlation between Alanine inhibition of pyruvate kinase and composition of K-M hybrids.
Müller, W.A., Faloona, G.R., and Unger, R.H. (1971). The effect of alanine on glucagon secretion. J. Clin. Invest. 50, 2215–2218.
Balasse, E., Ooms, H., and Lambilliotte, J. (1970). Evidence for a stimulatory effect of ketone bodies on insulin secretion in man. Horm. Metab. Res. 2, 371–372.
Biden, T.J., and Taylor, K.W. (1983). Effects of ketone bodies on insulin release and islet-cell metabolism in the rat. Biochem. J. 212, 371–377.
Myette-Côté, É., Caldwell, H.G., Ainslie, P.N., Clarke, K., and Little, J.P. (2019). A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial. Am. J. Clin. Nutr. 110, 1491–1501.
Taggart, A.K.P., Kero, J., Gan, X., Cai, T.Q., Cheng, K., Ippolito, M., Ren, N., Kaplan, R., Wu, K., Wu, T.J., et al. (2005). (D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652.
Wang, W., Basinger, A., Neese, R.A., Christiansen, M., and Hellerstein, M.K. (2000). Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women. Am. J. Physiol. Endocrinol. Metab. 279, E50-9.
Stumvoll, M., Meyer, C., Perriello, G., Kreider, M., Welle, S., and Gerich, J. (1998). Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. Am. J. Physiol. 274, E817–E826.
Chiasson, J.L., Liljenquist, J.E., Sinclair Smith, B.C., and Lacy, W.W. (1975). Gluconeogenesis from alanine in normal postabsorptive man. Intrahepatic stimulatory effect of glucagon. Diabetes 24, 574–584.
Chiasson, J.L., Atkinson, R.L., Cherrington, A.D., Keller, U., Sinclair-Smith, B.C., Lacy, W.W., and Liljenquist, J.E. (1980). Effects of insulin at two dose levels on gluconeogenesis from alanine in fasting man. Metabolism. 29, 810–818.
Orii, K.E., Fukao, T., Song, X.-Q.Q., Mitchell, G.A., and Kondo, N. (2008). Liver-Specific Silencing of the Human Gene Encoding Succinyl-CoA: 3-Ketoacid CoA Transferase. Tohoku J. Exp. Med. 215, 227–236.
Usenik, A., and Legiša, M. (2010). Evolution of allosteric citrate binding sites on 6- phosphofructo-1-kinase. PLoS One 5, e15447.
Beylot, M., Khalfallah, Y., Riou, J.P., Cohen, R., Normand, S., and Mornex, R. (1986). Effects of ketone bodies on basal and insulin-stimulated glucose utilization in man. J. Clin. Endocrinol. Metab. 63, 9–15.
Erdfelder, E., Faul, F., Buchner, A., and Lang, A.G. (2009). Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav. Res. Methods 41, 1149–1160.
WMA (2013). WMA Declaration of Helsinki – Ethical principles for Scientific Requirements and Research Protocols. World Med. Assoc., 29–32.
Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Todd King, M., Musa-Veloso, K., Ho, M., Roberts, A., Robertson, J., VanItallie, T.B., et al. (2012). Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul. Toxicol. Pharmacol. 63, 401–408.

Competing interest reported. The intellectual property covering the uses of ketone bodies and ketone esters are owned by BTG Plc, Oxford University Innovation Ltd and the US National Institutes of Health. Professor Kieran Clarke, as an inventor, will receive a share of the royalties under the terms prescribed by each institution. Professor Clarke is a director of TdeltaS Ltd, a company spun out of the University of Oxford to develop products based on the science of ketone bodies in human nutrition. The other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.

Fig01.png
Graphical Abstract. Top panel, Background: Patients with type 2 diabetes have elevated rates of hepatic gluconeogenesis and hyperglycaemia. L-alanine (L-ala) is an important gluconeogenic substrate secreted by skeletal muscle tissue. Bottom panel, Crossover Study: The ketone body, β-hydroxybutyrate (βHB), inhibits L-ala release from skeletal muscle in vitro, in line with its evolutionary function to preserve gluconeogenic lean tissue during starvation. This crossover study involved ten participants who ingested an exogenous ketone monoester containing βHB (25 g) in the absence or presence of 2 g L-ala. The additional supplementation of L-ala attenuated the hypoglycaemic effect βHB, demonstrating for the first time that a βHB -mediated decrease in L-ala availability for gluconeogenesis is a major contributor in the well-documented hypoglycaemic effect of acute ketosis.

Download PDF

Version 1

posted

You are reading this older preprint version

Read the latest preprint version →

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

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1