Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study

Irene J Hoogeveen, Foekje de Boer, Willemijn F Boonstra, Caroline J van der Schaaf, Ulrike Steuerwald, Anita J Sibeijn-Kuiper, Riemer J K Vegter, Johannes H van der Hoeven, M Rebecca Heiner-Fokkema, Kieran C Clarke, Pete J Cox, Terry G J Derks, Jeroen A L Jeneson, Irene J Hoogeveen, Foekje de Boer, Willemijn F Boonstra, Caroline J van der Schaaf, Ulrike Steuerwald, Anita J Sibeijn-Kuiper, Riemer J K Vegter, Johannes H van der Hoeven, M Rebecca Heiner-Fokkema, Kieran C Clarke, Pete J Cox, Terry G J Derks, Jeroen A L Jeneson

Abstract

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31 P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak βHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31 P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03011203.

Keywords: 31P-MRS; acute nutritional ketosis; exercise; glycogen storage disease; ketone-ester.

Conflict of interest statement

The intellectual property and patents covering the uses of ketone bodies and esters are owned by BTG Ltd., The University of Oxford, the NIH and TdeltaS Ltd. Should royalties ever accrue from these patents, Kieran C. Clarke and Pete J. Cox as named inventors may receive a share of royalties as determined by the terms of the respective institutions. Kieran C. Clarke is director of TdeltaS Ltd., a spin out company of the University of Oxford, to develop and commercialize products based on the ketone‐ester. Irene J. Hoogeveen, Foekje de Boer, Willemijn F. Boonstra, Caroline J. van der Schaaf, Riemer J. K. Vegter, Johannes H. van der Hoeven, M. Rebecca Heiner‐Fokkema, Terry G. J. Derks, and Jeroen A. L. Jeneson declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Figures

FIGURE 1
FIGURE 1
Changes of blood and urine metabolites after ingestion of either carbohydrates (CHO) or carbohydrates and ketone‐ester (KE + CHO) drink before, during, and after exercise. A, βHB kinetics after ingestion of KE + CHO; B, βHB concentrations; C, AcAc concentrations; D, glucose concentrations; E, insulin concentrations; F, lactate concentrations; and G, FFA concentrations. In panel (B‐G), n = 4 for time points t = 105 and t = 110 (during in‐magnet exercise), n = 6 for all other time points in both study arms. Light gray columns represent the time frame of exercise at 30% Wmax, dark gray columns represent the time frame of exercise at 60% Wmax. Values expressed as mean ± SEM. *P < .05, §P < .01, ±P < .0001; linear mixed model analysis with post hoc contrast analysis. βHB, beta‐hydroxybutyrate; FFA, free fatty acid
FIGURE 2
FIGURE 2
Heart rate and indirect calorimetry measurements at rest, 30% Wmax, and 60% Wmax during the upright bicycle protocol in both study arms. A,B, Pooled data (n = 6); C, Data presented as subgroups based on muscle phenotype, n = 3 in both groups. Dashed line represents the RQ of βHB (0.89). Data presented as mean ± SD. βHB, beta‐hydroxybutyrate; RQ, respiratory quotient
FIGURE 3
FIGURE 3
Outcomes of in vivo 31P‐MR spectra of quadriceps muscle during 10‐minute supine in‐magnet exercise and recovery in both study arms. A, Intramuscular Pi/PCr ratios at equivalents of 30% and 60% Wmax in four subjects; B, Exercise duration and related spectra, in both study arms for subject #3; C, Example of intramuscular Pi recovery time course from subject #3 in the KE + CHO arm (left panel), table represents individual rates of metabolic recovery vs healthy controls 30 (right panel). 31P‐MR, 31 phosphorus magnetic resonance; CHO, carbohydrates; KE, ketone‐ester; PCr, phosphocreatine; Pi, inorganic phosphate

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