Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease typeIIIaare 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

*Corresponding author for this work

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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 31P-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 31P 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.

Original languageEnglish
Pages (from-to)226-239
Number of pages14
JournalJournal of Inherited Metabolic Disease
Issue number1
Early online date16-Aug-2020
Publication statusPublished - Jan-2021


  • P-31-MRS
  • acute nutritional ketosis
  • exercise
  • glycogen storage disease
  • ketone-ester
  • WORK

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