Clinical trial NCT03011203: Acute Nutritional Ketosis in GSD IIIa
Official title: Acute Nutritional Ketosis and Exercise in Glycogen Storage Disease Type IIIa
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Glycogen Storage Disease IIIA
Keywords: glycogen storage disease type IIIa
exercise
ketone esters
magnetic resonance spectroscopy
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: University of the Faroe Islands
name: University of Oxford
name: Stichting Stofwisselkracht
name: Stichting Metakids
First posted: 2017-01-05
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: The investigators will study if acute nutritional ketosis in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.

Detailed description: Glycogen Storage Disease type IIIa (GSD IIIa) is an inborn error of carbohydrate metabolism caused by impaired glycogen debranching enzyme (GDE) activity. The ageing GSD IIIa cohort shows that muscle involvement -despite dietary management- is a common disabling phenotype in adulthood. Currently, no specific therapy has been established for muscle problems in adult GSD IIIa patients.

However, it could be hypothesized that nutritional ketosis (NK) will be highly beneficial to patients. Amongst others, ketone bodies could take on the role of primary energy source in exercising muscle. Recently, acute NK in exercise was studied in humans. NK was found to enhance muscle mitochondrial function in athletes.

The investigators will study if acute NK in adult GSD IIIa patients can boost muscle mitochondrial function in vivo.

Eligibility criteria: Inclusion Criteria:

* GSD III confirmed with enzyme assay and/or AGL mutation analysis and GSD IIIa further specified as deficient debranching enzyme activity in muscle or clinical and/or biochemical signs of cardiac and/or skeletal muscular involvement.

Exclusion Criteria:

* contraindications for MRI studies (assessed by standardised questionnaire)
* inability to perform bicycle exercise.
* intercurrent illness which may influence exercise tolerance (anemia, musculoskeletal injury, or other undiagnosed illness under investigation).
* known coronary artery disease, positive history for angina or cardiomyopathy.
* insulin-dependent diabetes mellitus.
* loss of, or an inability to give informed consent.
* pregnancy or current breastfeeding.
* any other cause which in the opinion of the investigators, may affect the participant's ability to participate in the study

Primary outcomes:
measure: Description of in vivo energy and proton balance during exercise in MR scanner with and without ketone ester drink: steady-state intramuscular levels of glycogen, Pi, PCr and pH and kinetic rate constant of metabolic recovery.
timeFrame: 10 minutes; during in-magnet exercise test of session II and III.
Secondary outcomes:
measure: time of individual desired workload
timeFrame: through completion of the maximum exercise test (of approximately 12 minutes) during study session I.
measure: completion of supine bicycling bout at desired workload in scanner
timeFrame: 10 min
measure: Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles.
timeFrame: Together with the muscle force examination this assessment will take 1.5 hour.
measure: Muscle force unilateral
timeFrame: Together with the muscle ultrasound this assessment will take 1.5 hour.
measure: Subjective fatigue and muscle ache score
timeFrame: after each exercise bout and 24 hours after exercise
measure: International Physical Activity Questionnaire
timeFrame: This questionnaire will take 10 minutes to fill out. Participants will be asked to fill out the questionnaire one week before study session II and III
measure: Structural muscle parameters: fat infiltration.
timeFrame: During the in-magnet exercise test of 10 minutes during session II and III
measure: Change in blood glucose levels
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood ketones level (β-hydroxybutyrate, acetoacetate).
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Change of blood pH
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of free fatty acids
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of insulin
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of creatine kinase
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of ammonia
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of NT-proBNP
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Blood levels of lactate
timeFrame: Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
measure: Change of urine levels of myoglobin, ketones, tetraglucoside
timeFrame: Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm.
measure: optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy.
timeFrame: This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
measure: optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density
timeFrame: This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
measure: Individual physical performance during exercise; VO2 and VCO2 dynamics.
timeFrame: During session I; the maximum exercise test of approximately 12 minutes and during the exercise tests of 15 minutes outside the MR scanner at session II and III.
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University of Groningen, UMC Groningen
Study officials:
affiliation: University Medical Center Groningen
name: T.G.J. Derks, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab. 2016 Aug 9;24(2):256-68. doi: 10.1016/j.cmet.2016.07.010. Epub 2016 Jul 27.
citation: Diekman EF, Visser G, Schmitz JP, Nievelstein RA, de Sain-van der Velden M, Wardrop M, Van der Pol WL, Houten SM, van Riel NA, Takken T, Jeneson JA. Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. PLoS One. 2016 Feb 16;11(2):e0147818. doi: 10.1371/journal.pone.0147818. eCollection 2016.
citation: Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, Steuerwald U, Beauchamp NJ, Taybert J, Laforet P, Petit FM, Hubert A, Labrune P, Smit GPA, Derks TGJ. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis. 2016 Sep;39(5):697-704. doi: 10.1007/s10545-016-9932-2. Epub 2016 Apr 22.
citation: Verbeek RJ, Sentner CP, Smit GP, Maurits NM, Derks TG, van der Hoeven JH, Sival DA. Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III. Ultrasound Med Biol. 2016 Jan;42(1):133-42. doi: 10.1016/j.ultrasmedbio.2015.08.013. Epub 2015 Oct 3.
citation: Preisler N, Laforet P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, Galbo H, Vissing J. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology. 2015 Apr 28;84(17):1767-71. doi: 10.1212/WNL.0000000000001518. Epub 2015 Apr 1.
citation: Hoogeveen IJ, de Boer F, Boonstra WF, van der Schaaf CJ, Steuerwald U, Sibeijn-Kuiper AJ, Vegter RJK, van der Hoeven JH, Heiner-Fokkema MR, Clarke KC, Cox PJ, Derks TGJ, Jeneson JAL. Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study. J Inherit Metab Dis. 2021 Jan;44(1):226-239. doi: 10.1002/jimd.12302. Epub 2020 Sep 7.