Acute Nutritional Ketosis in GSD IIIa

Acute Nutritional Ketosis and Exercise in Glycogen Storage Disease Type IIIa

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

Study Overview

• Status: Completed
• Conditions: Glycogen Storage Disease IIIA
• Intervention / Treatment: Other: physical exercise

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • University of Groningen, UMC Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketone-ester drink; Oral intake - physical exercise	Other: physical exercise; In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.
Active Comparator: Carbohydrate drink; Oral intake - physical exercise	Other: physical exercise; In session II and III participants will perform an exercise test on a bicycle inside and outside the MR scanner.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	10 minutes; during in-magnet exercise test of session II and III.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time of individual desired workload	#minutes	through completion of the maximum exercise test (of approximately 12 minutes) during study session I.
completion of supine bicycling bout at desired workload in scanner	(yes/no; if no, #minutes)	10 min
Muscle ultrasound density of the biceps, quadriceps, calf (gastrocnemius and/or soleus) and tibialis anterior muscles.	Will be performed during study session I by a neurologist.	Together with the muscle force examination this assessment will take 1.5 hour.
Muscle force unilateral	Will be performed during study session I by a neurologist.	Together with the muscle ultrasound this assessment will take 1.5 hour.
Subjective fatigue and muscle ache score	scale 0-10	after each exercise bout and 24 hours after exercise
International Physical Activity Questionnaire		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
Structural muscle parameters: fat infiltration.		During the in-magnet exercise test of 10 minutes during session II and III
Change in blood glucose levels	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood ketones level (β-hydroxybutyrate, acetoacetate).	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Change of blood pH	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of free fatty acids	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of insulin	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of creatine kinase	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of ammonia	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of NT-proBNP	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Blood levels of lactate	#1 and #2 at baseline, #3 after 10 min, #4 after 15 minutes, #5 at the start of bicycle exercise test inside scanner, #6 after 10 minutes of in-magnet exercise and #7 three hours post-exercise inside scanner.	Up to 7 samples will be taken during the 25 minutes exercise test (session II and III).
Change of urine levels of myoglobin, ketones, tetraglucoside		Urine will be collected through study session II and III. A study session will take place from 8 am till 2 pm.
optional: muscle metabolic profile (according to Cox et. al. 2016] of a muscle biopsy.	optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.	This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
optional: individual phenotypic muscle properties (fiber type, mitochondrial density, capillary density	optional, on a patient-voluntary basis. If consent has been given a total of 4 muscle biopsies will be performed.	This procedure takes 30 minutes each time and will be performed prior to and immediately post-exercise during study session II and III.
Individual physical performance during exercise; VO2 and VCO2 dynamics.		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.

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: University of Oxford; University of the Faroe Islands; Stichting Stofwisselkracht; Stichting Metakids
• Investigators: Principal Investigator: T.G.J. Derks, MD PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2017
• Primary Completion (Actual): March 23, 2018
• Study Completion (Actual): March 23, 2018

Study Registration Dates

• First Submitted: December 22, 2016
• First Submitted That Met QC Criteria: January 2, 2017
• First Posted (Estimate): January 5, 2017

Study Record Updates

• Last Update Posted (Actual): May 1, 2018
• Last Update Submitted That Met QC Criteria: April 30, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: exercise; magnetic resonance spectroscopy; glycogen storage disease type IIIa; ketone esters
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Glycogen Storage Disease
• Other Study ID Numbers: NL59081.042.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No