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,M Rebecca Heiner‐Fokkema,Terry G J Derks,Johannes H Van Der Hoeven,Caroline J Van Der Schaaf,Kieran C Clarke,Anita J Sibeijn‐Kuiper,Riemer J K Vegter,Willemijn F Boonstra,Jeroen A L Jeneson,Pete J Cox,Ulrike Steuerwald,Foekje De Boer

doi:10.1002/jimd.12302

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 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 numberClinicalTrials.gov identifier: NCT03011203.

Highlights

Glycogen storage disease type IIIa (GSDIIIa; OMIM #232400) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the AGL gene, resulting in impaired glycogen debranching enzyme (GDE) activity in liver, cardiac, nerve, and muscle tissue
This study in six adults with GSDIIIa investigated whether acute nutritional ketosis (ANK) in response to oral ingestion of a KE can supply oxidative substrate to exercising muscle
ANK was efficiently induced within 1 hour after ingestion of KE + CHO, KE was well tolerated, and improved glucose homeostasis

Summary

| INTRODUCTION

Glycogen storage disease type IIIa (GSDIIIa; OMIM #232400) is an inborn error of carbohydrate metabolism caused by pathogenic variants in the AGL gene, resulting in impaired glycogen debranching enzyme (GDE) activity in liver, cardiac, nerve, and muscle tissue. Ketone-ester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate; KE) for human application was described that can achieve acute nutritional ketosis (ANK) via oral ingestion without any sodium loading.[17] In trained athletes, oral KE ingestion resulted in glycogen sparing during exercise, and a slight enhancement of endurance exercise performance and recovery.[18,19] Recently, oral KE ingestion prior to exercise was shown to be effective to deliver oxidative substrate to exercising leg muscle and improve intramuscular energy balance during submaximal cycling exercise in patients with a fatty acid oxidation (FAO) defect.[20] All subjects provided written informed consent prior to inclusion in the study

| Study design

| Procedures

| RESULTS

Findings

| DISCUSSION