Healthy Clinical Trial
Official title:
Application of Novel Techniques to Devise Nutritional Therapies in Subjects With Glycogen Storage Disease Type I
Glycogen storage disease type I (GSD I) caused by deficiency of glucose-6-phosphatase enzyme leading to build up of a complex sugar called glycogen in liver and low blood glucose level. Nutritional treatment involves supplying carbohydrates and uncooked cornstarch. Glycosade® (modified cornstarch) has shown promise in maintaining normal blood glucose level in GSD I. But the difficulty in nutritional treatment is determining the best type of carbohydrate to be given to avoid low blood glucose. Thus, there is a need to develop a simple test to examine glucose digestion and measure the utilization of different carbohydrates in GSD I and healthy controls.
Purpose: Glycogen storage disease type I (GSD I), also known as Von Gierke disease is caused
by deficiency of glucose-6-phosphatase (G6Pase) enzyme affecting 1:100,000 births worldwide.
Therefore, deficiency of this enzyme results in accumulation of glycogen in liver and
inadequate production of glucose leading to fasting hypoglycemia. Dietary treatment for GSD I
is based on supplying complex carbohydrates with small frequent meals, and use of uncooked
cornstarch (UCCS). Glycosade® (modified cornstarch) has shown promise in maintaining normal
blood glucose concentrations in subjects with GSD I. However, the primary dilemma in the
dietary treatment of GSD I is the choice of the exogenous carbohydrate sources to achieve a
desirable metabolic control and prevent hypoglycemia. In addition, the previous studies were
invasive, which required several blood samples, long study days (~10 h) and could not offer
mechanistic details of glucose metabolism in subjects with GSD I. Thus, there is a need to
develop a minimally-invasive method to examine glucose metabolism and measure the utilization
of different carbohydrate sources directly in subjects with GSD I and healthy controls. This
simple breath test will help individualize treatment and tailor carbohydrate supply in
subjects with GSD I.
Hypothesis: 1) Investigators hypothesize that the oxidation of 13CO2 from U-13C-glucose can
be detected in expired air; and13CO2 oxidation will be a sensitive measure to examine glucose
oxidation/metabolism.
2) Investigators hypothesize that 13CO2 oxidation from Glycosade® will have lower peak
enrichment (Cmax) compared to other carbohydrate source UCCS in patients with GSD I and
healthy controls.
Justification: The difficulty in nutritional treatment of GSD I is determining the best type
of carbohydrate to be given to avoid hypoglycaemia. Therefore glucose metabolism and the
utilization of different carbohydrates need to be measured using minimally invasive test.
Objectives: 1) Our first objective is to establish the use of U-13C-glucose breath test
(13C-GBT) and its oxidation to 13CO2 as a minimally-invasive technique to examine in vivo
glucose oxidation in healthy controls.
2) Our second objective is to measure the utilization of different exogenous carbohydrate
sources: UCCS and the extended release waxy maize cornstarch Glycosade® in healthy controls
and patients with GSD I using a minimally invasive 13C-GBT.
Research Method: The project consists of two experiments.
Experiment 1 - Pilot Study to Establish the Use of U-13C-Glucose Breath Test (13C-GBT) in
Healthy Controls A. Pre-study Day Protocol Written informed consent will be obtained from
participants before participating in the study. All participants will be requested to fast
overnight (~ 12 hours) and will be asked to come to the Clinical Research and Evaluation Unit
for a preliminary assessment (pre-study day) to measure basic anthropometry (weight and
height), body composition and resting energy expenditure (REE). Weight and height will be
measured by using a digital scale and a stadiometer, respectively. REE will be measured by
continuous, open-circuit indirect calorimetry (CareFusion Vmax Encore, VIASYS), which will be
calibrated prior to use. Total energy expenditure (TEE) and basal metabolic rate (BMR) are
associated to fat free mass (FFM); therefore body composition will be determined using
bioelectrical impedance analysis (BIA) (Quantum IV RJL systems). BIA measures resistance,
reactance and impedance by applying electrodes placed at the right wrist and right ankle.
Three readings for resistance, reactance and impedance will be taken for each participant -
then the mean of these readings will be used to determine FFM and fat mass (FM). FFM and FM
will be calculated using the manufacturer's software system (RJL Systems, Body Composition
Analysis V.2.1). A general questionnaire will be used during the pre-study day to give a
clear idea about medical history, nutritional status, supplement intake and physical
activity. Finally, 3-day dietary record sheets will be distributed to the participants to
record food consumption for any two days during the week and one day on the weekend.
B. Two-Day Dietary Standardization During the two days prior to study, subjects will consume
a balanced diet containing at least 150 g of carbohydrate. This diet consisted of everyday
foods, however an outline will be given to subjects to ensure sufficiency based on foods
commonly eaten.
C. Study day Protocol For pilot study, 10 healthy adults (19-35 y) will undergo 13C-GBT
protocols in two separate study days as a proof-of-principle, once without oral isotope dose
and once with oral isotope dose (U-13C-glucose), each study separated by ≥ 1 week. Thus, 10
healthy adults will be studied for a total of n = 20 studies. After obtaining informed
consent from the subject, the subject will be enrolled in the study. The participant will
arrive for the study day after fast (~4 h) to standardize measurements at the Clinical
Research and Evaluation Unit (CREU) at BC Children's Hospital. Basic anthropometric
measurements (body weight and height) will be collected and a brief study day questionnaire
will be administered to collect information on medical, diet and physical activity history. 2
Baseline breath samples will be collected to determine natural background 13C abundance.
Subjects will receive on study day 1 glucose (75 g/day) dissolved in sterile water, study day
2 U-13C-glucose (75 mg/day) (99 atom% 13C enrichment, Cambridge Isotope Laboratories Inc.,
Andover, MA) with glucose (75 g/day) dissolved in sterile water.
Subjects will remain fasting and resting in CREU for the entire period of the study to
eliminate variability in CO2 production. Breath samples in quadruplicates will be collected
at 20,40,60,80,100,120,140,160,180, 200, 220 and 240 min after oral administration of
glucose. During the study visit, the rate of carbon dioxide production (VCO2) will be
measured for 20 minutes, two hours (120 minutes) after the oral glucose dose using an
indirect calorimeter (Vmax Encore, Viasys Healthcare Inc. Yorba Linda, CA). Assessment of
body composition will be performed using the Bioelectrical Impedance Analysis (BIA-Quantum
IV, RJL Systems, MI). BIA calculated resistance, reactance and impedance by applying
electrodes would be placed at the right wrist and ankle. Three readings for resistance,
reactance and impedance will be taken for each subject then the mean of these readings will
be used to determined fat free mass (FFM) and fat mass (FM). FFM and FM will be calculated
using the manufacturer's software system (RJL Systems, Body Composition Analysis V.2.1).
Finger-prick blood glucose samples will be assessed at the beginning and hourly until the end
of the study day using glucometer (One Touch® Ultra®, LifeScan, Inc).
Sample Collection and Analysis: Breath samples will be collected using breath bags (single
use collection bags, EasySampler System, QuinTron Instrument Company, Inc. Milwaukee, WI) in
disposable glass Exetainer® tubes (Labco Limited, Buckinghamshire, UK) using a collection
mechanism that permits removal of dead air space. The breath enrichment of 13CO2 will be
measured using isotope ratio mass spectrometer (IRMS).
Statistical Analysis Subject characteristics will be expressed as the mean (SD). 13C-glucose
oxidation as 13CO2 will be the primary outcome measured, as this best describes the whole
body oxidation capacity for glucose. Area under the curve (AUC) for each subject's 13CO2
oxidation from t0 to t240, the time to reach maximum 13CO2 oxidation (tmax) and the maximum
peak enrichment in13CO2 oxidation (Cmax) will be calculated. A repeated-measures analysis
using restricted maximum likelihood estimation will be used to get the estimated parameters
with the MIXED procedure using SAS software (SAS/STAT; Version 9.2). A paired t-test will be
used to compare the 13CO2 oxidation at each time point without and with U-13C-glucose. All
values will be presented for individual subjects, and significance is set at P<0.05.
Statistical analysis will be performed using GraphPad Prism 4.0 (GraphPad Software Inc, CA).
Experiment 2 - Minimally Invasive 13C-Glucose Breath Test to Measure the Utilization of
Different Exogenous Carbohydrate Sources in Healthy Controls and Subjects with Glycogen
Storage Disease Type I For initial set of studies, 10 healthy children (5-18 y) and 10
healthy adults (19-35 y) will undergo 13C-GBT four times. Then, 3 children and 5 adults with
GSD I will be recruited in 4 separate study days from our Pediatric and Adult metabolic
clinic at BC Children's and Vancouver General Hospital, respectively (if recruitment is a
challenge, we plan to approach clinics across Canada). After fast (~ 4 h for healthy controls
and 2 h for GSD I) subjects will receive on study day 1- UCCS (2 g/kg/day), study day 2-
U-13C-glucose (75 mg for adults; 1.5 mg/kg for children) (99 atom% 13C enrichment, Cambridge
Isotope Laboratories Inc., Andover, MA) with UCCS (2 g/kg/day), study day 3- the extended
release waxy maize cornstarch Glycosade® (2 g/kg/day) (Vitaflo International Ltd, Liverpool,
England), and on study day 4- U-13C-glucose (75 mg for adults; 1.5 mg/kg for children) with
Glycosade® (2 g/kg/day) dissolved in sterile water. On each study day, breath samples will be
collected every 20 min for 240 min. The rate of CO2 production will be measured at 120 min
after oral dose using indirect calorimetry. Blood glucose will be measured using glucometer
and finger-prick blood samples will be assessed at the beginning and hourly until the end of
the study day. The percentage of test carbohydrates exhaled, as 13CO2 will be measured over a
4 h period.
Statistical Analysis Subject characteristics will be expressed as the mean (SD). 13C-glucose
oxidation as 13CO2 will be the primary outcome measured, as this best describes the whole
body oxidation capacity for glucose. Area under the curve (AUC) for each subject's 13CO2
oxidation from t0 to t240, the time to reach maximum 13CO2 oxidation (tmax) and the maximum
peak enrichment in13CO2 oxidation (Cmax) will be calculated for UCCS and Glycosade®. The
values obtained from the carbohydrate sources will be compared by using a two-tailed paired
t-test. Significance will be set at P<0.05.
Statistical analysis will be performed using GraphPad Prism 4.0 (GraphPad Software Inc, CA).
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