Exercise Snacks and Glutamine to Improve Glucose Control in Adolescents With Type 1 Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 1, Autoimmune Diseases, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, Immune System Diseases, Metabolic Diseases
Sponsor: Nemours Children's Clinic

Complete Title of Protocol: Exercise Snacks and Glutamine to Improve Glucose 
Control in Adolescents with Type 1 Diabetes
NCT: NCT03199638
Date: April 24, 2015

 
 
 
 
I. 
Specific Aims : To determine whether the sustained use of  short bouts of exercise (‘exercise snacks’), 
with or without the administration of the amino acid glutamine results in diminished glycemic variability and/or 
improved glucose control in adolescent with T1 diabetes.  
 
II. 
Background and Significance: Puberty is associated with a physiological decline in insulin sensitivity 
[1,2] and such a decline leads to increased difficulty in achieving glycemic control in adolescents with T1D 
[3,4]. Designing innovative ways to improve diabetes control in adolescents is a highly desirable and 
challenging goal. Exercise increases glucose uptake by skeletal muscle [5,6], through an insulin-independent  
mechanism [7,8], and exercise training increases mitochondrial biogenesis and therefore muscle respiratory 
capacity and the expression of GLUT-4, the main glucose transporter in skeletal muscle [9]. Literature 
suggests exercise  improves glucose tolerance in healthy individuals [10], and increases insulin sensitivity as 
measured by the euglycemic clamp in adolescents with T1D [11]. A recent meta-analysis concluded that  
regular aerobic training improves HbA1c in patients with T1D [13]. Nutritional supplements are critical for 
conditions of malnutrition caused by either decreased intake or chronic medical illnesses. Diabetes, especially 
when poorly controlled, is a state of relative malnutrition with impaired glucose transport and relatively 
decreased amino acid flux. We have previously shown that oral supplementation with glutamine, a non 
essential amino acid dietary supplement given prior to exercise decreases overnight post-exercise blood 
glucose in adolescents with long-standing T1D who do not retain residual insulin secretion [17,18]. These data 
suggest that a simple dietary supplement may be beneficial improving diabetes control. Using hyperinsulinemic 
euglycemic clamps we further examined whether this effect of glutamine was secondary to increased insulin 
sensitivity in adolescents with T1D (Torres-Santiago, et al, manuscript to be submitted ). Lack of time is the 
most commonly perceived reason  preventing the performance of exercise  in both  healthy and diabetic 
subjects [14,15].  Recently, John Hawley, an Australian scientist who will serve as a consultant in this grant 
and colleagues, showed that performing 6 bouts of just x1 min of intense exercise (90% maximal heart rate; 
termed ‘exercise snacks’) 30 min before meals, improved glycemic control in obese adults with impaired 
glucose tolerance [16]. This novel approach is partciularly attractive due to its simplicity and low cost,but this 
has never been investigated in adolescents with T1D previously. 
 
III. 
Preliminary Studies/Progress Report (Not to exceed 3 pages.) 
a). Pilot studies on the effect of glutamine and exercise in adolescents with T1D  [17].  Mauras, et al, 
Diabetes Care 2011. 
Post-exercise hypoglycemia is a common problem in youth with T1D. Approximately 20% of endogenous 
glucose production comes from gluconeogenesis via amino acid (AA) precursors, particularly GLN and AA 
depletion occurs in insulin-induced hypoglycemia. As GLN is a major contributor to gluconeogenesis, we 
studied the effects of GLN on glucose concentrations during afternoon exercise as well as overnight post 
exercise. We studied ten adolescents with uncomplicated T1D (mean age 151 yr-old, 5M, 5F) who had been 
diabetic for 6.23.3 years and wore insulin pumps, with a mean HbA1c of 6.90.9%, and a normal BMI 
(between the 10
thand 85
th percentiles). They were on no chronic medications.  
Subjects were studied twice in the Clinical Research Center CRC during 1-h exercise session starting at 3PM. 
Mean blood glucose was in the mid 100 mg/dL range prior to exercise. Sessions consisted of 4, 15-min 
treadmill exercise (heart rate 140 bpm) with 5-min rest breaks interspersed. Blood glucose was continuously 
monitored during exercise and overnight. Basal insulin rates were continued during the study. Subjects were 
randomized to receive a drink containing either glutamine (before exercise and at bedtime (0.5 g/kg per dose), 
or a calorie- and nitrogen-free placebo. Studies were repeated within 3 weeks, and in randomized order. 
Plasma GLN concentrations measured 16 h post exercise the following morning were higher during the GLN 
study day than after placebo (316 vs. 200 µmol/L, p<0.001). 
However, regardless of the dietary supplement received prior to exercise, plasma GLN concentrations 
 measured in the postabsorptive state the following day, were below normal as compared to healthy, age-      
matched controls measured at rest (p<0.001) [33].  In earlier studies performed under resting conditions and 
using the same assay, we consistently observed that adolescents with T1D had plasma GLN concentrations in 
the normal range at rest as normal age-matched controls (48425 vs. 51329 µmol/L, NS) [33]. This suggests 
that intense exercise likely depletes plasma GLN in adolescents with T1D, as it does in healthy adults. Blood 
RESEARCH PLAN 

Fig.4 Time to post-exercise, nocturnal hypoglycemia (defined as first drop below 70mg/dL) in adolescents with T1DM after 
oral ingestion o glutamine or placebo [17] 
Figure 1. Time to Overnight Hypoglycemia (70mg/dL)*                                           p=0.02
P=0.02
Figure 1. Time to Overnight Hypoglycemia (70mg/dL)*                                           p=0.02
P=0.02
glucose was similar at baseline on both study days (14331 and 16254 mg/dL on the GLN and placebo study 
day, respectively; p=0.44), and blood glucose dropped comparably (5215% vs. 529% on the GLN and 
placebo study day, respectively; p=0.84) during exercise on both days. Yet overnight, post-exercise low blood 
glucose levels (defined as either <70 mg/dL or <60 mg/dL) were significantly more frequent (P=0.03, and 0.05, 
respectively) after GLN than after placebo. The cumulative probability of overnight hypoglycemia was 
increased on the GLN day (80%) compared with placebo (60%, p=0.02, Fig 4). We concluded that GLN 
supplementation increases the incidence of post exercise nighttime hypoglycemia. [17]. Taken in aggregate, 
our preliminary studies suggest that, in adolescents with T1D performing heavy exercise, plasma GLN is low 
after exercise; and GLN supplementation increases the likelihood of hypoglycemia after exercise.  
As the patients studied presumably had no residual endogenous insulin secretion, our findings suggest that 
GLN may enhance glucose uptake and/or increase insulin sensitivity. These data, in addition to the data 
reviewed from other studies suggest that GLN supplementation may affect insulin sensitivity either at the 
peripheral or hepatic level in T1D. If proven true, these results could have important implications to improve 
glycemic control in T1D.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b). Glucose-lowering Effects of Glutamine in Adolescents with Type I Diabetes [18] Torres, et, al 
(manuscript to be submitted for publication) 
Thirteen pubertal adolescents (15.96±1.6 years [SD], 8M; 5F;  BMI 69th ±16 centiles 6, HbA1C 8.2 ±0.5%, T1D: 
7.5±4 yrs) on insulin pumps were randomized to receive a drink with GLN or placebo pre-exercise, bedtime 
and early morning (0.25 g/kg/dose) in a double-blind crossover design over 4 weeks. Exercise session (3pm) 
consisted of four 15-min treadmill/5-min rest cycles. Blood glucose (BG) was monitored during exercise and 
overnight. The following morning, a 5-hr primed, continuous infusion of D-[6, 6-2H2] glucose was administered, 
during a 2-dose hyperinsulinemic, euglycemic clamp (low dose: 8 mU/m2/min; high dose: 80 mU/m2/min) in the 
post absorptive state. BG levels dropped comparably during exercise on both days. However, the total number 
of nocturnal hypoglycemic events (17 vs. 7, p=0.045) and the cumulative probability of overnight hypoglycemia 
(50% vs. 33%, (p=0.02) were higher on the glutamine day than on the placebo day. During clamp, glucose 
infusion rate did not differ between days (7.7 ±1 mg/kg/min vs. 7.0 ± 1; glutamine vs. placebo; p=0.4). A 
correlation was noted between nocturnal hypoglycemic events and SI on the glutamine day. 
Our findings confirm our previous observations that glutamine has glucose-lowering effects in adolescents with 
type 1 diabetes after exercise no consistent change in insulin sensitivity was observed. Although a correlation 
was noted between nocturnal hypoglycemic events and insulin sensitivity on the glutamine day. The 
mechanisms mediating the effect of glutamine remain to be elucidated.   
 
 
 
 
 
 

C). ‘Exercise snacks’ before meals to improve glycemic control in individuals with insulin resistance 
[16]. Francois, et al, Diabetologia, 2014   
This study investigated whether small doses of intense exercise before each main meal (‘exercise snacks’) 
would result in better blood glucose control than a single bout of prolonged, continuous, moderate intensity 
exercise in individuals with insulin resistance. Nine adults with impaired glucose tolerance or type 2 diabetes 
completed three exercise interventions in randomized order. Measures were recorded across 3 days with 
exercise performed on the middle day, as either: 1) traditional continuous exercise (CONT), comprising  30 min 
moderate-intensity (60% of maximal heart rate [HRmax]) incline walking before dinner; (2) exercise snacking 
(ES), consisting of 6×1 min intense (90% HRmax) incline walking intervals 30 min before each meal; or (3) 
composite exercise snacking (CES), encompassing 6×1 min intervals alternating between walking and 
resistance-based exercise,30 min before meals. Meal timing and composition were controlled within 
participants for exercise interventions. Results: ES attenuated mean 3 h postprandial glucose concentration 
following breakfast (by 1.4±1.5 mmol/l, p=0.02) but not lunch (0.4±1.0 mmol/l, p=0.22), and was more effective 
than CONT following dinner (0.7±1.5 mmol/l below CONT; p=0.04). ES also reduced 24 h mean glucose 
concentration by 0.7±0.6 mmol/l (p=0.01) and this reduction persisted for the subsequent 24 h (lower by 
0.6±0.4 mmol/l vs CONT, relative to their baselines; p=0.01). CES was just as effective as ES (p>0.05 for all 
glycemic variables) at improving glycemic control. Conclusions/interpretation dosing exercise as brief, intense 
exercise snacks before main meals is a time-efficient and effective approach to improve glycemic control in 
individuals with insulin resistance. The effect of exercise snacks on glycemic control has not been 
addressed in adolescents with T1D. 
 
d). Interrupting Prolonged Sitting Modulates Glycemic Control in Adults with Type 2 Diabetes [David 
Dunstan and John Hawley to be presented at ADA meeting in 2015] 
In this randomized crossover study, overweight/obese/ inactive adults with type 2 diabetes were included to 
study the effects of brief bouts of light intensity walking or simple resistance activities on lowering postprandial 
plasma glucose and improve glycemic control in TD patients. Eucaloric diet was consumed over 22 h (9am – 
7am) while wearing a continuous glucose monitor system for 3 x 8 h conditions (6-day washout). 
There were 3 groups 1) SIT: uninterrupted sitting (control); 2) LW: sitting + 3 min bouts of light-intensity walking 
at 3.2 km/h every 30 min; and 3) SRA: sitting + 3 min bouts of simple resistance activities (alternating half-
squats, calf raises, brief gluteal contractions and knee raises) every 30 min (see below).  
 
  
 
 
Over 22 h, both LW and SRA significantly reduced mean [interstitial] glucose, time in hyperglycemia and 
glycemic variability (quantified via the SD of mean glucose and mean amplitude of glycemic excursions) 
relative to uninterrupted sitting (Table).  These simple interruptions to sitting significantly reduced the time in 
hyperglycemia, mean glucose and glycemic variability in adults with T2D. This approach has not been 
studied yet in adolescents with type 1 diabetes. 
  

Table (A) Participant Characteristics and (B) Effects of the Three Trial Conditions on Glycemic Control  
 
(A) Participant 
characteristics 
 
(B) Effects of the three trial conditions on measures of 
glycemic control over 22 h 
 
 
Characteristic 
N or 
mean 
(95% 
CI) 
Measure of glycemic 
control 
SIT 
(control) 
LW 
 
SRA 
Number of 
study 
participants 
14 M 
10 F 
Time in hyperglycemia 
(%) 
60.3 
(49.2, 
71.3) 
37.5 
(26.5, 
48.6)** 
26.5 (15.5, 
37.6)** 
Age (yr) 
 
62.3 
(64.8, 
59.8) 
Time in hyperglycemia 
(hr) 
13.3 
(10.8, 
15.7) 
8.3 (5.8, 
10.7)** 
5.8 (3.4, 
8.3)** 
BMI (kg/m2) 
 
33 
(34.4, 
31.7) 
Mean interstitial 
glucose (mg/dl) 
11 (10.2, 
11.8) 
9.4 (8.5, 
10.2)** 
8.6 (7.8, 
9.4)** 
HbA1c (%) 
 
7.2 
(7.5, 7) 
 
SD of mean interstitial 
glucose 
2.2 (2, 
2.5) 
 
1.9 (1.7, 
2.2)** 
1.7 (1.5, 2)** 
Note: All participants 
were Metformin/diet 
controlled individuals 
with type 2 diabetes. 
MAGE (mg/dl) 
 
104.94 
(92.11, 
117.78) 
85.5 
(72.66, 
98.34)** 
76.18 (63.35, 
89.02)** 
 
SD=standard deviation; MAGE=mean amplitude of glycemic 
excursions.  
*difference from SIT (P < 0.05);  
**difference from SIT (P < 0.001);  
Analysed using multi-level mixed models, controlling for age 
and BMI. Data are mean (95% CI).  
 
 
IV. 
Research Design and Methods  
In this protocol we will determine whether ‘exercise snacks’, alone or in combination with dietary glutamine 
supplementation over a period of 3 months improve glycemic control in adolescents with type 1 diabetes. 
 
Inclusion/Exclusion Criteria: 
Twenty-four  adolescents with T1D for at least 12 months, between 13-19 yr-old will be recruited after informed 
written consent from their parents and the youngsters themselves. We will strive to recruit patients with 
comparable phenotype in both groups. They will be of normal weight (BMI between 10th  and <85th percentile)  
and will be in puberty (at least Tanner stage III breast or genitalia) with a HbA1 between 7.5  and 9%. Subjects 
will be on either multiple daily injections (MDI) or insulin pump therapy. They will be recruited among the 
~1,000 patients with T1D followed at Nemours Children’s Clinic Jacksonville. We will exclude subjects with 
biopsy proven celiac disease, cystic fibrosis, chronic steroid therapy, mental retardation, microalbuminuria or 
evidence of other diabetic complications. Subjects involved in an active exercise program or in an organized 
sport team will be excluded. Studies will be conducted at least 2 weeks after resolution of any intercurrent 
infection.  
 
 Procedures: All subjects will have a full physical exam including Tanner staging as well as waist circumference 
measurement. A HbA1c, will be obtained as well as fasting triglycerides. A continuous glucose monitor (CGM 
IPro®, Medtronic Minimed, or a DexCom ^4) will be worn blindly for 6 days and data downloaded. Subjects will 
then be randomized to 2 study groups of 12 patients each: 
(A) an ‘exercise group’, in which subjects will perform daily ‘exercise snacks’ within 30 min before breakfast, 
lunch, and/or dinner or bedtime snack, along with a placebo drink;  

 (B) an ‘exercise + glutamine group’, in which subjects will receive a glutamine drink (0.25 g/kg per dose) 
before meals TID, and perform ‘exercise snacks’ before each meal.  
Allocation to the exercise only or the exercise + glutamine group will be tsratified according to HbA1c range 
(eg, 7.5-7.9%; 8.0-8.4%; 8.5-9.0%), so as to ensure the comparability of groups. 
The placebo and glutamine drink will be prepared at home using measuring spoons of glutamine or placebo 
powder to be mixed in a calorie-free, flavored  soft drink tailored to the child’s individual taste. Patients, families 
and investigators will be blinded as to the contents of the supplement. 
Exercise snacks will be designed to be feasible using 6 min worth of simple resistance activities (SRA’s) 
designed by the exercise physiology consultants, Drs. Churilla and Hawley. These will consist of activities such 
as alternating half-squats, calf raises, brief gluteal contractions and knee raises. A short video will be created 
showing the participants how to conduct these exercises and these will be updated periodically in order to keep 
their interest and compliance. We elected not to use an accelerometer as the data to be gathered from these 
would be less useful for the study given the short nature of these bouts of exercise. These will be completed 30 
min before breakfast, lunch and dinner.  
 
Patients will keep a record of their dietary intake and physical activity for 2 days while CGM is placed (one 
weekday+ one weekend day) at baseline, and at 1,and 3 months during the study. If the family has a smart 
phone, a free application will be installed which is “My diet diary calorie count “ for better assesment of total 
caloric intake during this  study. Otherwise, a log book would be used. Compliance will be monitored by weekly 
contact with the study subjects either via phone call or text messaging or via MyNemours. A system of rewards 
will be implemented with a $10 gift card given per week with at least 50% compliance with study program, with 
an extra $25 for succesful wearing and downloading of the CGM at baseline and 3 months ($10x12w=$120, 
+$25x3=$75, Total=$195 per subject).  
 
At one month visit after the enrollement, CGM will be placed again for 6 days, then all baseline studies, 
including CGM, HbA1c and triglycerides will be repeated at 3 months. Every patient will undergo a body 
composition analysis using a dual X-ray absorptiometry ( DEXA ) at the end of the study.Total insulin dosing 
will be carefully recorded as units/kg/day during the study. 
 
 
 
 
 
• 3- month study: body composition, HbA1c, triglycerides, CGM
Group 2: Exercise + GLN
Group 1: Exercise+ Placebo
+ 
•    Randomization 
CGM after 1 month 
• 
Enrolment 
• Baseline study: HbA1c, triglycerides+ CGM

- Assays – HbA1C will be measured using a DCA 2000 in clinic [17,18]. Triglycerides (TG) will be performed 
using an Olympus AU400e Chemistry. 
-Calculations - An insulin sensitivity score (ISS) will be calculated as previously described using the 
SEARCH ISS model: logeIS = 4.64725 – 0.02032 (waist, cm) – 0.09779(HbA1c, %) – 0.00235(TG, mg/dl) 
(R2=0.74 in the initial SEARCH model) [34-35]. This has been validated using the hyperinsulinemic 
euglycemic clamp, considered the gold standard for insulin sensitivity measures [34,35]. CGM data will be 
downloaded and used to calculate % blood glucose (BG) at, below or above target and the mean 
amplitude of glycemic excursions using a SAS program (MAGE) as previously described [17,21,22].  
 
-Statistical Analysis and Statistical Power.  
 To determine whether short bouts of exercise and/or glutamine improve glycemic variability and  diabetes 
control, we will compare the following parameters between baseline and 3 months:  
a) Changes in HbA1C 
b) Changes in MAGE 
c) Changes in % BG at target (70-180), below target (<70), above target (>180) 
d) Changes in ISS 
e) Changes in total insulin dosing (units/kg/day) 
A mixed effects models and/or generalized estimating equations (GEE), which ever appropriate, will be used 
within and between subjects and groups  comparisons. Model assumptions will be checked before analyses. 
Significance will be established at p<0.05.  
 
-Sample Size Justification: A sample size of 24  patients is planned assuming no more than 10% attrition 
rate. The main judgment criterion will be the mean amplitude of glycemic excursion (MAGE, measured using 
CGM).  In the Australian study by Dunstan et al. [36]described above in the Preliminary results section of this 
application performed in adults with type 2 diabetes, MAGE was 104.9±12.8 mg/dl (mean ±SD) in the 
sedentary group of patients with type 2 diabetes, vs. 76.2±12.8 mg/dl—i.e., a drop by 28.7in the group 
performing short bouts of resistance exercise.  To the best of our knowledge, there is no earlier study of such 
type of exercise in adolescents with T1D published in literature. Assuming ‘exercise snacks’ will decrease 
MAGE to the same extent in our population of children with T1D as in adults with T2D, such reduction will 
amount to an effect size of /=28.7/12.82.24, where   is the expected change in MAGE (104.9-76.2=28.7), 
and ² the estimated variance of MAGE (=12.8, calculated based on John Hawley et al’s data). Using 
equations for unpaired studies, the number (n) of subjects per group needed to detect such difference with an 
 risk<0.05, and a statistical power(1-) of 80% can be estimated as:  n= 2  (Z + Z)² / (²/² ) [37], where 
Z=1.96, and   Z=0.84, therefore n=2  (1.96 + 0.84)² / (2.24)² =2   7.84/5.02=3.1. The enrolment of 12 
patients per group therefore should be amply sufficient to test our hypothesis, even if we take into account a 
putative 25% attrition rate. 
 
- Future Directions:   These simple and short resistance activities as it was shown in previous studies [16, 36] 
have significantly reduced the time in hyperglycemia, mean glucose and glycemic variability in adults with T2D. 
With the ubiquity of sedentary behaviors and the low adherence to structured exercise, this approach has the 
potential to be beneficial and practical. This interesting approach has not been studied yet with combination of 
glutamine in patients with type 1 diabetes. 
 
 
V.  Facilities Required/Physical Location of Study  
This study will be performed in outpatient settings and will recruit patients who are followed at the deivision of 
Endocrinology at the Nemours Children’s Healthy System in Jacksonville.  
 
 
 
 
 
 
 
 
 
 

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