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The Effect of Exercise with or Without Metformin on Glucose Profiles in Type

2 Diabetes: A Pilot Study

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DOI: 10.1016/j.jcjd.2015.08.015

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Perspectives in Practice

The Effect of Exercise with or Without Metformin on Glucose Profiles

in Type 2 Diabetes: A Pilot Study
Étienne Myette-Côté MSc, Tasuku Terada PhD, Normand G. Boulé PhD *
Faculty of Physical Education & Recreation, Alberta Diabetes Institute, University of Alberta, Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta, Canada

a r t i c l e i n f o a b s t r a c t

Article history: The study’s goals were 1) to confirm the previously observed increase in postprandial glucose levels imme-
Received 12 December 2014
diately after exercise in people with type 2 diabetes who are being treated with metformin; 2) to deter-
Received in revised form
mine how long the increased glucose persists; 3) to examine the effect of skipping a dose of metformin
12 August 2015
Accepted 26 August 2015 before or after exercise. We recruited 10 participants with type 2 diabetes who were taking metformin.
They completed 4 experimental conditions in random order: 1) morning and evening metformin doses,
without exercise (M-M); 2) morning and evening metformin doses, with exercise (M-Ex-M); 3) exercise
Keywords:
biguanide with evening metformin dose only (Ex-M); and 4) morning metformin dose only, with exercise (M-Ex).
continuous glucose monitor Exercise consisted of walking for 50 minutes at a moderate intensity at 11 am on the first day of each
fasting glucose condition. Glucose was measured for 72 hours using continuous glucose monitoring systems. Standard-
glucose variability ized breakfasts were provided for 3 days in each condition, and standardized lunches and dinners were
physical activity provided on the first day. Compared to M-M, M-Ex-M increased the average 2-hour incremental post-
postprandial glucose prandial area under the curve following the 5 standardized meals (p<0.01) but did not affect daily mean
glucose or fasting glucose concentrations. M-Ex (p<0.05), but not Ex-M (p=0.08) increased mean glucose
concentrations compared to M-Ex-M on day 1. There were no differences among the 3 exercise condi-
tions for fasting or postprandial glucose concentrations. The addition of a bout of exercise to metformin
led to an increase in postprandial glucose levels without affecting mean glucose concentrations. Remov-
ing a metformin dose before or after exercise did not attenuate this negative effect.
© 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

r é s u m é
Mots clés :
Les objectifs de l’étude étaient les suivants: 1) confirmer l’augmentation de la glycémie postprandiale
biguanide
glucomètre
précédemment observée immédiatement après l’exercice chez les personnes souffrant du diabète de type
glucose à jeun 2 qui sont traitées par la metformine; 2) déterminer la durée de l’augmentation de la glycémie; 3) exam-
variabilité glycémique iner l’effet de l’omission d’une dose de metformine avant ou après l’exercice. Nous avons recruté 10 par-
activité physique ticipants souffrant du diabète de type 2 qui prenaient de la metformine. Ils se soumettaient aux 4 conditions
glucose post-prandiale expérimentales selon un ordre aléatoire: 1) doses de metformine le matin et le soir, sans exercice (M-M);
2) doses de metformine le matin et le soir, avec exercice (M-Ex-M); 3) exercice avec une dose de metformine
le soir seulement (Ex-M); 4) dose de metformine le matin seulement, avec exercice (M-Ex). L’exercice
consistait en une marche de 50 minutes à intensité modérée à 11 h le premier jour de chacune des con-
ditions. La glycémie était mesurée durant 72 heures à l’aide de systèmes de surveillance de la glycémie
en continu. Des déjeuners standards étaient fournis durant 3 jours pour chacune des conditions, puis des
dîners et des soupers standards étaient fournis le premier jour. Comparativement à la condition
expérimentale M-M, la M-Ex-M augmentait l’aire incrémentale moyenne sous la courbe de la glycémie
postprandiale 2 heures après les 5 repas standards (p<0.01), mais n’affectait pas la glycémie moyenne
quotidienne ou la glycémie à jeun. La condition expérimentale M-Ex (p<0.05), mais non la Ex-M (p=0.08),
augmentait la glycémie moyenne comparativement à la M-Ex-M le jour 1. Aucune différence dans la glycémie
à jeun et la glycémie postprandiale n’était observée entre les 3 conditions ayant recours à l’exercice. L’ajout

* Address for correspondence: Normand G. Boulé, PhD, University of Alberta, Li Ka Shing Center for Health Research Innovation, 8602, 112 Ave NW, Edmonton, Alberta
T6G 2H9, Canada.
E-mail address: nboule@ualberta.ca

1499-2671 © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcjd.2015.08.015
174 É. Myette-Côté et al. / Can J Diabetes 40 (2016) 173–177
d’une période d’exercice à la prise de metformine menait à une augmentation de la glycémie postprandiale
sans affecter la glycémie moyenne. La suppression d’une dose de metformine avant ou après l’exercice
n’atténuait pas cet effet négatif.
© 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
Introduction
The glucose-lowering effects of exercise are one of the most well-
documented findings in diabetes research. The average effect on gly-
cemic control is clinically meaningful, but it is important to consider
that there can be variability in the responses to exercise (1). Prac-
titioners and patients alike may be surprised by the suggestion that
2 of the first-line treatments for managing type 2 diabetes,
metformin and exercise, may interfere with each other’s effects.
Exploring approaches to combining them in better ways has become
particularly relevant in light of recent studies demonstrating that
their combination led to no better or even to poorer improve-
ments in glycemic control or insulin sensitivity than either treat-
ment alone (2–4).
The lower-than-expected improvement in glycemic control, or
insulin sensitivity, when exercise and metformin are combined is
unlikely to prevent these therapies from being recommended
together because the benefits of exercise, and perhaps metformin,
are not limited to lowering glucose concentrations. Consequently,
novel strategies to combine metformin and exercise more opti-
mally are needed.
After oral consumption, peak plasma metformin concentration
is reached after approximately 2 to 4 hours, and 90% of the absorbed
metformin is eliminated in the urine, unchanged, after about
20 hours (5).
It may therefore be possible to improve the concomitant use of
these therapies by exercising at a time of reduced plasma metformin
concentrations or by reducing metformin consumption during the
postexercise period. Similar approaches have been successfully trans-
lated into practical recommendations. For example, leading authori-
ties, including the Canadian Diabetes Association, regularly
emphasize the importance of modifying insulin doses in response
to changes in physical activity (6,7).
The objectives of the present study are threefold: 1) to confirm
the previously observed increase in postprandial glucose immedi-
ately after exercise; 2) to determine whether this increase per-
sists beyond 1 meal; 3) to examine the novel hypothesis that
skipping a single dose of metformin before or after exercise could
help to improve glycemic control more efficiently when exercising.
Methods
Participants
For this study, we recruited 10 volunteers with type 2 diabetes
(5 men, 4 postmenopausal women and 1 premenopausal woman)
who were taking metformin. The study was approved by the Uni-
versity Health Research Ethics Board. The premenopausal partici-
pant was tested in the follicular phase in all experimental conditions.
Participants met the following eligibility criteria: 1) being between
40 and 70 years of age; 2) taking metformin for at least 3 months
without any other glucose-lowering medication; 3) absence of
diabetes-related complications or limitations to regular exercise;
and 4) glycated hemoglobin (A1C) levels <9% and resting blood pres-
sure <140/90 mm Hg.
Baseline assessment
During the first meeting, the eligibility of the participants was
confirmed, and A1C levels were assessed (DCA 2000; Siemens
Healthcare Diagnostics, Tarrytown, New York, United States). Par-
ticipants reported a second time to the laboratory to perform a
submaximal graded exercise test on a treadmill so as to deter-
mine ventilatory thresholds (VTs) using a TrueMax (Parvo Medics,
Sandy, Utah, United States) metabolic measurement system.
Study design
The study followed a randomized crossover design. Each par-
ticipant completed 4 conditions: 1) metformin with breakfast and
dinner, without exercise (M-M); 2) metformin with breakfast and
dinner, with exercise (M-Ex-M); 3) metformin with dinner only, with
exercise (Ex-M); and 4) metformin with breakfast only, with exer-
cise (M-Ex). A single exercise session was performed 3 hours after
breakfast on the first day of each exercise conditions.
Study protocol
Eligible participants took part in a treadmill habituation phase
consisting of 3 exercise sessions lasting 30, 40 and 50 minutes,
respectively. Participants were then invited to the laboratory on the
evening preceding the first condition day to insert a continuous
glucose monitor system (CGMS) (iPro2; Medtronic, Brampton,
Ontario, Canada). The CGMS was used and calibrated as in our pre-
vious reliability study (8).
On day 1 of each condition, participants arrived at the labora-
tory at 7:45 am after an overnight fast. Between 8:00 and 8:15 am
they received a standardized breakfast, and in all conditions except
Ex-M, they consumed their regular metformin doses. Following
breakfast, participants remained sedentary until 11:00 am, at which
time the exercise session, or the rest period for the M-M condi-
tion, began. The exercise protocol consisted of 50 minutes of walking
at 85% of VT and a 5-minute cool down. Participants then rested
for 15 minutes and had their standardized lunch at 12:10 pm. Before
leaving the laboratory, 3 standardized meals were provided (day
1 dinner and days 2 and 3 breakfasts). In all conditions except M-Ex,
participants consumed their regular metformin doses with day 1
dinners. Participants were asked to refrain from structured exer-
cise for the remainder of the 72-hour periods and to eat their break-
fasts immediately after waking up. On days 2 and 3, participants
were asked to consume the same standardized breakfasts as on
day 1, after which they were advised to consume their regular
diets.
Dietary intake and pills adherence
On the first day of the first condition, participants were allowed
to eat ad libitum from a selection of items (breakfast, lunch and
dinner), knowing they would have to consume the exact same meals
in subsequent conditions. Adherence was assessed by self-reported
journals, which were then discussed with the study coordinator at
each meeting. Mean (SD) macronutrient proportions and total kilo-
calories were as follows: breakfasts (69±3% carbohydrate, 20±3% fat,
and 11±1% protein; 566±140 kcal); lunch (56±13% carbohydrate,
24±10% fat, and 20±5% protein; 614±241 kcal); and dinner (61±7%
carbohydrate, 16±5% fat, and 23±2% protein; 796±236 kcal).
Continuous glucose monitoring system measures
Participants consumed their breakfasts at 8:00 am on day 1, but
at times of their convenience on days 2 and 3, so not all had 24-hour
data from breakfast to breakfast. Thus, the CGMS data from a
 É. Myette-Côté et al. / Can J Diabetes 40 (2016) 173–177 175

21.5-hour period on days 1, 2 and 3 were used for analysis. Several
outcome variables were calculated, including fasting blood glucose
(15-minute period mean prior breakfast), mean rest or exercise-
induced glucose change (from 11:00 to 11:55 am), daily mean
glucose (21.5-hour period average) and mean nocturnal glucose
(5-hour period prior to the 15-minute fasting blood glucose period).
The mean amplitude of glycemic excursions (MAGE) was calcu-
lated using EasyGV 8.8.2.R2 (Nathan R. Hill, Copyright University
of Oxford, 2010–2014). The 2-hour postprandial area under the curve
(pAUC) and the incremental postprandial area under the curve
(I-pAUC) for each of the 5 standardized meals were computed using
the trapezoid method. The 5 standardized meals pAUC and I-pAUC
were summed and averaged (Average Meal 1 to 5). To avoid poten-
tial bias caused by nonstandardized meals ingested between the
breakfast on days 2 and 3, averages of the 4 consecutive standard-
ized meals (Average Meal 1 to 4) were also calculated. Although the
pAUC from day 1 breakfast would not be influenced by subse-
quent exercise, it was included in the Average Meal 1 to 5 or 1 to
4 because day 1 breakfasts could be affected by skipping the morning
metformin dose in the Ex-M condition.
Statistics
Differences among conditions were examined using the paired
Student t test. To increase statistical power while reducing the poten-
tial for type 2 error, we chose to examine only 3 of a potential of 6
multiple comparisons without adjusting the alpha. The 3 prespecified
comparisons that addressed the objectives of the study were: 1) M-M
vs. M-Ex-M; 2) M-Ex-M vs. Ex-M; 3) M-Ex-M vs. M-Ex. All analy-
ses were performed using SPSS v. 21.0 for Windows (SPSS, Chicago,
Illinois, United States), with statistical significance set at p<0.05.
Results are given as mean ± SD.
Results
Participants’ ages were 59.0±9.6 years, and their durations of dia-
betes were 7.7±5.2 years. They had been taking metformin for
6.1±4.6 years, with a mean dose of 1200 mg per day, ranging from
1000 to 2000 mg per day, and their A1C levels were 6.6±0.6%. Their
body mass indices were 29.5±4.7 kg/m2 (height=1.66±0.11 meters,
body weight=81.3±18.5 kg); their VTs occurred at an oxygen con-
sumption of 22.1±6.4 mL O2/kg/minute. Other medications taken by
participants included: statins (n=5), fibrates (n=1), angiotensin-
converting enzyme inhibitors (n=2), angiotensin II receptor antago-
nists (n=2), aldosterone antagonists (n=1) and acetylsalicylic acid
(n=2). Participants reported excellent compliance with the stan-
dardized diet; no conditions needed to be repeated or dropped from
the analyses.
No differences were observed for the 3 prespecified compari-
sons in terms of fasting and nocturnal glucose levels and time above
8 or under 4 mmol/L (Table 1). Daily mean glucose concentrations
were similar across conditions except for M-Ex on day 1, which were
elevated compared to M-Ex-M (p=0.04). Also, MAGE was similar
across conditions, except for M-Ex on day 3, which was elevated
as compared to M-Ex-M (p=0.02). The 50-minute exercise or rest
period significantly lowered glucose concentrations in every
condition (all p<0.02).
I-pAUC after lunch (M-Ex-M, 289±146; M-M 104±130 mmol
•L−1•min) and dinner (M-Ex-M 174±89, M-M 79±123 mmol•L−1•min)
as well as the average meals 1 to 4 and meals 1 to 5 were increased
in M-Ex-M as compared to M-M (all p<0.05), whereas no differ-
ences were observed between M-Ex-M and the 2 other exercise con-
ditions (Figure 1). Results were similar when pAUC was used. Indeed,
the average meals 1 through 4 pAUC and pAUC after dinner were
increased after M-Ex-M as compared to M-M (both p<0.05). The

Table 1
Glycemic parameters across conditions

Day M-M M-Ex-M Ex-M M-Ex p values p values p values

M-M vs. M-Ex-M Ex-M vs. M-Ex-M M-Ex vs. M-Ex-M

Fasting glucose (mmol/L) Day 1 6.6±1.1 6.8±1.4 7.1±1.3 6.7±1.3 0.69 0.35 0.80
Day 2 6.8±1.4 6.7±0.5 6.8±1.2 7.1±1.3 0.89 0.79 0.41
Day 3 7.3±1.5 6.7±1.2 6.9±1.3 6.8±1.1 0.10 0.36 0.83
Daily mean glucose (mmol/L) Day 1 7.2±1.3 7.0±1.4 7.5±1.5 7.5±1.6 0.32 0.08 0.04a
Day 2 7.4±1.8 7.4±1.2 7.5±1.9 7.6±1.6 0.97 0.70 0.47
Day 3 7.6±1.3 7.4±1.9 7.7±2.0 7.4±1.9 0.52 0.26 0.97
Nocturnal glucose (mmol/L) Day 1 6.7±1.0 6.4±0.7 6.2±0.9 6.7±1.2 0.18 0.64 0.23
Day 2 7.1±1.8 7.5±1.7 6.5±1.1 6.9±0.5 0.28 0.07 0.23
Day 3 7.3±1.1 7.0±1.5 7.2±1.7 6.6±1.2 0.47 0.69 0.38
MAGE (mmol/L) Day 1 3.4±1.5 3.9±1.7 4.4±1.2 3.5±1.3 0.37 0.29 0.48
Day 2 3.8±1.2 3.3±1.7 3.5±1.2 4.0±1.9 0.42 0.49 0.18
Day 3 3.2±1.2 3.5±1.8 3.6±2.3 4.4±1.7 0.67 0.78 0.02a
Time over 8 mmol/L (min) Day 1 316±351 243±302 423±350 377±338 0.33 0.07 0.06
Day 2 382±419 351±382 428±410 326±266 0.65 0.30 0.69
Day 3 457±404 382±431 383±403 413±354 0.31 0.99 0.74
Time under 4 mmol/L (min) Day 1 2±5 31±46 10±22 0±0 0.08 0.25 0.06
Day 2 13±31 7±21 46±83 9±29 0.17 0.14 0.84
Day 3 10±21 31±58 16±49 38±101 0.23 0.25 0.87
Glucose change during 50-min Day 1 −0.9±0.9 −2.8±3.0 −2.3±1.8 −2.4±2.4 0.06 0.28 0.54
exercise/rest period
(mmol/L)
2-hr postprandial AUC Breakfast 1 1062±241 1053±279 1135±252 1094±375 0.88 0.11 0.54
(mmol•L−1•min) Lunch 845±202 883±139 968±190 878±183 0.37 0.10 0.91
Dinner 807±143 884±168 988±207 919±173 0.04a 0.02a 0.27
Breakfast 2 975±275 1057±250 1061±385 1086±358 0.19 0.94 0.57
Av. meal 1–4 922±193 969±191 1038±233 992±251 0.03a 0.07 0.54
Breakfast 3 1005±226 1067±301 1076±360 1069±251 0.49 0.86 0.98
Av. meal 1–5 939±192 989±206 1046±256 1007±245 0.12 0.11 0.57
AUC, area under the curve; Av, Average; Ex-M, exercise-metformin condition; MAGE, mean amplitude of glycemic excursions; M-Ex, metformin-exercise condition;
M-Ex-M, metformin-exercise-metformin condition; M-M, metformin-metformin condition.
a
Significantly different between conditions.
Note: Data are presented as means ± SD.
176 É. Myette-Côté et al. / Can J Diabetes 40 (2016) 173–177
350
300 **
2-hr I-pAUC (mmol•L-1•min)
250
200
150
100
50
0
Average from Meals 1-4
Figure 1. The 2-hour incremental postprandial area under the curve across conditions. M-M, morning and evening metformin doses, without exercise; M-Ex-M, morning
and evening metformin doses, with exercise; Ex-M, exercise with evening metformin dose only; M-Ex, morning metformin dose only, with exercise. Data are presented as
means ± SEM. Significantly different from M-M, **p=0.004, *p=0.013; no difference between exercise conditions.
average meals 1 through 5 pAUC, however, were not significantly
different between M-M and M-Ex-M (p=0.12). Compared to M-Ex-M,
Ex-M increased 2-hour pAUC after dinner (p=0.02), but no other dif-
ferences were observed in our 3 prespecified comparisons (all
p≥0.07).
Discussion
The primary finding of our study is that, contrary to the well-
known acute (9) and chronic (1) glucose-lowering effects of exer-
cise in people with diabetes, we were unable to detect improvements
in glycemic control by adding a bout of exercise in participants
treated only with metformin. Our results are in line with previous
studies suggesting that the addition of exercise does not further
improve insulin sensitivity compared with metformin treatment
alone (2,3). Additionally, our attempt to restore the insulin-
sensitizing effect of exercise by removing the metformin dose before
or after exercise did not result in improved glycemic control and
may have increased glycemic variability (MAGE) at some time points.
Another important finding of this study is that, compared to
metformin alone, the mean postprandial glycemic response to stan-
dardized meals was increased following more than a single meal
when a single bout of exercise was combined with metformin. This
finding expands upon the previous study by Boulé et al., which
observed an increased plasma glucose response to a single meal
when exercise was added to metformin (4).
The increase in glucose in M-Ex-M compared to M-M corre-
sponds to an increase of about 1 mmol/L during the 120-minute
postprandial period. The clinical significance of these acute increases
is difficult to ascertain but may be important, given that the acute
fluctuations of glucose and postprandial hyperglycemia increase oxi-
dative stress (10) and are considered independent risk factors for
vascular complications (11,12). The mechanisms explaining the
observed increase in glucose concentrations in the M-Ex-M vs. the
M-M conditions are difficult to determine from the present study.
Previous investigations had suggested increased hepatic glucose pro-
duction or glucagon (3,4) and reduced insulin sensitivity (5) when
exercise and metformin were combined. Our results build upon these
observations and suggest that the increased glucose may persist
longer than initially observed.
The lack of improvement in postmeal and daily plasma glucose
concentrations on the exercise days should not discourage the use
*
M-M
M-Ex-M
Ex-M
M-Ex
Average from Meals 1-5
of exercise as a treatment modality because it has countless other
benefits that are independent of changes in glucose levels. In addi-
tion, we timed our exercise bouts to coincide with peak metformin
concentration. It would be of interest to study the impact of exer-
cising at lower metformin concentrations, such as before taking
metformin in the morning, or to do so shortly after ingestion.
Ortega et al. observed a nonsignificant 43% (p=0.08) improve-
ment in the insulin sensitivity index with metformin and exercise
compared to either condition alone (13). Discrepancies among
studies may be due to the timing of exercise in relation to metformin
consumption or the outcome of interest. In our study, removing a
metformin dose prior to or after an exercise bout did not improve
glycemic control but did not have a serious deleterious effect com-
pared to the M-Ex-M condition.
A limitation of our pilot study was the low statistical power. In
addition, food intake and daily activities following breakfast on days
2 and 3 were not standardized. Despite these limitations, the results
of this study are strengthened by its crossover design, which allowed
each participant to perform each condition, and the CGMS that
allowed us to examine outcomes over an extended period of time
compared to previous studies.
In conclusion, our study reports new insights regarding the com-
bination of metformin with aerobic exercise. First, adding an aerobic
exercise session to regular daily metformin did not improve average
daily glucose concentrations and may increase postprandial glucose
levels over several meals. Second, removing a metformin dose before
or after exercise did not restore the glucose-lowering effect of
exercise.
Acknowledgements
The study was supported by the Alberta Diabetes Institute’s Physi-
cal Activity and Diabetes Laboratory. Mr. Myette-Côté was sup-
ported by a studentship from the Alberta Diabetes Institute and the
Muttart Diabetes Research and Training Centre and an Art Quinney
Award and Doctoral Recruitment Scholarship from the Faculty of
Physical Education and Recreation, University of Alberta. The authors
thank the participants for their time and effort throughout the study.
Disclosure Statement
NG Boulé received continuous glucose monitoring systems from
Medtronic of Canada for a previous study.
 É. Myette-Côté et al. / Can J Diabetes 40 (2016) 173–177
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