Am J Physiol Endocrinol Metab 320: E425–E437, 2021.

First published December 28, 2020; doi:10.1152/ajpendo.00534.2020

RESEARCH ARTICLE

Separating insulin-mediated and non-insulin-mediated glucose uptake during

and after aerobic exercise in type 1 diabetes
Thanh-Tin P. Nguyen,1 Peter G. Jacobs,2 Jessica R. Castle,3 Leah M. Wilson,3 Kerry Kuehl,4
Deborah Branigan,3 Virginia Gabo,3 Florian Guillot,3 Michael C. Riddell,5 Ahmad Haidar,6 and
Joseph El Youssef2,3
1
School of Medicine, Oregon Health & Science University (OHSU), Portland, Oregon; 2Department of Biomedical Engineering,
Oregon Health & Science University (OHSU), Portland, Oregon; 3Harold Schnitzer Diabetes Health Center, Oregon Health &
Science University, Portland, Oregon; 4Department of Sports Medicine, Oregon Health & Science University (OHSU), Portland,
Oregon; 5School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada; and 6Institut de Recherches
Cliniques de Montre
al, Montreal, Quebec, Canada

Abstract
Aerobic exercise in type 1 diabetes (T1D) causes rapid increase in glucose utilization due to muscle work during exercise, followed by
increased insulin sensitivity after exercise. Better understanding of these changes is necessary for models of exercise in T1D. Twenty-
six individuals with T1D underwent three sessions at three insulin rates (100%, 150%, 300% of basal). After 3-h run-in, participants per-
formed 45 min aerobic exercise (moderate or intense). We determined area under the curve for endogenous glucose production
(AUCEGP) and rate of glucose disappearance (AUCRd) over 45 min from exercise start. A novel application of linear regression of Rd
across the three insulin sessions allowed separation of insulin-mediated from non-insulin-mediated glucose uptake before, during,
and after exercise. AUCRd increased 12.45 mmol/L (CI = 10.33–14.58, P < 0.001) and 13.13 mmol/L (CI = 11.01–15.26, P < 0.001)
whereas AUCEGP increased 1.66 mmol/L (CI = 1.01–2.31, P < 0.001) and 3.46 mmol/L (CI = 2.81–4.11, P < 0.001) above baseline
during moderate and intense exercise, respectively. AUCEGP increased during intense exercise by 2.14 mmol/L (CI = 0.91–3.37,
P < 0.001) compared with moderate exercise. There was significant effect of insulin infusion rate on AUCRd equal to 0.06 mmol/L
per % above basal rate (CI = 0.05–0.07, P < 0.001). Insulin-mediated glucose uptake rose during exercise and persisted hours after-
ward, whereas non-insulin-mediated effect was limited to the exercise period. To our knowledge, this method of isolating dynamic
insulin- and non-insulin-mediated uptake has not been previously employed during exercise. These results will be useful in inform-
ing glucoregulatory models of T1D. The study has been registered at www.clinicaltrials.gov as NCT03090451.
NEW & NOTEWORTHY Separating insulin and non-insulin glucose uptake dynamically during exercise in type 1 diabetes has not
been done before. We use a multistep process, including a previously described linear regression method, over three insulin infusion
sessions, to perform this separation and can graph these components before, during, and after exercise for the first time.

aerobic exercise; clamp study; glucose tracer; insulin-mediated glucose uptake; type 1 diabetes

INTRODUCTION hypoglycemia. The use of continuous glucose monitoring

The pathognomonic feature of type 1 diabetes (T1D) is in-
sulin insufficiency due to autoimmune destruction of beta
cells (1). People with T1D may exhibit features of type 2 dia-
betes (T2D), such as insulin resistance and metabolic syn-
drome (2). Therefore, current T1D guidelines include the
importance of regular physical exercise (3). Physical exercise
confers other health benefits besides improving glycemic
control, including reducing cardiovascular risk factors,
weight loss, and improving overall physical and mental well-
being (4). Despite these positive effects, several barriers exist
for people with T1D trying to achieve recommended exercise
goals (5), the most significant being exercise-induced
(CGM) and closed-loop technology helps detect and reduce
the likelihood of hypoglycemia in T1D (6, 7), but rapid
changes during aerobic exercise and the slow time action
profile of subcutaneous insulin makes it challenging to com-
pletely eliminate the risk of hypoglycemia. Improving our
understanding of glucose metabolism during exercise will
help to improve models of T1D and allow better adjustment
of insulin therapy before, during, and after exercise.
During exercise, glucose uptake into active muscle
increases dramatically, initially through non-insulin-medi-
ated effects, namely, increased substrate penetration due to
contraction and improved perfusion to muscles, and then
through a more protracted increase in insulin sensitivity

Correspondence: J. El Youssef (elyoussj@ohsu.edu).

Submitted 29 October 2020 / Revised 15 December 2020 / Accepted 15 December 2020

http://www.ajpendo.org 0193-1849/21 Copyright © 2021 the American Physiological Society E425

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES
that persists even after exercise is complete (8, 9). The exact
time course of these two independent components of glu-
cose uptake is not well understood. Wasserman et al. (10)
demonstrated a dramatic change in insulin sensitivity in
healthy individuals after exercise, but the time course was
not elucidated, and this experiment was not repeated in peo-
ple with T1D. In addition, Wasserman et al. (10) and Shumak
et al. (11) observed linearity between insulin-dependent glu-
cose utilization across a wide range of physiological and
pharmacological plasma insulin levels. Shumak et al. (11)
used linear regression analysis to demonstrate that non-in-
sulin-mediated glucose uptake occurs at rest in individuals
with T1D, at modest rates depending on glucose levels, but
participants did not perform exercise in this study. Basu et
al. (12) estimated endogenous glucose production (EGP) and
rate of disappearance of glucose (Rd) in individuals with T1D
during exercise using a triple tracer method, providing an
expected dynamic profile of EGP during aerobic exercise.
Although Schiavon et al. (13, 14) calculated insulin sensitivity
at rest and during exercise in healthy individuals, they did
not disambiguate non-insulin-mediated glucose uptake
from insulin-mediated glucose uptake during exercise.
In this study, using a previously described tracer method-
ology in a novel way, we aimed to identify the dynamic insu-
lin-dependent and insulin-independent effects of aerobic
exercise on glucose uptake in individuals living with T1D.
METHODS
Ethical Outline and Study Oversight
This study was designed and implemented by the
Oregon Artificial Pancreas group at Oregon Health and
Science University (OHSU) and was funded by the
National Institute of Diabetes and Digestive and Kidney
diseases (NIDDK). All study procedures were reviewed
and approved by the OHSU Institutional Review Board
and followed ethical principles outlined by the World
Medical Association in the Declaration of Helsinki. All
study procedures, protocol modifications, accrued data,
and adverse events were reviewed by an assigned data
monitor to ensure patient safety. Written informed con-
sent was obtained from all participants or a legally
accepted representative. The study has been registered at
www.clinicaltrials.gov (NCT03090451).
Cohort
Participants living with T1D were recruited from OHSU
clinics, via flyers posted in approved places at OHSU or
posted on the OHSU Harold Schnitzer Diabetes Health
Center webpage, Facebook page, and electronic newsletter,
and from the OHSU Subject Recruitment website. A prescre-
ening waiver was obtained to review patient records from
the Harold Schnitzer Diabetes Health Center to find poten-
tial participants.
Eligible participants were recruited based on the following
inclusion criteria: 1) 18–45 yr of age at the time of randomiza-
tion, 2) T1D diagnosis for at least 12 mo, 3) hemoglobin
A1c < 10%, 4) ability to perform 45 min of aerobic treadmill
exercise. Major exclusion criteria included: 1) pregnancy, 2)
cardiovascular disease significant enough to limit physical
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activity or to put the participant at risk for a cardiovascular
event during exercise including, but not limited to, history
of stroke, heart failure, myocardial infarction, unstable an-
gina, and second- or third-degree heart block, 3) significant
renal or hepatic failure, 4) history of severe hypoglycemia or
hypoglycemic unawareness based on an eight-point ques-
tionnaire, and 5) insulin resistance requiring more than 200
units per day of insulin.
Study Design
We designed a single center, randomized, two-treatment,
three-dose (2
3) study of aerobic exercise in adult partici-
pants living with T1D. Participants were initially randomized
into each arm of the study (see Fig. 1) to either moderate or
intense exercise using a simple randomization scheme. In
each arm, participants were then randomized to receive a
low (L), medium (M), or high (H) insulin infusion rate (IIR)
using block-of-six pseudorandomization for combinations of
the three sessions, that is, L-M-H, L-H-M, M-L-H, M-H-L, H-
L-M, H-M-L.
Study Procedures and Materials
Participants underwent a 2-h screening procedure, with
review of medical history and medications, physical exami-
nation, consenting, and evaluation of maximum V_ O2
(V_ O2max) on a Medgraphics Ultima CardiO2 gas exchange an-
alyzer (MGC Diagnostics, MN). Participants completed the
Clarke Hypoglycemia Unawareness questionnaire (15) and
Physical Activity Readiness questionnaire (16) (PAR-Q) and,
once successfully screened, were randomized. Review of
total daily basal and bolus insulin by study clinicians
allowed estimation of basal intravenous IIR in units/h
needed to maintain a target glucose of 120 mg/dL, called the
low IIR rate. The medium IIR rate was 1.5 times the basal
rate, and the high IIR rate was 3 times the basal rate. Loess
regression analysis of data from VO2max testing established
heart rate ranges for 40%–45% of VO2max (moderate exer-
cise target) and 60%–65% of VO2max (intense exercise tar-
get). A minimum period of 2 wk was respected between
visits. Participants of child-bearing potential not on hormo-
nal methods of birth control were scheduled during the fol-
licular phase of their cycle to limit changes in insulin
sensitivity.
Participants were advised to avoid physical activity
beyond light walking for 2 days before visits and were pro-
vided structured, low-fat meals for dinner and breakfast
through the OHSU Bionutrition Department for home con-
sumption. Participants on multiple daily injections of insulin
were advised to take morning basal insulin doses on the day
before the session and to take 50% of their evening basal
doses no later than 7 PM. Participants ate breakfast 2 h before
the start of the session with their rapid-acting insulin bolus
and did not take any basal insulin injections. Insulin pumps
were suspended after the breakfast dose. Participants were
admitted to the OHSU in-patient research center and those
of childbearing potential had a repeat pregnancy test. Two
intravenous catheters were placed, one on each arm, for
drawing blood and infusing study drugs. Heating pads facili-
tated venous blood draws through a double stop-cock system
on the drawing arm, whereas a sequential Y-catheter system
 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

ENROLLMENT Assessed for eligibility = 38 Subgroup randomization for session order

Excluded = 10 Group 1: Moderate exercise (n=14)

- 4 failed screening
- 4 withdrew before sessions began LMH LHM MLH MHL HLM HML
- 2 no shows 3 2 2 2 2 3*
Randomized = 28 Group 2: Intense exercise (n=13)
ALLOCATION LMH LHM MLH MHL HLM HML
Group 1 Group 2
Moderate Intense exercise 3 2 2 2 2 2
exercise = 14 = 14
Session order groups:
Dropped out L = low IIR, M = medium IIR, H = high IIR.
before sessions * One subject only completed initial session
began = 1
Final session count by subgroup
Each subject scheduled for 3 sessions: low,
medium and high insulin infusion rate Moderate Intense Total
Exercise Exercise
Group 1 Group 2
ANALYSIS
Moderate Intense exercise Low IIR 13(14) 13(13) 26(27)
exercise = 14 = 13
Medium IIR 13(14) 13(14) 26(28)
Dropped out after
High IIR 14(15) 13(13) 27(28)
first session = 1
TOTAL 40(43) 39(40) 79(83)
Group 1 Group 2
Subjects included Subjects
Numbers in parentheses are all sessions
= 14 included = 13
completed, numbers outside parentheses are all
Sessions included Sessions
sessions included in analysis.
= 40 included = 39
Figure 1. Transparent reporting of enrollment, with final study counts. Twenty-six participants underwent three sessions each after successful screening,
and one participant completed only the first session before dropping out, for a total of 79 sessions included in the final analysis. Four sessions had to be
repeated due to technical difficulties (included in the study counts within parentheses in the lower right table). IIR, insulin infusion rate.

allowed infusions of regular human insulin at 0.5 units/mL,
6,6 di-deuterated glucose tracer (Sigma Aldrich, St. Louis,
MO) at 10 mg/mL and 10% dextrose solution supplemented
with 2% tracer. 10 mEq/L of potassium was added to the dex-
trose solution for medium and high IIR sessions.
Participants’ glucose levels were clamped during the
initial 3-h run-in period to a target of 120 mg/dL using a
proportional-integral algorithm based on a paper by
Bequette (17).
During the run-in period, insulin and concentrated tracer
infusion rates were constant, whereas the 10% dextrose solu-
tion infusion rate was adjusted based on recommendations
by the clamp algorithm. The tracer infusion rate was based
on data obtained from Shetty et al. (18) and a triple-tracer
study by Mallad et al. (19): at 0 min, priming bolus of 3.3 mg/
kg, followed by infusion rates in (mg/kg)/h as follows:
minutes 0–180, 2.4; minutes 180–190, 3.5; minutes 190–210,
4.2; minutes 210–225, 4.8; minutes 225–245, 3.5; and after mi-
nute 245, 2.4. Tracer infusion rates were based on an
expected rise in EGP during exercise of 2–2.5 times the pre-
exercise rate.
Participants exercised using a portable treadmill. At mi-
nute 150, dextrose infusion was fixed between 1.5 and 2 times
the baseline rate determined during the run-in period to
prevent significant hypoglycemia during exercise while
allowing constant glucose infusion during and after exercise.
Before exercise began, a Zephyr bio-patch heart rate monitor
and accelerometer (Medtronic Zephyr, Boulder, CO) was
attached to participants and secured using a chest strap.
Exercise began at minute 180 for 45 min and was maintained
by achieving the target heart range determined during
VO2max testing.
Samples of blood were drawn at various intervals
before, during, and after exercise for measurement of se-
rum total and tracer glucose, insulin, glucagon, catechol-
amines (epinephrine and norepinephrine), and free fatty
acids (FFA). Commercially available ELISA assay kits
were used to measure insulin (Mercodia, Inc., Winston,
Salem, NC) and catecholamines (Diagnostica GMBH,
Hamburg 61348, Germany). Glucagon was measured
using a radioimmunometric assay (EMD Millipore Corp,
Burlington, MA) and FFA by a colorimetric method
(Zenbio, Research Triangle Park, NC).
Participants were monitored for 3 h after exercise ended
and provided a meal at the end of the study period.
Subcutaneous insulin was given and overlapped with intra-
venous insulin for a minimum of 30 min. Basal insulin doses
were provided, or insulin pumps restarted, before discharge

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

from the research center. A follow-up phone call was con-
ducted within 48 h of discharge.
Data Analysis
The data from our tracer sessions were analyzed in two
steps. First, we used a simple two-compartment model of
glucose fluxes and solved for EGP and Rd using Bayesian pa-
rameter estimation. Then, we disambiguated insulin-medi-
ated and non-insulin-mediated effects using a novel method
involving linear regression of Rd across insulin-loading
conditions.
To solve for the parameters of interest EGP and Rd, we
used a two-compartment model to estimate internal glucose
fluxes (Fig. 2A) originally described by Radziuk (20) and Mari
(21). The first compartment is termed the accessible com-
partment and its content is estimated by blood glucose
measurements—all intravenous infusions enter into this
compartment. The second compartment is the inaccessible
compartment, through which glucose circulates but from
which it is not eliminated. Given glucose infusions and blood
glucose levels, we can solve for the glucose mass moving out
of the first compartment (Rd), and alternately, the EGP enter-
ing into the first compartment. The system of ordinary dif-
ferential equations (ODEs) is given by the following
equations (18, 20):
Q_ S1 ¼ ðk01 þ k21 ÞQS1 þ k12 QS2 þ US ; ð1Þ
Q_ S2 ¼ k21 QS1  k12 QS2 ; ð2Þ
QS
GS ¼ ; where VG ¼ 0:16 L=kg: ð3Þ
VG
The subscript S denotes the glucose species and can be
replaced with either T (for total glucose) or D (for tracer
deuterated glucose). Q S1 and QS2 denote the glucose
mass (mmol/kg) within either the accessible compart-
ment (QS1) representing plasma or the inaccessible com-
partment (QS2). G S is the glucose concentration (mmol/
L) and can be calculated from the volume of distribution
of glucose (VG). US is the glucose rate of appearance
(mmol/kg/min) where U T = u D10 þ u D2 þ EGP and UD =
uD2. u D10 is the D10% infusion rate and uD2 is the tracer
infusion rate.
The fluxes between compartments are defined by k12 and
k21; the values of these rate constants were derived from pre-
vious experiments by Hovorka et al. (22) and kept fixed dur-
ing the experiment, whereas k01 and EGP are parameters
that were solved at each time point. Initial conditions of the
two-compartment model were solved by assuming steady-
state conditions. In additional, a 10-min delay was imple-
mented on the glucose infusions into the first compartment.

A C

US k21
QS1 QS2 Exercise
Session
k01 k12
QT1, QD1, UT, UD

Two-
Compartment
B Model

k01, EGP, Rd, Ra

H y = mx + b
Rd M b = NIMGU Linear
L m = IMGU Regression of
Insulin vs. Rd
% basal insulin NIMGU, IMGU
High Insulin
Rd Continuous
IMGU and
Medium Insulin NIMGU
Estimates
Low Insulin

time
Figure 2. A: schematic of the Radziuk–Mari two-compartment model. B: method for calculating insulin- vs. non-insulin-mediated glucose uptake. Linear
regression was performed at each time point across three different insulin infusion curves. The slope of the line at each point is the insulin-mediated glu-
cose uptake and extrapolating the line to theoretical zero insulin gives the non-insulin-mediated glucose uptake. (C) workflow showing inputs and out-
puts for each step of data analysis. EGP, endogenous glucose production; k, rate constant; (N)IMGU, (non) insulin-mediated glucose uptake; Q, mass
compartment; Rd, glucose rate of disappearance; Ra, glucose rate of appearance; S, glucose species; U, glucose input.

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

Table 1. Baseline characteristics of participants in each study arm

P
Moderate Exercise Intense Exercise Value
n 14 13 –
Male, n (%) 4 (28.6) 6 (46.2) 0.345
Age, yr, means ± SD 32.6 ± 6.6 28.2 ± 6.1 0.079
Duration of diabetes, yr, means ± SD 19 ± 9.4 15.3 ± 7.4 0.146
Weight, kg, means ± SD 79.1 ± 16.4 76.2 ± 8 0.572
BMI, kg/m2, means ± SD 26.3 ± 4.5 24.8 ± 2.95 0.332
Hemoglobin A1c, %, mmol/mol means ± SD 7.4 ± 1.1 (57.6 ± 11.7) 7.4 ± 1 (57.9 ± 10.4) 0.950
TDI, units/day, means ± SD 54.3 ± 13.1 54 ± 16 0.959
Percent of TDI as basal, means ± SD 54.8% ± 6.3% 55.9% ± 6.1% 0.638
MDI users, n (%) 5 (35.7) 2 (15.4) 0.228
CSII (pump) users, n (%) 9 (64.3) 11 (84.6)
Student’s two-tailed, unpaired t test used for nominal data, v2 test for categorical data. CSII, continuous subcutaneous insulin infu-
sion; MDI, multiple daily injections; TDI, total daily insulin.

For the unknown parameters, we defined a Bayesian prob- Carlo algorithm to explore the posterior. Our Bayes posterior
ability function, with study data used to calculate the likeli- distribution is defined as follows:
hood. Bayes parameter estimation was chosen to constrain
parameter values to physiologically probable values and was

PðG T ; G D jk01 ; EGPÞPðk01 ; EGPÞ
performed using the R-STAN software package (23) in which P k01 ; EGPjG T ; G D ¼
: ð4Þ
the ODE parameters were fitted using a Hamiltonian Monte P GT ; GD

EGP During Moderate Exercise EGP During Intense Exercise

0.25 0.25 Low Insulin

Medium Insulin
High Insulin

0.2 0.2
EGP (mmol/L/min)
EGP (mmol/L/min)

0.15 0.15

0.1 0.1

0.05 0.05

150 200 250 300 350 400 450 150 200 250 300 350 400 450
time (min) time (min)
Figure 3. Interquartile plots of endogenous glucose production (EGP) across insulin conditions and exercise arms. Area under the curve (AUC)EGP was
higher in the patients undergoing intense exercise (3.46 mmol/L over baseline, 95% CI = 2.81–4.11, P < 0.001) compared with moderate exercise
(1.66 mmol/L over baseline, 95% CI = 1.01–2.31, P < 0.001) with a difference between exercise groups of 2.14 mmol/L (95% CI = 0.91–3.37, P < 0.001).
There was no difference in AUCEGP across insulin infusion groups, P = 0.7. Exercise occurred during the shaded interval.

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

PðG T ; G D jk01 ; EGPÞ is the likelihood and represents a com-
parison between model-generated values, given a particular
k01 and EGP, and the data, which is accepted as ground
truth. In other words, the likelihood function is a normal dis-
tribution centered on the data value of G T and G D from the
tracer sessions with input to the Gaussian function equal to
their generated values from the ODE model.
We implemented uniform priors for both k01 and EGP. Taken
together, the likelihood penalizes simulated glucose values that
result in glucose too far away from experimental values and the
uniform prior, as opposed to a prior that forces a correlation
between time points, reduces smoothing and the influence of
model error on adjacent k01 and EGP estimations. Our k01 and
EGP values were then used to calculate glucose rate of appear-
ance (Ra) and glucose rate of disappearance (Rd) as follows:
Ra ðtÞ ¼ UD2 þ UD10 þ EGP þ k12
GT2 ;
Rd ðtÞ ¼ ðk01 þ k21 Þ
GT1 ;
The second step aimed to identify glucose disposal at each
time point that was due to insulin versus disposal that was
independent of insulin. For a given patient and at a given
time point, we plotted Rd against insulin infusion rate. We
applied a linear regression to approximate the Rd per
amount insulin infusion, and extrapolated the linear model
to the point on the y-axis, where insulin equals zero; this was
taken to be the insulin-independent effect (Fig. 2B). The in-
sulin-dependent effect, then, was taken to be the slope of the
linear regression line of best fit. A flow chart of the steps in
data analysis is provided in Fig. 2C.
Statistical Analysis
Power analysis and sample size determination were per-
formed using Gpower software (24). A sample size of 13 sub-
jects per arm (26 participants total) was found to be adequate
to show at least a 30% difference in the peak effect for insu-
ð5Þ
lin- and non-insulin-mediated changes. This assumed at
least 25% standard deviation between groups and a pre-
ð6Þ
dicted effect size of 1.37, with an a error of 5% and power of
90%. Sample size minimum was 10 per group and 13 was
chosen in case of higher than expected standard deviation.

Rd During Moderate Exercise Rd During Intense Exercise

1.3 1.3 Low Insulin

Medium Insulin
High Insulin
1.2 1.2

1.1 1.1

1 1
R (mmol/L/min)

R d (mmol/L/min)

0.9 0.9

0.8 0.8
d

0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

150 200 250 300 350 400 450 150 200 250 300 350 400 450
time (min) time (min)
Figure 4. Interquartile plots of glucose rate of disappearance (Rd) across insulin conditions and exercise arms. Rd was systematically higher for higher ba-
sal insulin dosing. AUCRd increased 12.45 mmol/L (95% CI = 10.33–14.58, P < 0.001) during moderate exercise and 13.13 mmol/L (95% CI = 11.01–15.26,
P < 0.001) during intense exercise compared with baseline, with a significant effect of insulin infusion rate equal to 0.06 (mmol/L)/% above basal rate
(95% CI = 0.05–0.07, P < 0.001). There was no difference in AUCRd between moderate and intense exercise groups, P = 0.34. Exercise occurred during
the shaded interval.

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

AUCRd and AUCEGP were calculated over the 45-min exer-
cise period, as well as during the preexercise baseline period.
AUC is presented in units of mmol/L representing the total
glucose mass moved during the exercise or baseline period.
A linear mixed effects model was used to determine the sig-
nificance of the effect of insulin infusion rate and exercise
intensity on AUCRd and on AUCEGP, with study participant
as the random effect and insulin infusion rate and exercise
level as the fixed effects. Single-factor ANOVA and paired t
test analyses were used to compare differences in hormone
and FFA levels across insulin-infusion conditions.
RESULTS
Participant baseline characteristics are shown in Table 1.
There was an increase in EGP during the intense exercise
period that continued after exercise stopped (Fig. 3). Our
mixed effects model analysis demonstrated no significant
effect of insulin infusion rate (P = 0.700) on AUCEGP, but
showed an increase of 1.66 mmol/L (95% CI = 1.01–2.31, P <
0.001) during moderate exercise compared with baseline,
versus 3.46 mmol/L (95% CI = 2.81–4.11, P < 0.001) during
intense exercise. When comparing moderate-to-intense exer-
cise, we found a significant increase of 2.14 mmol/L on
AUCEGP (95% CI = 0.91–3.37, P < 0.001) in the intense exer-
cise group.
There was a separation between insulin infusion groups
on the interquartile plots of Rd (Fig. 4), showing that for
higher insulin infusion rates, the rate of disposal of glucose
increased. AUCRd was found to be affected by insulin infu-
sion (Fig. 5). Linear mixed effects analysis showed that the
AUCRd increased 12.45 mmol/L (95% CI = 10.33–14.58, P <
0.001) during moderate exercise and 13.13 mmol/L (95%
CI = 11.01–15.26, P < 0.001) during intense exercise compared
with baseline, with a significant effect of insulin infusion
rate equal to 0.06 (mmol/L)/% above basal rate (95%
CI = 0.05–0.07, P < 0.001) such that as insulin infusion
increased from 100% to 300%, AUCRd increased by 12 mmol/L.
Comparing moderate-to-intense exercise, there was no signifi-
cant effect of exercise intensity on AUCRd (P = 0.34).
We found a sharp increase in non-insulin-mediated glu-
cose uptake with the start of exercise, whereas insulin-medi-
ated glucose uptake saw a more gradual increase (Fig. 6). In
addition, non-insulin-mediated glucose uptake increased at
the onset of exercise and decreased when exercise ended,
whereas insulin-mediated glucose uptake remained elevated
for longer after exercise (Fig. 6). Interestingly, the insulin-
mediated glucose uptake started to rise around minute 150
before the onset of exercise, which may have been caused by

AUC of R d during moderate exercise AUC of R d during intense exercise

60 60

55 55

50 50

45 45
AUC (mmol/L)

AUC (mmol/L)

40 40

35 35

30 30

25 25

20 20
100 150 300 100 150 300
Insulin Basal Rate (%) Insulin Basal Rate (%)
Figure 5. Glucose disposal during 45 min of exercise. Red lines indicate medians, blue boxes indicate 25th–75th percentile, and horizontal black lines
indicate lower and upper adjacent. Medians for low, medium, and high insulin infusion rates during moderate exercise are 28.077 (Q1 = 26.474,
Q3 = 29.383), 34.160 (Q1 = 32.427, Q3 = 36.583), and 44.505 (Q1 = 40.842, Q3 = 46.300) mmol/L, respectively. For intense exercise, medians were 26.913
(Q1 = 24.485, Q3 = 31.247), 31.844 (Q1 = 27.006, Q3 = 39.720), and 48.558 (Q1 = 43.027, Q3 = 55.838) mmol/L, respectively. Q, mass compartment.

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Rd /%Basal Insulin (mmol/L/min)
0.6
0.5
0.4
0.3
0.2
0.1
150
0.7
0.6
Rd (mmol/L/min)
0.5
0.4
0.3
0.2
0.1
150
Figure 6. Insulin-mediated and non-insulin-mediated glucose uptake plotted across the duration of the experiment. Asterisks indicate time points where
Rd is significantly different from baseline at minutes 150. Exercise occurred during the shaded time period. 95% confidence intervals are shown in dotted
lines.
the increased dextrose infusion applied before exercise to
help avoid hypoglycemia during exercise (Fig. 7). We there-
fore used the period from minute 120 to minute 150 as a base-
line for comparison of changes in both insulin- and non-
insulin-mediated glucose uptake during and after exercise,
as shown in Fig. 6.
Insulin plasma levels corresponded appropriately with the
insulin infusion rate during sessions, showing a rise during
the exercise period as previously demonstrated by Mallard
(19) (Fig. 8). Insulin levels showed a significant increase
across different infusion sessions by ANOVA (P < 0.001) and
were significantly higher on average between low and me-
dium (P < 0.001), medium and high (P < 0.001), and low and
high (P < 0.001) sessions via paired t test. Data for free fatty
acid, glucagon, and catecholamine levels are presented in
Fig. 9. For free fatty acid levels, Student’s t test showed sig-
nificance (P < 0.01) between low and high IIR sessions for
both moderate and intense exercise groups at all except the
200-min time point. For glucagon levels, there was signifi-
cance (P < 0.05) between low and high IIR sessions from mi-
nute 200 and onwards, but this did not persist after
accounting for exercise intensity, whereas for catecholamine
levels, significance between moderate and intense exercise
groups from minute 120 to minute 200 (P < 0.05) did not per-
sist after accounting for insulin conditions.
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AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES
Insulin-Mediated Glucose Uptake
Moderate Exercise
Intense Exercise
200 250 300 350 400 450
Non-Insulin-Mediated Glucose Uptake
200 250 300 350 400 450
time (min)
DISCUSSION
In this paper, we present results showing how aerobic
exercise impacts insulin- and non-insulin-mediated glucose
uptake. To the best of our knowledge, the methods that we
use to calculate insulin- and non-insulin-mediated glucose
uptake as a function of exercise have not been previously
published. We used methods described by Shumak et al (11),
where non-insulin-mediated glucose uptake was determined
in participants living with T1D (resting only), by measuring
glucose disposal at three different insulin infusion rates and
then linearly extrapolating to an infusion rate of zero. We
extended this by measuring both insulin- and non-insulin-
mediated uptake before, during, and after different exercise
intensities to quantify how exercise impacts glucose dis-
posal. This method assumes linearity of the insulin dose-
response curve when extrapolating to zero insulin. The main
strength of our estimation method is that glucose uptake
was obtained directly from physiological data using a mini-
mal model blind to both insulin and exercise conditions.
Our results show an increase in insulin-mediated glucose
disposal during exercise, which persists for several hours af-
ter a single bout of aerobic exercise is completed before
returning to baseline. Also, the non-insulin-mediated effect
appears to be limited to the exercise period, rising quickly
 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

A Glucose Infusion Rate (ml/hr of D10%W) Glucose Infusion Rates

250 Low IIR

Med IIR
High IIR
200

150

100

50
0 50 100 150 200 250 300 350 400 450

Glucose Levels Across All Subjects

B 300
Med Exercise
15.0
Intense Exercise
250
Average

Glucose (mmol/L)
Glucose (mg/dL)

12.0
200

9.0
150

100 6.0

50 3.0
0 50 100 150 200 250 300 350 400 450
time (min)
Figure 7. Glucose infusion rates for each insulin infusion group and glucose levels across all study participants. A: the upper graph shows the dextrose
infusion rate for the low, medium, and high insulin infusion groups, with standard deviations. Dextrose infusion was increased at minutes 150 to limit
hypoglycemia and to allow a constant dextrose infusion rate during exercise. B: the lower graph shows average glucose levels for each exercise condi-
tion, with gray lines denoting individual study participants. The average for both conditions in shown in bold with bars indicating standard deviations.

during exercise and then dropping quickly at the end of exer- which can persist for hours, may be responsible for the
cise (Fig. 6). Other groups including Berger et al. (25) have longer term impact on glucose uptake as reported by
demonstrated that there can be a sharp increase in insulin McMahon et al. (26).
sensitivity during aerobic exercise. They showed a several- Our results also show an increase in Rd and EGP during
fold increase in plasma levels of tracer [3H]-insulin between exercise (Figs. 4 and 5), which correspond with the rise in in-
15 and 90 min after the start of exercise compared with sulin-mediated and non-insulin-mediated glucose uptake
during a rest control period. The insulin-mediated effect, (Fig. 6). There was also a clearly defined dose effect across

† †
100 * * * * * * *
Average - High IIR
Average - Med IIR Figure 8. Plasma insulin levels during
80 Average - Low IIR exercise across insulin infusion groups,
Insulin (mIU/L)

* * showing a rise in insulin plasma levels dur-

60 ing exercise, despite a constant intrave-
nous infusion rate of insulin. Shaded area,
exercise period; IIR, insulin infusion rate.
40 P < 0.01 for High vs. Med and High vs.
Low. †P < 0.0001 for minutes 200 and
20 minutes 220 insulin plasma levels com-
pared with minute 180 for Low, Med, and
0 High IIR.
90 120 150 180 210 240 270 300 330 360 390 420 450 480 510
Time from study start (min)

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

MODERATE EXERCISE INTENSE EXERCISE

Average - Low IIR
400 Average - Medium IIR 400
Free Fatty 300 Average - High IIR
300
Acid Levels
(μmol/L) 200 200
Mean ± SD
100 100

0 0
60 120 180 240 300 360 420 480 60 120 180 240 300 360 420 480
80 80
70 70
60 60
Glucagon 50 50
(ng/L) 40 40
Mean ± SD 30 30
20 20
10 10
0 0
60 120 180 240 300 360 420 480 60 120 180 240 300 360 420 480
2000 2000

1500 1500
Epinephrine
(pg/mL) 1000 1000
Mean ± SD
500 500

0 0
60 120 180 240 300 360 420 480 60 120 180 240 300 360 420 480
120 200
100
Nor- 150
epinephrine 80
(pg/mL) 60 100
Mean ± SD
40
50
20
0 0
60 120 180 240 300 360 420 480 60 120 180 240 300 360 420 480

Figure 9. Free fatty acid, glucagon, and catecholamine levels separated by insulin infusion rate and exercise intensity. Shaded area shows the period of
exercise.

insulin infusion subgroups on Rd, with Figs. 5 and 6 showing
that Rd increases significantly for higher insulin infusion
conditions. Surprisingly, there was not a significant impact
of exercise intensity on either insulin-mediated or non-insu-
lin-mediated glucose uptake using our methods, as com-
pared with the effect seen with estimates of EGP, though this
may be due to the fact that the levels of exercise intensity
chosen for moderate and intense exercise were not suffi-
ciently separated. The participants in the study had varying
levels of fitness (27), which may have impacted the lack of
separation on Rd between the two study arms as well. As
noted in Fig. 6, the calculation for insulin-mediated glucose
uptake was based on percentage of basal insulin infusion
rate rather than on insulin concentration, to equalize the
assessment across varying insulin sensitivity profiles.
The findings reported here may be helpful as exercise
metrics are incorporated into automated insulin and gluca-
gon delivery systems to help prevent exercise-induced

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES

hypoglycemia (6, 7, 28, 29). It may also be helpful in decision
support systems and meal bolus calculators that rely on
accurate estimations of insulin sensitivity that is affected by
exercise. For example, Fabris et al. report on use of a smart
meal bolus calculator that is informed about changes in in-
sulin sensitivity caused by aerobic exercise. They found that
use of the exercise information to inform changes in insulin
sensitivity helped to reduce hypoglycemia and rescue carbo-
hydrates (30).
Models of glucose homeostasis in individuals with type 1
diabetes continue to be refined, with the inclusion of addi-
tional aspects of human behavior that can impact glucose
levels, such as exercise, meals, sleep, and even stressful
events by using appropriate sensors (31). The results that
we present here may help enable improved glycemic con-
trol by allowing the control algorithms to adjust insulin
dosing based on changing insulin sensitivity; such adapt-
ive changes in insulin sensitivity within models have been
shown to be beneficial in adaptive controls (32). Current
guidelines provide expert advice based on observations of
glucose changes during exercise (33), but these recommen-
dations from a consensus statement remain broad and do
not provide quantitative resolution for use in control algo-
rithm models. This study represents a first step toward
quantifying and separating the dynamic effect of exercise
on insulin-mediated and non-insulin-mediated glucose
flux before, during, and after exercise for the purpose of
inclusion in such models.
It is apparent in Fig. 6 that the insulin-mediated glucose
uptake appears to increase before exercise. This phenom-
enon is also apparent in Fig. 4 that shows Rd increasing
before the onset of exercise. We looked carefully at this in
each session and determined that this was due to an artifact
of the experimental method. At minute 150, the dextrose
infusion was increased to help prevent hypoglycemia during
exercise scheduled at minute 180. Consequently, in Fig. 6,
the insulin-mediated glucose uptake can be seen rising
before exercise begins, at roughly minute 150. Implementing
a delay variable for intravenous dextrose infusion into our
glucose model to account for the time for infused dextrose to
take effect only shifted the sudden rise in insulin-mediated
glucose uptake but did not correct the effect. This implies a
nonphysiological effect caused by inadequate accounting for
the sudden change in dextrose infusion rate. The absence of
tracer glucose data between minutes 120 and minutes 165
likely contributed to this nonphysiological effect. The non-
insulin-mediated glucose uptake in Fig. 6 did not show a
similar rise before the start of exercise, suggesting that this
effect is not present at the extrapolated zero-insulin thresh-
old. In some participants, the artifact was not present as

A 0.4

0.9
Rd (mmol/L/min)

0.8

0.7

0.6

0.5

0.4
150 200 250 300 350 400 450

B
0.9

0.8
Rd (mmol/L/min)

0.7

0.6

0.5

0.4
150 200 250 300 350 400 450
time (min)
Figure 10. Representative Rd traces during two experiments. A: Rd for one participant that shows increase at the start of exercise as is expected. B: Rd
for another participant that shows a nonphysiological increase at minute 150 at the time that dextrose was increased to help prevent hypoglycemia dur-
ing exercise.

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 AEROBIC EXERCISE PHYSIOLOGY STUDY IN TYPE 1 DIABETES
shown in Fig. 10A, whereas for others, the artifact was
observed to start around minute 150, but then dissipated by
minute 180 as shown in Fig. 10B. Likely, the variability in
timing of this artifact’s onset and offset caused the average
effect to appear as is in Fig. 6.
There are several limitations to this study. First, as noted
above there was an issue with the increase in dextrose infu-
sion before the start of exercise. Although we could have
avoided this artifact by not increasing dextrose so close to the
start of exercise, this would have increased the risk of hypo-
glycemia occurring in the participants during the study. We
wanted to keep study participants safe while also maintaining
consistent dextrose infusions during the exercise period with-
out supplying an increase in dextrose to respond to a hypogly-
cemic event. Also, there appears to be similarity between the
change in dextrose infusion rates (Fig. 7) and the change in in-
sulin-mediated glucose uptake (Fig. 6), which may represent
an inherent, model-based correlation. Second, our parame-
ters for k12 and k21 were fixed at previously published values,
which may have limited how the sampling method accounted
for physiological differences between patients. Finally, it is
unclear if the methods that we used to estimate non-insulin-
mediated glucose uptake using the linear extrapolation to
zero insulin as described by Shumak et al. (11) are optimal. We
could have potentially used a nonlinear extrapolation such as
a Michaelis–Menton relationship between substrate concen-
tration and reaction velocity. However, this may have
resulted in significant global underestimation of the non-in-
sulin-mediated effect, and so, we chose to use the linear
extrapolation method that has been used by others.
In conclusion, we have described a novel method to quantify
insulin-mediated and insulin-independent uptake before, dur-
ing, and after aerobic exercise in individuals living with T1D,
which has been thus far difficult to identify. We found that
non-insulin-mediated glucose uptake rose and fell within the
exercise period, whereas insulin-mediated glucose uptake had
a broader, prolonged response, remaining high after comple-
tion of exercise. Basal insulin and exercise intensity each had a
significant impact on Rd. Our unique method of using three
different infusion rates and two different exercise arms give us
some preliminary data points that may be expanded to
enhance models used in glycemic control algorithms.
ACKNOWLEDGMENTS
We acknowledge Dr. Dennis Koop and Jenny Luo from the
OHSU Pharmacokinetics Core Lab, Dr. Clive Woffendin and
Aaron Clemons from the OHSU Oregon Clinical and Translational
Research Institute (OCTRI) research lab, and, in particular, Brian
Senf who worked as a research technician in the Division of
Endocrinology at OHSU during this study and dedicated signifi-
cant time and effort to the completion of this project.
GRANTS
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) Grant 1R01 DK110175.
DISCLOSURES
Peter G. Jacobs has a financial interest in Pacific Diabetes
Technologies, Inc., a company that may have a commercial interest
in the results of this type of research and technology. This potential
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conflict of interest has been reviewed and managed by OHSU. In
addition, he reports research support from Xeris, Dexcom, and
Tandem Diabetes Care. Jessica R. Castle has a financial interest in
Pacific Diabetes Technologies, Inc., a company that may have a
commercial interest in the results of this type of research. This
potential conflict of interest has been reviewed and managed by
OHSU. In addition, she reports advisory board participation for
Zealand Pharma, Novo Nordisk, Insulet, and AstraZeneca, consult-
ing for Dexcom, and a U.S. patent on the use of ferulic acid to stabi-
lize glucagon. Michael C. Riddell reports grant funding from Insulet,
nonfinancial support from Dexcom, and personal fees from
Medtronic, Novo Nordisk, Lilly, and Zucara. Ahmad Haidar received
research support/consulting fees from Eli Lilly, Medtronic,
AgaMatrix, Tandem, and Dexcom, and has pending patents in the
artificial pancreas area. None of the other authors has any conflicts
of interest, financial or otherwise, to disclose.
AUTHOR CONTRIBUTIONS
P.G.J., J.R.C., K.K., D.B., V.G., M.C.R., A.H., and J.E.Y. conceived
and designed research; J.R.C., L.M.W., K.K., D.B., V.G., F.G., and
J.E.Y. performed experiments; T-T.P.N., P.G.J., D.B., V.G., F.G., and
J.E.Y analyzed data; T-T.P.N., P.G.J., J.R.C., L.M.W., M.C.R., A.H.,
and J.E.Y. interpreted results of experiments; T-T.P.N., P.G.J., D.B.,
V.G., and J.E.Y. prepared figures; T-T.P.N., P.G.J., J.R.C. and J.E.Y
drafted manuscript; T-T.P.N., P.G.J., J.R.C., L.M.W., K.K., M.C.R.,
and J.E.Y. edited and revised manuscript; T-T.P.N., P.G.J., J.R.C.,
and J.E.Y approved final version of manuscript.
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