Acute Effects of Aerobic and Resistance Exercise on Maternal Glucose Metabolism and Vascular Function in Obese Pregnancy
Phase: NA
Conditions: Pregnancy Complications, Obesity, Pre-Eclampsia, Gestational Diabetes
Sponsor: Duke University

 
 
 
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Acute Effects of Aerobic and Resistance Exercise on Maternal Glucose 
Metabolism and Vascular Function in Obese Pregnancy  
 
William Todd Cade, PT, PhD 
__________________ 
Washington University School of Medicine 
4444 Forest Park Ave 
Campus Box 8502 
St. Louis, MO 63108 
 
Study Team: 
Alison G. Cahill, MD, MSCI 
Dominic N. Reeds, MD 
Kathryn Bohnert, MS 
________________ 
 
Protocol #: REACT2018 
Version date: 06/23/2018 
 
NCT03750695 
 
 

 
 
 
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TABLE OF CONTENTS 
A 
INTRODUCTION ..................................................................................................................... 4 
A1 
STUDY ABSTRACT .............................................................................................................. 4 
A2 
PRIMARY HYPOTHESIS ....................................................................................................... 4 
 ACUTE AEROBIC AND RESISTANCE REHABILITATIVE EXERCISE WILL IMPROVE POST-EXERCISE GLUCOSE 
METABOLISM AND VASCULAR FUNCTION IN OBESE WOMEN DURING MID-PREGNANCY. ............... ERROR! 
BOOKMARK NOT DEFINED. 
A3 
PURPOSE OF THE STUDY PROTOCOL .................................................................................. 4 
B 
BACKGROUND ...................................................................................................................... 5 
B1 
PRIOR LITERATURE AND STUDIES ....................................................................................... 5 
B2 
RATIONALE FOR THIS STUDY ............................................................................................... 7 
C 
STUDY OBJECTIVES ............................................................................................................. 7 
C1 
PRIMARY AIM ..................................................................................................................... 7 
C2 
SECONDARY AIM ................................................................................................................ 7 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES .................................................. 7 
D 
REGISTRATION PROCEDURES ........................................................................................... 8 
D1 
CONFIRMATION OF PATIENT ELIGIBILITY .............................................................................. 8 
D2 
PATIENT REGISTRATION IN THE SITEMAN CANCER CENTER ONCORE DATABASE .................. 8 
D3 
ASSIGNMENT OF UPN ........................................................................................................ 8 
E 
STUDY DESIGN ...................................................................................................................... 8 
E1 
OVERVIEW OR DESIGN SUMMARY ....................................................................................... 8 
E2 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................. 8 
2.a 
Inclusion Criteria .......................................................................................................... 8 
2.b 
Exclusion Criteria ......................................................................................................... 8 
2.c 
Inclusion of Women and Minorities .............................................................................. 9 
2.d 
Subject Recruitment Plans and Consent Process ....................................................... 9 
2.e 
Early Withdrawal of Subjects ....................................................................................... 9 
2.f Data Collection and Follow-up for Withdrawn Subjects .................................................. 9 
D 
STUDY PROCEDURES .......................................................................................................... 9 
 
D1 
SCREENING FOR ELIGIBILITY ............................................................................................... 9 
D2 
VISIT 1 .............................................................................................................................. 9 
D3 
VISIT 2 ............................................................................................................................ 11  
D4 
VISIT 3 ............................................................................................................................ 11 
 
E 
SAFETY AND ADVERSE EVENTS .................................................................................... 133 
E1 
DEFINITIONS .................................................................................................................. 133 
1.a 
Adverse Events ........................................................................................................ 133 
1.b 
Serious Adverse Event (SAE) ................................................................................. 144 
1.c 
Unexpected Adverse Experience ............................................................................ 144 
1.d 
Life-Threatening Adverse Experience ..................................................................... 144 
1.e 
Unanticipated Problems........................................................................................... 144 
1.f Noncompliance ............................................................................................................ 144 
1.g 
Serious Noncompliance ........................................................................................... 144 
1.h 
Protocol Exceptions ................................................................................................. 154 
E2 
REPORTING TO THE HUMAN RESEARCH PROTECTION OFFICE (HRPO) AT WASHINGTON 
UNIVERSITY ............................................................................................................................... 155 

 
 
 
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E3 
TIMEFRAME FOR REPORTING REQUIRED EVENTS ............................................................ 155 
F 
STATISTICAL PLAN........................................................................................................... 166 
F1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................... 166 
F2 
INTERIM MONITORING AND EARLY STOPPING ................... ERROR! BOOKMARK NOT DEFINED.6 
F3 
STATISTICAL METHODS .................................................................................................. 166 
G 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................... 177 
H 
STUDY ADMINISTRATION ................................................................................................ 189 
H1 
ORGANIZATION AND PARTICIPATING CENTERS ................................................................. 189 
H2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ............................................................. 189 
H3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................. 189 
I 
REFERENCES ...................................................................................................................... 20 
 

 
 
 
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A Introduction 
A1 Study Abstract 
Obesity before and during pregnancy is associated with a higher risk for a number of 
obstetric and metabolic complications in women and their offspring. Of particular 
importance, obese women have a higher risk of developing gestational diabetes and 
preeclampsia. In addition, obese women have larger offspring who have a higher risk for 
the development of obesity and diabetes; both largely attributed to higher maternal 
glycemia and glucose intolerance during pregnancy. Thus, identifying rehabilitative 
interventions that improve maternal and offspring metabolic and cardiovascular health in 
obese pregnancy are critical and have immediate and generational impact. Resistance 
and aerobic exercise training is a clinical staple for improving musculoskeletal, metabolic 
and cardiovascular health in non-gravid adolescents and adults with obesity however 
little is known regarding the effects of exercise during obese pregnancy. This study 
proposes to collect preliminary data on the independent effects of acute aerobic and 
resistance rehabilitative exercise on glucose metabolism and vascular function during 
pregnancy in n=15 obese women in order to inform a large, multisite clinical trial 
examining the acute and chronic effects of aerobic and resistance exercise on glucose 
metabolism and vascular function in normal weight, overweight and obese women 
during pregnancy.   
 
Primary Hypothesis  
Acute aerobic and resistance rehabilitative exercise will improve post-exercise glucose 
metabolism and vascular function in obese women during mid-pregnancy. 
 
 
A2 Purpose of the Study Protocol 
The overall goal is to obtain preliminary proof-of-concept data for a larger study 
examining acute and chronic physiologic and molecular effects of aerobic and resistance 
exercise on glucose metabolism and vascular function in normal weight, overweight and 
obese women during pregnancy. We will also track the number of eligible participants 
including those who consented and declined for sample size estimation for a larger 
future study.  
 
 

 
 
 
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B Background 
B1 Prior Literature and Studies 
Obesity is a metabolic disease that is associated with several comorbidities including 
cardiovascular, musculoskeletal and neurological conditions. Maternal obesity 
prevalence is at a historic high with over 1 in 3 women entering pregnancy obese and 1 
in 10 extremely obese1. Obesity before and during pregnancy is associated with a higher 
risk for a number of obstetric and metabolic complications in women and their offspring2 
including increased rates of preeclampsia, gestational diabetes, fetal growth disorders, 
stillbirth, preterm birth and cesarean delivery, which are further exacerbated by 
excessive gestational weight gain that often occurs in overweight and obese women3.  In 
addition, physical inactivity in combination with excess maternal adiposity can alter the 
intrauterine metabolic environment and contribute to adverse fetal programming leading 
to unfavorable infant outcomes with long-term health implications for the child4,5. Thus, 
identifying rehabilitative interventions in obese women during pregnancy that improve 
maternal and offspring metabolic and cardiovascular health are critical and have 
immediate and generational impact.  
 
Obese women have a higher risk of developing gestational diabetes than normal weight 
women6 as obese women have lower pre-gravid insulin sensitivity that is exaggerated 
during pregnancy7. Specifically, obese and morbidly obese pregnant women are 3.5x 
and 8.5x more likely to develop gestational diabetes, respectively6. Gestational diabetes 
mellitus is defined as glucose intolerance with onset or first recognition during 
pregnancy. In addition to the adverse risks of obesity during pregnancy, obese women 
who develop gestational diabetes are at an increased risk of adverse perinatal, maternal 
and neonatal outcomes, recurrence of gestational diabetes in subsequent pregnancies, 
and the development of type 2 diabetes postpartum8.  In addition, obese women, 
especially those who develop gestational diabetes, have larger offspring with greater 
adiposity; largely attributed to higher maternal glycemia9 and glucose intolerance10 
during pregnancy. High birth weight can increase the risk for cesarean delivery11 and 
shoulder dystocia12 and these high birth weight infants are at increased risk of 
developing obesity13-15 and diabetes13,14. Moreover, increased adiposity in infants is 
significant because similar to adults16,17 adiposity is likely a more sensitive and specific 
risk factor for future obesity, insulin resistance, and cardiovascular disease than weight. 
This notion is supported by the significant positive relationship between neonatal and 
childhood adiposity18 and the finding that body fat, not weight, was associated with 
cardiovascular disease risk factors later in life19,20. Together, these data indicate that 
obese women, with and without gestational diabetes, often give birth to infants who have 
high birth weight and adiposity that are at risk of developing adult obesity, diabetes, and 
cardiovascular disease21,22 and that these risks appear to be primarily mediated by 
impaired maternal glucose metabolism. 
 
Obese women also have a 2-3x greater risk of developing preeclampsia23.  A systematic 
review that included 1.4 million women revealed that the risk of preeclampsia doubles for 
every six unit increase in pre-pregnancy BMI24.  Preeclampsia, the most common 
hypertensive disorder during pregnancy, can be life-threatening for both pregnant 
women and their fetuses with 10-15% of all maternal deaths related to preeclampsia and 
eclampsia25. Altered vascular function, caused by inflammatory, metabolic and 
thrombotic responses, characterizes preeclampsia26.  Maternal preeclampsia may lead 
to premature cardiovascular disease, chronic hypertension, ischemic heart disease, and 

 
 
 
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stroke27. In addition, offspring of women who had preeclampsia during their pregnancy 
have an increased risk of stroke, heart disease, and metabolic syndrome in 
adulthood28,29.  Currently, there are no effective treatments for preeclampsia except the 
delivery of the fetus and placenta. 
 
In non-gravid obese adolescents and adults, moderate-to-high intensity rehabilitative 
exercise improves metabolic and cardiovascular health30-32. Specifically, aerobic33-36 and 
resistance37 exercise training independently improves glucose tolerance and insulin 
sensitivity in obese adults where combination aerobic and resistance exercise training 
appears to have the greatest benefit on insulin sensitivity38.  In addition, previous studies 
in non-gravid normal weight adults have shown that both resistance and aerobic 
exercise training reduces systolic and diastolic blood pressure39 and aerobic exercise 
training improves blood pressure34,40 and plasma markers of vascular function36 in 
overweight/obese non-gravid adults. However, during obese pregnancy, little is known 
regarding the effects of acute and chronic rehabilitative exercise training on glucose 
tolerance and vascular function and nothing is known regarding potential differences 
between modes (i.e. aerobic vs. resistance) of exercise.  
 
Recent guidelines from the American College of Obstetricians and Gynecologists 
(ACOG) recommends all women with uncomplicated pregnancies engage in aerobic and 
resistance exercise throughout their pregnancy41.  These recommendations are based 
off of studies that have demonstrated that moderate exercise training during pregnancy 
is safe and effective in improving several maternal and neonatal outcomes in normal 
weight, overweight, and obese populations41,42. In particular, observational studies 
suggest that exercise in pregnancy in normal weight women reduces the risk of 
gestational diabetes43 and the risk of preeclampsia and other hypertensive disorders44,45. 
These findings might extend to overweight and obese pregnant  women as physical 
activity during pregnancy appears to attenuate the increase in blood pressure and the 
loss of parasympathetic tone associated with  obese pregnancy46. In addition, higher 
maternal physical activity during obese pregnancy improves plasma markers of insulin 
resistance47,48 and systemic inflammation compared to their inactive obese 
counterparts49.  Despite the observed preliminary benefits of rehabilitative exercise 
during pregnancy in obese women, several questions remain. These include: 1) “What 
are the acute and chronic effects of maternal exercise on glucose metabolism and 
vascular function during pregnancy?”, 2) “Are there different effects of aerobic and 
resistance type exercise on glucose metabolism and vascular function?”, and 3) “What 
are the physiologic and molecular transducers of maternal exercise for changes in 
maternal glucose metabolism and vascular function during pregnancy?” This pilot project 
aims to collect preliminary data on these questions. In the planned subsequent clinical 
trial(s), we hope to answer the following additional questions: Are physiologic and 
molecular responses to AE/RE similar or different between a) gravid and non-gravid 
women, b) lean and overweight/obese women, and c) different stages of pregnancy? 
Data from this pilot trial will be used to begin a line of research inquiry aimed to elucidate 
the optimal mode, intensity, duration (i.e. dose), and timing (i.e. stage of pregnancy) as 
well as the molecular transducers of rehabilitative exercise training in overweight and 
obese pregnancy. These data are crucial for an optimal, individualized, and precise 
exercise prescription in overweight/obese women for the treatment and prevention of 
maternal and offspring metabolic and cardiovascular disease.        

 
 
 
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B2 Rationale for this Study 
This proposal would be the first study aimed to collect preliminary data on the 
independent effects of aerobic and resistance rehabilitative exercise in pregnancy, and 
further, in obese women; a population with high morbidity during gestation. In addition, 
this proposal would inform a large, multisite clinical trial examining the acute and chronic 
effects of aerobic and resistance exercise on glucose metabolism and vascular function 
in obese women during pregnancy.  Moreover, this proposal would provide initial 
evidence of molecular transducers of acute physical activity/rehabilitative exercise 
necessary for a large, comprehensive clinical trial examining molecular transducers of 
rehabilitative exercise in normal weight, overweight and obese women during all stages 
of pregnancy. Physiologic and molecular mediators of physical activity is an area of high 
clinical and scientific importance, evidenced by a dedicated $170 million NIH funding for 
the creation of a comprehensive map of the molecular signals that transmit the health 
effects of physical activity in healthy, non-gravid humans (MoTrPAC trial, 
https://www.motrpac.org/). Our pilot proposal and subsequent planned clinical trial study 
design aims to mirror the MoTrPAC trial study design, thereby exponentially increasing 
the impact of the resulting data through the comparison of the physiologic and molecular 
effects of aerobic and resistance exercise in gravid and non-gravid humans. Ultimately, 
these pilot data would set the stage for a multisite clinical trial examining the maternal 
and offspring physiologic effects of and molecular transducers for rehabilitative aerobic 
and resistance exercise training in overweight and obese women during pregnancy.  
 
 
C Study Objectives 
C1 Primary Aims 
• 
To characterize the acute effects of aerobic and resistance exercise on glucose 
metabolism (tolerance, insulin sensitivity and β-cell function) in obese women 
during mid-pregnancy.   
• 
To characterize the acute effects of aerobic and resistance exercise on vascular 
function in obese women during mid-pregnancy. 
C2 Secondary Aim 
• 
To explore the molecular transducers of physiologic responses in glucose 
metabolism and vascular function following acute aerobic and resistance 
exercise in obese women during mid-pregnancy. 
C3 Rationale for the Selection of Outcome Measures 
The primary outcome variables for this pilot trial are the Matsuda Whole-Body 
Composite Insulin Sensitivity Index (ISI) following an oral glucose tolerance test (OGTT), 
and the digital pulse volume response to arterial occlusion (blood pressure cuff) 
measured by reactive hyperemia peripheral tonometry (EndoPAT 2000, Itamar Medical, 
Caesarea, Israel). ISI= 10 000/√ (glucosefasting × insulinfasting) (glucosemean × insulinmean) is 
strongly associated with the glucose-clamp procedure which is considered the gold 
standard for measuring insulin sensitivity50,51. The EndoPAT 2000 has good 
reproducibility (ICC=0.74) and has been validated as a measure of endothelial function 

 
 
 
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with an 82% sensitivity and 77% specificity to diagnose coronary endothelial 
dysfunction52. 
 
C4 Confirmation of Patient Eligibility 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, BMI and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
C5 Assignment of UPN 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
Study Design  
C6 Overview or Design Summary 
The overall study design is a quasi-randomized, observational, 3-condition comparison 
of the acute effects of rest, resistance exercise or aerobic exercise on glucose 
metabolism and vascular function in obese women (n=15) during mid pregnancy. 
C7 Subject Selection and Withdrawal  
7.a 
Inclusion Criteria  
1. 
First trimester BMI ≥ 30.0 and <45.0 kg/m2 (calculated from clinical weight and height) 
2. 
Singleton gestation, between 23 weeks and 0/7 days and 28 weeks and 0/7 days 
3. 
Normal fetal anatomy (no major structural abnormalities identified on standard of care survey 
before enrollment) 
4. 
Established prenatal care at Women’s Health Clinic before 18 weeks of gestation, plans to deliver 
at Barnes-Jewish Hospital 
5. 
Permision from Obstetrics physician provider to participate in study. 
7.b 
Exclusion Criteria  
 
 
1. 
Gestational  or pre-gestational diabetes diagnosis 
2. 
Inability to provide voluntary consent 
3. 
Currently using illegal drugs (e.g., cocaine, methamphetamine, opiates) (safety risk and potential 
confounding) 
4. 
Current smoker who does not agree to stop (confounding)  
5. 
Participation in routine (>1x/week) exercise program (may improve glucose metabolism/vascular 
function)  
6. 
History of heart disease, orthopedic, metabolic or neurological condition that would contraindicate 
exercise (safety risk) 

 
 
 
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Inclusion of Women and Minorities 
  
Women and members of all races and ethnic groups are eligible for this trial.  Men are 
not eligible. 
7.c 
Subject Recruitment Plans and Consent Process 
Participants will be recruited from the Center of Women’s Health at Washington 
University School of Medicine/Barnes Jewish Hospital. All obese (BMI ≥ 30) patients with 
on-going pregnancies will be approached for study participation at the first visit in the the 
trained clinical research coordinator. Patients will be approached through direct personal 
recruitment through the clinic and consented.  
7.d 
Early Withdrawal of Subjects  
Research participation will occur on three separate visits. Participants will be withdrawn 
if they are unable to complete the procedures during any of the research visits.  
7.e 
Data Collection and Follow-up for Withdrawn Subjects  
There will be no follow up of withdrawn participants.  
D Study Procedures  
D1 Screening for Eligibility 
Pregnant women with obesity:  Eligibility criteria of patients attending the Center of 
Women’s Health at Washington University School of Medicine/Barnes Jewish Hospital 
will be reviewed by Dr. Cahill and by the research coordinator.  
D2 Visit 1  
These procedures will be performed on over 3 visits separated by ≥ 4 days. Participants 
will be studied within gestation weeks 23-30.  The evening before the study visits, 
participants will consume a standardized meal consisting of 55% carbohydrate, 30% fat, 
and 15% protein provided by the WUSM Bio-Nutrition Facility. The following morning, 
fasted participants (10 hrs) will be admitted to the Clinical Translational Research Unit of 
the Institute of Clinical and Translational Sciences at Washington University School of 
Medicine (WUSM CTRU) at 8:00 am. Maternal weight (calibrated scale) and height 
(stadiometer) will be measured.  
 
Body Composition Measurement: Whole-body fat will be quantified using through 
skin-fold anthropometry (Harpenden, West Sussex, UK).   
 
Assessment of Laboratory Clinical Variables:  Venous blood will be collected from 
the participants to assess 1) CBC, 2) HbA1C, 3) complete metabolic panel, and blood 
hormone/metabolites including plasma glucose, insulin, c-peptide, free fatty acid, 
placental growth factor and vascular endothelial growth factor (VEGF).  
 
The participant will quietly lie in bed for 45 minutes. 
 
 

 
 
 
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Immediately following the 45-minute rest period: 
 
Assessment of Laboratory Clinical Variables:  Venous blood will be collected from 
the participants to assess 1) CBC, 2) HbA1C, 3) complete metabolic panel, and blood 
hormone/metabolites including plasma glucose, insulin, c-peptide, free fatty acid, 
placental growth factor and vascular endothelial growth factor (VEGF). 
 
Assessment of Vascular Function 
Endothelial Function: Reactive hyperemia peripheral tonometry (RHPT, 
EndoPAT2000, Itamar Medical, Caesarea, Israel) will be measured before, and 
immediately post-exercise to assess digital pulse volume responses to arterial occlusion 
(blood pressure cuff). Briefly, the participant is placed in a sitting position and two 
disposable, inflatable probes are placed on the index fingers. Following 10 min of 
baseline signal recording, a blood pressure cuff is inflated for 3-min and following 
release, the hyperemic response is recorded for 5-min. The EndoPAT 2000 has good 
reproducibility (ICC=0.74) and has been validated as a measure of endothelial function 
with an 82% sensitivity and 77% specificity to diagnose coronary endothelial 
dysfunction52.  
 
Large Artery Function:  Central aortic blood pressure and pressure waveforms. Pressure 
waves will be recorded sequentially from different sites, and transit time calculated using 
registration with a simultaneously recorded ECG by use of the SphygmoCor™ system 
(AtCor, Sydney, Australia), which has been well-validated and is approved by the FDA for 
the noninvasive assessment of central blood pressures and central aortic compliance by 
measurement of pulse wave velocity (PWV) and augmentation index (AIx). In this system, 
a single high-fidelity applanation tonometer (Millar) is used to obtain a proximal (i.e. carotid 
artery) and distal pulse (i.e. radial or femoral) recorded sequentially a short time apart; 
from this, the PWV is calculated from the transit time between the two arterial sites, 
determined in relation to the R-wave of the ECG. The time between the ECG and the 
proximal pulse is subtracted from the time between ECG and distal pulse to obtain the 
pulse transit time. In the case of stiff arteries, PWV rises and the reflected wave arrives 
back at the central arteries earlier, adding to the forward wave and augmenting the systolic 
pressure. This phenomenon can be quantified through the augmentation index (AIx), 
which is defined as the difference between the second and first systolic peaks (P2-P1) 
expressed as a percentage of the pulse pressure 
 
Central hemodynamics and aortic compliance will be characterized using the 
SphygmoCor™ system. Pressure waves will be recorded sequentially from different sites 
using the SphygmoCor™ system (AtCor) using methods described by our group.53 
Derived indices include the central blood pressures and central aortic compliance 
characterized as the augmentation index (AIx) and pulse-wave velocity (PWV).  
 
At 60-minutes following the end of the rest period: 
 
Assessment of Glucose Metabolism 
Two-hour oral glucose tolerance test (OGTT):  At 60-min following the end of the rest 
period, a 2-hr oral OGTT will be conducted.  Venous samples for glucose, insulin, and C-
peptide will be drawn at time 0 and then 30, 60, 90 and 120 minutes after starting 

 
 
 
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ingestion of glucola (1.75 g/kg of body weight to a maximum of 75 g). Insulin sensitivity 
and insulin secretion will be estimated by the Matsuda Whole-Body Composite Insulin 
Sensitivity Index (ISI), HOMA-IR, Insulinogenic Index and C-peptide Index. ISI= 10 000/√ 
(glucosefasting × insulinfasting) (glucosemean × insulinmean), HOMA-IR (Insulint0’ mU/L×Glucoset0’ 
mmol/L) /22.5), Insulinogenic Index (∆I30/∆G30) and C-peptide index (∆C-peptide30/∆G30) will 
be calculated as previously described54-56. Area under the curve for glucose, C-peptide 
and insulin levels will also be calculated by trapezoidal integration over the entire OGTT 
for glucose tolerance assessment.  
Lunch will be provided. 
 
At 30-minutes following lunch: 
 
Peak Exercise Testing (VO2peak)  
Participants will perform a graded exercise test on a recumbent cycle ergometer located 
on the WUSM CTRU. Continuous ECG/BP and oxygen consumption (VO2) will be 
recorded during the graded exercise test to determine peak exercise capacity (VO2peak). 
The graded exercise test protocol consists of 1-min incremental stages, beginning with a 
20-watt workload, progressing every minute by 10-20-watts until volitional exhaustion or 
symptom limitation. Exercise tests will be considered maximal if peak heart rate ≥ 85% 
predicted maximum (220-age) and/or respiratory exchange ratio ≥ 1.1 according to the 
American College of Sports Medicine57. Peak exercise testing will be supervised by a 
licensed physical therapist and the CTRU nursing staff. 
 
Ten-Repetition Maximum Strength testing (10RM) 
10RM will be determined on 4-upper body and 4-lower body exercises on Universal 
exercise machines (Body Master®) located on the WUSM CTRU. 10-RM is the 
maximum amount of weight a participant can lift 10 times using proper form and only 
primary muscle groups required for the lifting motion. 10RM will be determined on each 
exercise device by trial and error.  
 
 
D3 Visit 2 
 
The evening before the study visit #2, participants will consume a standardized meal 
consisting of 55% carbohydrate, 30% fat, and 15% protein provided by the WUSM Bio-
Nutrition Facility. The following morning, fasted participants (10 hrs) will be admitted to 
the WUSM CTRU) at 7:00 am. Maternal weight (calibrated scale) and height 
(stadiometer) will be measured. 
 
Acute Aerobic Exercise or Resistance Exercise Session 
Visit # 2 will consist of either: A) a 45-minute aerobic exercise (AE) session on a 
recumbent cycle ergometer at 70% VO2peak, or B): a 45-minute resistance exercise (RE) 
session.  The RE session will consist of 3 sets of 8-10 repetitions at their 10RM load 
according to the Adult NIH Molecular Transducers of Physical Activity in Humans 
(MoTrPAC) Study Protocol: https://www.motrpac.org/protocols.cfm. The acute RE 
session will be individualized, based on the measurements taken from a 10RM 
(measured without Valsalva maneuver) tests during Visit #1 for 1) knee extension, 2) 
knee flexion, 3) leg press (i.e. hip and knee extension), 4) ankle plantar flexion, 5) chest 
press, 6) seated row, 7) bicep curl (elbow flexion), and 8) overhead press. For each 
exercise, 3 sets of 8-10 repetitions will be performed with a 2-minute rest in between 

 
 
 
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sets. A 3-second contraction duration for the concentric and a 3-second contraction 
duration for the eccentric phase of the lift will be targeted. Fasting blood samples will be 
taken at pre-AE/RE/rest, at 20-min during AE/RE, immediately post-AE/RE/rest, and 60-
min post AE/RE/rest as per MoTrPAC protocol. All visits with be separated by 1 week 
and rest, AE and RE visit order will be randomized through a computerized 
randomization program. The study scheme is presented in the Figure. 
 
 
Assessment of Glucose Metabolism 
At 60-min following the completion of AE/RE, a 2-hr oral OGTT will be conducted as 
described in Visit 1.   
 
Assessment of Vascular Function 
Endothelial and large artery function testing will be performed as described in Visit 1.   
 
 
D3 Visit 3 
 
The evening before the study visit #3, participants will consume a standardized meal 
consisting of 55% carbohydrate, 30% fat, and 15% protein provided by the WUSM Bio-
Nutrition Facility. The following morning, fasted participants (10 hrs) will be admitted to 
the WUSM CTRU at 7:00 am. Maternal weight (calibrated scale) and height 
(stadiometer) will be measured. 
 
Acute Aerobic Exercise or Resistance Exercise Session 
Visit # 3 will consist of either: A) a 40-minute aerobic exercise (AE) session on a 
recumbent cycle ergometer at 70% VO2peak, or B): a 40-minute resistance exercise (RE) 
session as decribed above.   
 
Assessment of Glucose Metabolism 
At 60-min following the completion of AE/RE, a 2-hr oral OGTT will be conducted as 
described in Visit 1.   
 
Assessment of Vascular Function 
Endothelial and large artery function testing will be performed as described in Visit 1.  
 
Plasma Hormone and Metabolites 
Before, during and immediately following the rest, AE and RE sessions and during the 
OGTT, maternal blood will be collected for analyses of plasma glucose insulin, C-
peptide, free fatty acid, vascular endothelial growth factor (VEGF), and placental growth 
factor. Additional blood will be collected for future exploratory analyses (e.g. 
metabolomic, proteomic, transcriptomic). Plasma glucose will be analyzed by an YSI 
glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH) located on the 
WUSM CTRU. Plasma hormone and analyte analyses will be performed by the 
University of Alabama at Birmingham (UAB) Diabetes Research Center Human 
Physiology Core Laboratory (see letter of support from Dr. Barbara Gower, Director of 
Core Laboratory).  
 
MicroRNA Expression 

 
 
 
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Before, immediately following, and 60-minutes following the rest, AE and RE sessions, 
maternal blood (6 ml) will be collected for analyses of microRNA (miRNA) expression of 
peripheral blood mononuclear cells. MicroRNAs are small noncoding ~19–24 nucleotide- 
(nt-) long RNA molecules that play an important role in the modulation of gene 
expression. Analysis will be performed using a Affymetrix Gene Chip and will be 
peformed by the Washington University Gene Technology Access Center.  
 
E Safety and Adverse Events  
The entities providing oversight of safety and compliance with the protocol require 
reporting as outlined below. 
 
The Washington University Human Research Protection Office (HRPO requires all 
events meeting the definition of unanticipated problem or serious noncompliance be 
reported as outlined in Section G2. 
E1 Definitions 
1.a 
Adverse Events 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. For purposes of this research project, AEs 
associated with peak exercise testing, 1-repetition maximum testing, aerobic or 
resistance exercise sessions, blood draw/OGTT, and vascular function testing will be 
tracked.  
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health and 
Human Services’ Office for Human Research Protections (OHRP).  A copy of this 
guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 

 
 
 
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1.b 
Serious Adverse Event (SAE) 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above 
1.c 
Unexpected Adverse Experience 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
1.d 
Life-Threatening Adverse Experience  
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death. 
1.e 
Unanticipated Problems 
Definition: 
 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
1.f 
Noncompliance 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, or determinations of the IRB. 
1.g 
Serious Noncompliance 
Definition: noncompliance that materially increases risks, that results in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 

 
 
 
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1.h 
Protocol Exceptions 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
E2 Reporting to the Human Research Protection Office (HRPO) 
at Washington University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• 
Any unanticipated problems involving risks to participants or others which occur at 
WU, any BJH or SLCH institution, or that impacts participants or the conduct of the 
study. 
• 
Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• 
Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
E3 Timeframe for Reporting Required Events 
Adverse events will be tracked for 24 hours after date of participation.  The event need 
not be causally related to 31P-MRS, blood draw, and echocardiogram to qualify as an 
adverse event to be collected. 
 
 

 
 
 
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F Statistical Plan  
F1  Sample Size Determination and Power 
The primary objective of this pilot grant is to obtain preliminary data necessary for proof-
of-concept and for sample size estimation for a large, multisite clinical trial. However, we 
anticipate having enough power to demonstrate independent acute effects of AE and RE 
on glucose metabolism and vascular function necessary for potential publication of these 
pilot data. Using data from non-gravid adults with obesity, Newsom et al.58 demonstrated 
an increase in next day insulin sensitivity following a low-intensity AE session. Rynders 
et al.59 found lower 2-hr OGTT glucose value following acute AE in prediabetic non-
gravid adults. Further, Breen et al.60 demonstrated a 17% improvement in glucose AUC 
following acute RE in normoglycemic non-gravid adults. Using these data, a sample size 
of n=14 would be adequate to see a statistical difference with either acute AE or RE on 
glucose metabolism. For vascular function, Haynes et al.61 demonstrated increased (~4-
12%) reactive hyperemic responses following acute RE and AE in older men.  Also, 
Kingsley and Figueroa62 found increased reactive hyperemic responses following acute 
RE in 24 obese older women. These data suggest that a sample size of n=11 will be 
necessary to see statistically significant differences in vascular function pre/post acute 
AE or RE, assuming similar responses.   
F2  Statistical Methods  
We plan to assess differences in glucose metabolism and vascular function between the 
three different conditions (i.e. acute, AE, RE) using a repeated measures ANOVA with 
post-hoc testing. We anticipate detecting differences between AE/RE and rest but likely 
will not have the power to detect potential differences between AE and RE. The two 
primary outcomes will be the Matsuda ISI and endothelial hyperemic response (digital 
pulse volume). Other glucose metabolism and plasma analyte variables will be secondary 
outcomes.    
  

 
 
 
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G Study Monitoring, Auditing, and Inspecting  
During monthly group meetings, the research team (Dr.’s Cade, Cahill) and the research 
coordinator will monitor and review: (a) Recruitment, screening and enrollment progress, 
goals and strategies; (b) Preliminary findings that might affect the risk/benefit ratio or 
alter the procedures described in the protocol; (c) Any out of range laboratory value and 
a course of action; (d) Any adverse or serious adverse events that might result from the 
research procedures. In monthly meetings, Drs. Cade and Cahill will monitor and review: 
(a) research-related risks that might alter the risk/benefit ratio, (b) any laboratory or 
blood pressure findings that are out of range and require follow-up with the participant, 
(c) any new information/findings about obese pregnancy that might facilitate this study, 
reduce risk or the burden of testing for participants.  All serious adverse events will be 
reported to the WUSM Human Research Protection Office (HRPO), NIH and the 
Research Subject Advocate on the WUSM Clinical Research Unit (CRU) within 15 days 
of the event. There are standard reporting forms for the WUSM CRU and the HRPO. 
Should there be a serious adverse event that increases the risks to participants, the 
study will be stopped, an investigation conducted, and findings generated before the 
study is resumed. These findings are shared with the HRPO, NIH and the Research 
Subject Advocate. If necessary, the research procedures are modified and appropriate 
revisions to the consent document and consent procedures are made. Each individual 
adverse event is reported to the WUSM HRPO which has the option of stopping or 
discontinuing this project if they deem that the risk/benefit ratio becomes too high. The 
HRPO may rule to continue the study once the research procedures are modified and 
appropriate revisions to the consent document and consent procedures are made. This 
Data Safety Monitor Committee plan is in compliance with and will be approved by The 
Research Advisory Committee of the CRU.  
 
 

 
 
 
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H Study Administration 
H1 Organization and Participating Centers 
Washington University is the only participating site. 
H2 Funding Source and Conflicts of Interest 
Departmental funding.  No conflicts of interest. 
H3 Subject Stipends or Payments  
Participants will receive a total of $150 for completion of the study. 
 
 

 
 
 
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I References 
 
 
1. 
Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in 
the distribution of body mass index among US adults, 1999-2010. Jama. Feb 1 
2012;307(5):491-497. 
2. 
Yogev Y, Catalano PM. Pregnancy and obesity. Obstetrics and gynecology 
clinics of North America. Jun 2009;36(2):285-300, viii. 
3. 
Doherty DA, Magann EF, Francis J, Morrison JC, Newnham JP. Pre-pregnancy 
body mass index and pregnancy outcomes. International journal of gynaecology 
and obstetrics: the official organ of the International Federation of Gynaecology 
and Obstetrics. Dec 2006;95(3):242-247. 
4. 
Barker DJ. The developmental origins of chronic adult disease. Acta paediatrica. 
Dec 2004;93(446):26-33. 
5. 
Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal obesity and fetal 
metabolic programming: a fertile epigenetic soil. American journal of physiology. 
Regulatory, integrative and comparative physiology. Sep 2010;299(3):R711-722. 
6. 
Chu SY, Callaghan WM, Kim SY, et al. Maternal obesity and risk of gestational 
diabetes mellitus. Diabetes care. Aug 2007;30(8):2070-2076. 
7. 
O'Reilly JR, Reynolds RM. The risk of maternal obesity to the long-term health of 
the offspring. Clinical endocrinology. Jan 2013;78(1):9-16. 
8. 
Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after 
gestational diabetes: a systematic review and meta-analysis. Lancet. May 23 
2009;373(9677):1773-1779. 
9. 
Kerenyi Z, Tamas G, Kivimaki M, et al. Maternal glycemia and risk of large-for-
gestational-age babies in a population-based screening. Diabetes care. Dec 
2009;32(12):2200-2205. 
10. 
Carlsen EM, Renault KM, Norgaard K, et al. Glucose tolerance in obese 
pregnant women determines newborn fat mass. Acta obstetricia et gynecologica 
Scandinavica. Apr 2016;95(4):429-435. 
11. 
Scifres CM, Feghali M, Dumont T, et al. Large-for-Gestational-Age Ultrasound 
Diagnosis and Risk for Cesarean Delivery in Women With Gestational Diabetes 
Mellitus. Obstetrics and gynecology. Nov 2015;126(5):978-986. 
12. 
Malinowska-Polubiec A, Romejko-Wolniewicz E, Szostak O, et al. Shoulder 
dystocia in diabetic and non-diabetic pregnancies. Neuro endocrinology letters. 
2014;35(8):733-740. 
13. 
Pettitt DJ, Nelson RG, Saad MF, Bennett PH, Knowler WC. Diabetes and obesity 
in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes 
care. Jan 1993;16(1):310-314. 
14. 
Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes 
conveys risks for type 2 diabetes and obesity: a study of discordant sibships. 
Diabetes. Dec 2000;49(12):2208-2211. 
15. 
Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes 
mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in 
a prospective cohort of 280,866 men from 248,293 families. Circulation. Jan 25 
2011;123(3):258-265. 
16. 
Thibault R, Genton L, Pichard C. Body composition: why, when and for who? 
Clinical nutrition. Aug 2012;31(4):435-447. 
17. 
Shea JL, King MT, Yi Y, Gulliver W, Sun G. Body fat percentage is associated 
with cardiometabolic dysregulation in BMI-defined normal weight subjects. 

 
 
 
______________________________________________________________________________________ 
Version 06/23/2018 
20
Nutrition, metabolism, and cardiovascular diseases : NMCD. Sep 
2012;22(9):741-747. 
18. 
Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for childhood 
obesity and metabolic dysregulation. The American journal of clinical nutrition. 
Nov 2009;90(5):1303-1313. 
19. 
Jansen MA, Uiterwaal CS, Visseren FL, van der Ent CK, Grobbee DE, Dalmeijer 
GW. Abdominal fat and blood pressure in healthy young children. Journal of 
hypertension. Sep 2016;34(9):1796-1803. 
20. 
Ma J, Wang Z, Dong B, Song Y, Hu P, Zhang B. Body fat and blood pressure: 
comparison of blood pressure measurements in Chinese children with different 
body fat levels. The British journal of nutrition. Nov 14 2012;108(9):1672-1677. 
21. 
Cnattingius S, Villamor E, Lagerros YT, Wikstrom AK, Granath F. High birth 
weight and obesity--a vicious circle across generations. International journal of 
obesity. Oct 2012;36(10):1320-1324. 
22. 
Ogonowski J, Miazgowski T, Engel K, Celewicz Z. Birth weight predicts the risk 
of gestational diabetes mellitus and pregravid obesity. Nutrition. Jan 
2014;30(1):39-43. 
23. 
Bodnar LM, Ness RB, Markovic N, Roberts JM. The risk of preeclampsia rises 
with increasing prepregnancy body mass index. Annals of epidemiology. Aug 
2005;15(7):475-482. 
24. 
O'Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of 
preeclampsia: a systematic overview. Epidemiology. May 2003;14(3):368-374. 
25. 
Duley L. The global impact of pre-eclampsia and eclampsia. Seminars in 
perinatology. Jun 2009;33(3):130-137. 
26. 
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. 
Lancet. Aug 21 2010;376(9741):631-644. 
27. 
Jeyabalan A. Epidemiology of preeclampsia: impact of obesity. Nutrition reviews. 
Oct 2013;71 Suppl 1:S18-25. 
28. 
Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth and 
coronary heart disease in later life: longitudinal study. Bmj. Apr 21 
2001;322(7292):949-953. 
29. 
Osmond C, Kajantie E, Forsen TJ, Eriksson JG, Barker DJ. Infant growth and 
stroke in adult life: the Helsinki birth cohort study. Stroke. Feb 2007;38(2):264-
270. 
30. 
Strasser B, Siebert U, Schobersberger W. Resistance training in the treatment of 
the metabolic syndrome: a systematic review and meta-analysis of the effect of 
resistance training on metabolic clustering in patients with abnormal glucose 
metabolism. Sports medicine. May 1 2010;40(5):397-415. 
31. 
Pattyn N, Cornelissen VA, Eshghi SR, Vanhees L. The effect of exercise on the 
cardiovascular risk factors constituting the metabolic syndrome: a meta-analysis 
of controlled trials. Sports medicine. Feb 2013;43(2):121-133. 
32. 
Ho SS, Radavelli-Bagatini S, Dhaliwal SS, Hills AP, Pal S. Resistance, aerobic, 
and combination training on vascular function in overweight and obese adults. 
Journal of clinical hypertension. Dec 2012;14(12):848-854. 
33. 
Ross R, Hudson R, Stotz PJ, Lam M. Effects of exercise amount and intensity on 
abdominal obesity and glucose tolerance in obese adults: a randomized trial. 
Annals of internal medicine. Mar 3 2015;162(5):325-334. 
34. 
Chung J, Kim K, Hong J, Kong HJ. Effects of prolonged exercise versus multiple 
short exercise sessions on risk for metabolic syndrome and the atherogenic 
index in middle-aged obese women: a randomised controlled trial. BMC women's 
health. Aug 22 2017;17(1):65. 

 
 
 
______________________________________________________________________________________ 
Version 06/23/2018 
21
35. 
Kim YS, Nam JS, Yeo DW, Kim KR, Suh SH, Ahn CW. The effects of aerobic 
exercise training on serum osteocalcin, adipocytokines and insulin resistance on 
obese young males. Clinical endocrinology. May 2015;82(5):686-694. 
36. 
Ryan AS, Ge S, Blumenthal JB, Serra MC, Prior SJ, Goldberg AP. Aerobic 
exercise and weight loss reduce vascular markers of inflammation and improve 
insulin sensitivity in obese women. Journal of the American Geriatrics Society. 
Apr 2014;62(4):607-614. 
37. 
Croymans DM, Paparisto E, Lee MM, et al. Resistance training improves indices 
of muscle insulin sensitivity and beta-cell function in overweight/obese, sedentary 
young men. Journal of applied physiology. Nov 1 2013;115(9):1245-1253. 
38. 
AbouAssi H, Slentz CA, Mikus CR, et al. The effects of aerobic, resistance, and 
combination training on insulin sensitivity and secretion in overweight adults from 
STRRIDE AT/RT: a randomized trial. Journal of applied physiology. Jun 15 
2015;118(12):1474-1482. 
39. 
Cornelissen VA, Smart NA. Exercise training for blood pressure: a systematic 
review and meta-analysis. Journal of the American Heart Association. Feb 1 
2013;2(1):e004473. 
40. 
Yoshikawa T, Kumagai H, Myoenzono K, Tsujimoto T, Tanaka K, Maeda S. 
Aerobic exercise training normalizes central blood pressure regulation after oral 
glucose loading in overweight/obese men. Clinical and experimental 
hypertension. Feb 27 2018:1-8. 
41. 
ACOG Committee Opinion No. 650: Physical Activity and Exercise During 
Pregnancy and the Postpartum Period. Obstetrics and gynecology. Dec 
2015;126(6):e135-142. 
42. 
Sui Z, Dodd JM. Exercise in obese pregnant women: positive impacts and 
current perceptions. International journal of women's health. 2013;5:389-398. 
43. 
Tobias DK, Hu FB, Forman JP, Chavarro J, Zhang C. Increased risk of 
hypertension after gestational diabetes mellitus: findings from a large prospective 
cohort study. Diabetes care. Jul 2011;34(7):1582-1584. 
44. 
Meher S, Duley L. Exercise or other physical activity for preventing pre-
eclampsia and its complications. The Cochrane database of systematic reviews. 
Apr 19 2006(2):CD005942. 
45. 
Magro-Malosso ER, Saccone G, Di Tommaso M, Roman A, Berghella V. 
Exercise during pregnancy and risk of gestational hypertensive disorders: a 
systematic review and meta-analysis. Acta obstetricia et gynecologica 
Scandinavica. Aug 2017;96(8):921-931. 
46. 
Stutzman SS, Brown CA, Hains SM, et al. The effects of exercise conditioning in 
normal and overweight pregnant women on blood pressure and heart rate 
variability. Biological research for nursing. Oct 2010;12(2):137-148. 
47. 
van Poppel MN, Oostdam N, Eekhoff ME, Wouters MG, van Mechelen W, 
Catalano PM. Longitudinal relationship of physical activity with insulin sensitivity 
in overweight and obese pregnant women. The Journal of clinical endocrinology 
and metabolism. Jul 2013;98(7):2929-2935. 
48. 
Vinter CA, Jorgensen JS, Ovesen P, Beck-Nielsen H, Skytthe A, Jensen DM. 
Metabolic effects of lifestyle intervention in obese pregnant women. Results from 
the randomized controlled trial 'Lifestyle in Pregnancy' (LiP). Diabetic medicine : 
a journal of the British Diabetic Association. Nov 2014;31(11):1323-1330. 
49. 
Tinius RA, Cahill AG, Cade WT. Low-intensity Physical Activity is Associated with 
Lower Maternal Systemic Inflammation during Late Pregnancy. Journal of obesity 
& weight loss therapy. Jun 2017;7(3). 

 
 
 
______________________________________________________________________________________ 
Version 06/23/2018 
22
50. 
Shen SW, Reaven GM, Farquhar JW. Comparison of impedance to insulin-
mediated glucose uptake in normal subjects and in subjects with latent diabetes. 
The Journal of clinical investigation. Dec 1970;49(12):2151-2160. 
51. 
DeFronzo RA, Beckles AD. Glucose intolerance following chronic metabolic 
acidosis in man. The American journal of physiology. Apr 1979;236(4):E328-334. 
52. 
Bonetti PO, Pumper GM, Higano ST, Holmes DR, Jr., Kuvin JT, Lerman A. 
Noninvasive identification of patients with early coronary atherosclerosis by 
assessment of digital reactive hyperemia. Journal of the American College of 
Cardiology. Dec 7 2004;44(11):2137-2141. 
53. 
Subherwal S, de las Fuentes L, Waggoner AD, Heuerman S, Spence KE, Davila-
Roman VG. Central aortic pressure is independently associated with diastolic 
function. Am. Heart J. Jun 2010;159(6):1081-1088. 
54. 
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 
Homeostasis model assessment: insulin resistance and beta-cell function from 
fasting plasma glucose and insulin concentrations in man. Diabetologia. Jul 
1985;28(7):412-419. 
55. 
Guerrero-Romero F, Rodriguez-Moran M. Glucose intolerance is predicted by the 
high Fasting Insulin-to-Glucose ratio. Diabetes & metabolism. Apr 2001;27(2 Pt 
1):117-121. 
56. 
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose 
tolerance testing: comparison with the euglycemic insulin clamp. Diabetes care. 
Sep 1999;22(9):1462-1470. 
57. 
American College oSM. ACSM’s guidelines for exercise testing and prescription 
6th ed. Baltimore: Lippincott, Williams & Wilkins; 2000. 
58. 
Newsom SA, Everett AC, Hinko A, Horowitz JF. A single session of low-intensity 
exercise is sufficient to enhance insulin sensitivity into the next day in obese 
adults. Diabetes care. Sep 2013;36(9):2516-2522. 
59. 
Rynders CA, Weltman JY, Jiang B, et al. Effects of exercise intensity on 
postprandial improvement in glucose disposal and insulin sensitivity in 
prediabetic adults. The Journal of clinical endocrinology and metabolism. Jan 
2014;99(1):220-228. 
60. 
Breen L, Philp A, Shaw CS, Jeukendrup AE, Baar K, Tipton KD. Beneficial 
effects of resistance exercise on glycemic control are not further improved by 
protein ingestion. PloS one. 2011;6(6):e20613. 
61. 
Haynes A, Linden MD, Robey E, et al. Acute Impact of Different Exercise 
Modalities on Arterial and Platelet Function. Medicine and science in sports and 
exercise. Apr 2018;50(4):785-791. 
62. 
Kingsley JD, Figueroa A. Effects of resistance exercise training on resting and 
post-exercise forearm blood flow and wave reflection in overweight and obese 
women. Journal of human hypertension. Nov 2012;26(11):684-690.