ARISTOTLE UNIVERSITY OF THESSALONIKI FACULTY OF HEALTH SCIENCES SCHOOL OF ...

57 Pages·2017·1.21 MB·English

ARISTOTLE UNIVERSITY OF THESSALONIKI
FACULTY OF HEALTH SCIENCES
SCHOOL OF MEDICINE

Oxygenation of the skeletal muscle and prefrontal lobe
during intermittent exercise in women with gestational diabetes
during and after pregnancy

A thesis submitted in fulfilment
of the requirements for the degree of
Master of Science in Medical Research Methodology
By

Elpida Vounzoulaki

Thessaloniki, December 2017
Oxygenation of the skeletal muscle and prefrontal lobe during intermittent
exercise in women with gestational diabetes during and after pregnancy

A MSc thesis submitted in fulfilment
of the requirements for the degree of
Master of Science in Medical Research Methodology

At
The Faculty of Health Sciences
School of Medicine
Aristotle University of Thessaloniki

By
Elpida Vounzoulaki

Thessaloniki, December 2017

Supervisor: Dimitrios G. Goulis

Word count: 8,170

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Members of examining committee:

Dimitrios G. Goulis
Associate professor, Medical School, Aristotle University of Thessaloniki

Konstantina Dipla
Assistant professor, School of Sports Science, Aristotle University of Thessaloniki

Stella Douma
Professor, Medical School, Aristotle University of Thessaloniki

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TABLE OF CONTENTS

PREFACE .............................................................................................................................................. 4
ABBREVIATIONS .................................................................................................................................. 5
GENERAL PART ....................................................................................................................................... 6
Chapter 1: Gestational Diabetes Mellitus – General Issues: Definitions, Diagnosis, Complications,
Treatment ........................................................................................................................................... 6
Chapter 2: Muscle and Cerebral Oxygenation during exercise: Studies during pregnancy and out of
it ........................................................................................................................................................ 13
Chapter 3: Short- and long-term effects of DM on endothelial function: Effect of GDM, T1DM and
T2DM ................................................................................................................................................. 15
SPECIAL PART ........................................................................................................................................ 18
Chapter 4: Rationale and Aim ........................................................................................................... 18
Chapter 5: Materials and Methods ................................................................................................... 19
Study type ..................................................................................................................................... 19
Clinical setting ............................................................................................................................... 19
Patient inclusion and exclusion criteria ........................................................................................ 19
Study protocol ............................................................................................................................... 19
Techniques - Instrumentation ....................................................................................................... 21
Study outcomes ............................................................................................................................ 23
Ethics ............................................................................................................................................. 23
Statistics ........................................................................................................................................ 23
Chapter 6: Results ............................................................................................................................. 25
Chapter 7: Discussion ........................................................................................................................ 40
Conclusions ....................................................................................................................................... 44
Abstract ............................................................................................................................................. 46
Acknowledgements ........................................................................................................................... 47
Reference list .................................................................................................................................... 48

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PREFACE

The present dissertation entitled “Oxygenation of the skeletal muscle and prefrontal lobe
during intermittent exercise in women with gestational diabetes during and after pregnancy”
has been conducted in the frames of the “Medical Research Methodology” Master of Science
(MSc) Programme of the Faculty of Medical School, Aristotle University of Thessaloniki,
Greece during the year 2017-2018.
Gestational diabetes mellitus (GDM) is a critical pregnancy complication with an increasing
worldwide prevalence over the last years, with a significant impact on endothelial function
that constitutes fertile ground for the development of cardiovascular disease. This
prospective observational cohort study aimed to estimate, for the first time, the in vivo
alterations in the oxygenation of the forearm skeletal muscle and the prefrontal lobe during
intermittent exercise in women diagnosed with GDM, during and after pregnancy.
Firstly, I would like to express my sincere gratitude to my supervisor Dr. Dimitrios G. Goulis
for the continuous support, for his patience, motivation and vast knowledge. Besides my
supervisor, I would like to thank the rest of the dissertation committee, Dr. Konstantina Dipla
and Dr. Stella Douma for their support, insightful comments, encouragement and valuable
assistance in the conduction of this dissertation.

Thessaloniki, December 2017

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ABBREVIATIONS

ACI Acceleration Index MRI Magnetic Resonance Imaging
BMI Body Mass Index MVC Maximal Voluntary Contraction
BR Brain NIRS Near infrared spectroscopy
CAD Coronary Artery Disease NO Nitric Oxide
CC Carpenter- Coustan OGTT Oral Glucose Tolerance Test
CHOL Cholesterol O Oxygen
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CIMT Carotid Intima-Media Thickness PAD Peripheral Arterial Disease
CO Cardiac Output PAT Pulse Amplitude Tonometry
DBP Diastolic Blood Pressure PEP Pre-ejection Period
DM Diabetes Mellitus PLT Platelets
EC Endothelial Cells PVD Peripheral Vascular Disease
FMD Flow-mediated dilatation RBC Red Blood Cells
GDM Gestational Diabetes Mellitus REO Rheocardiography
Hb Hemoglobin ROS Reactive Oxygen Species
HbO2 Oxygenated Hemoglobin RPE Rating of Perceived Exertion
HDL High- density Lipoprotein SBP Systolic Blood Pressure
HG Handgrip SGOT Serum Glutamic Oxaloacetic Transaminase
HHb Deoxygenated Hemoglobin SGPT Serum Glutamic Pyruvic Transaminase
HPD Heart Period Duration SI Stroke Index
HR Heart Rate SV Stroke Volume
Ht Hematocrit SVR/SVRI Stroke Volume Ration/ SVR Index
ICG Impedance Cardiography tHb Total Hemoglobin
IL Interleukin TFC/TFCI Thoracic Fluid Content/ TFC Index
IMT Intima-Media Thickness TNF Tumor Necrosis Factor
IQR Interquartile Range TSH Thyroid-stimulating Hormone
LCW/LCWI Left Cardiac Work/ LCW Index TSI Tissue Saturation Index
LDL Low-density Lipoprotein T1DM Type I Diabetes Mellitus
LVET Left-ventricular ejection T2DM Type II Diabetes Mellitus
MBP Mean Blood Pressure VI Velocity Index
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GENERAL PART

Chapter 1: Gestational Diabetes Mellitus – General Issues:
Definitions, Diagnosis, Complications, Treatment

Gestational Diabetes Mellitus (GDM) is a condition that is first diagnosed in the second or
third trimester of pregnancy, without any evidence of preexisting type 1 (T1DM) or type 2
diabetes (T2DM). (1) A variety of factors can contribute to the development of GDM, such as
obesity, weight gain throughout pregnancy, family history of diabetes mellitus (DM) and
previous history of GDM, older maternal age, fetal macrosomia, unexplained stillbirth and the
ethnicity of the woman in pregnancy. (2) The manifestation of GDM is reported in
approximately 7% of all pregnancies, with a prevalence ranging from 1 to 14%, based on the
population under investigation and the implemented diagnostic tests. (3)
The prevalence of the disease varies throughout the world with African American, Hispanic
American, Native American, Pacific Islander, and South or East Asian women being at higher
risk as compared to Caucasian women in the United States. (4)
Insulin is a hormone that possesses a crucial role in the development of normal tissue,
regulation of glucose homeostasis and metabolism of carbohydrates, lipids, and proteins. (5)
Pregnancy is usually accompanied by progressive insulin resistance, comparable to the insulin
resistance observed in patients with T2DM. However, the insulin resistance vanishes
immediately after delivery, indicating that the main reason behind this situation is placental
hormones. (6) The key hormones that are responsible for increased insulin resistance during
pregnancy are cortisol, leptin and Human Placental Lactogen (hPL). (7) Cortisol levels are
elevated while pregnancy advances; research has indicated that serum cortisol levels were
considerably lower in women with uncomplicated pregnancies as compared to those
diagnosed with GDM. (7) Leptin is a hormone produced by the adipose tissue that increases
during pregnancy. It has been established that serum leptin levels are increased in GDM-
complicated pregnancies as compared to uncomplicated ones and are highly correlated with
insulin resistance. (8) HPL, also known as human chorionic somatomammotropin (hCS), is a
hormone secreted by the placenta. (9) Several studies, that did not include pregnant
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participants though, have demonstrated that hPL is capable of causing peripheral insulin
resistance. (9)
It has been proved that adiponectin is responsible for the loss of insulin sensitivity, in both
GDM-complicated and uncomplicated pregnancies, as while pregnancy advances,
adiponectin levels are decreased.(10) It has been also identified that Tumor Necrosis Factor
(TNF) plays an important part in insulin resistance as elevated serum TNF-α, sTNFR-1, sTNFR-
2 and C-peptide levels were observed during the third trimester of both uncomplicated
pregnancies and those complicated by GDM. (11)
As for resistin, a hormone that has been reported to have a major role in insulin resistance
and the development of T2DM, results from systematic reviews could not ensure that there
is an association between circulating resistin levels and GDM. (12) Additionally, increased
interleukin 6 (IL-6) levels are related with GDM, independent of obesity levels both in
pregnancy and following labor. (13) Apart from IL-6, the plasma levels of interleukin 1
Receptor Antagonist (IL- 1Ra) have been estimated to be lower in GDM patients as compared
to healthy pregnant controls. (14) Therefore, since GDM women present lower levels of IL-
1Ra that attenuates the inflammatory process, IL-1 is able to proceed with the promotion of
inflammation which is connected to GDM. (14) In pregnant women with GDM, both clinical
and subclinical hypothyroidism was observed increased since serum thyroid-stimulating
hormone (TSH) levels were higher in them as compared to the levels in those with
uncomplicated pregnancies. (15) Thus, prompt screening of hypothyroidism and
administration of treatment, if necessary, is considered requisite in patients with GDM. (15)
The decrease of maternal insulin sensitivity demands a threefold raise in maternal insulin
secretion to preserve normal glucose tolerance during the final trimester of pregnancy and
women with an inadequate beta cell supply to face these demands develop glucose
intolerance. (16)
Women in gestation can be allocated into three risk categories regarding the manifestation
of GDM: high, low and average risk. As high risk GDM patients are defined those with obesity,
history of diabetes in a first-degree relative, a history of glucose intolerance, previous fetal
macrosomia or current glycosuria. In this category, screening should be conducted as soon as
possible. As low risk GDM patients are defined those that are younger than 25 years old,
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members of a low risk ethnic group, with a normal pregnancy weight gain and no previous
history of fetal macrosomia. Finally, as average risk GDM patients are defined those that do
not belong into none of the above categories and screening in them should be conducted, as
usual, at 24–28 weeks of gestation. (17)
Diagnosis of GDM can be performed with two different strategies: 1) The “One-step” 75-g
Oral Glucose Tolerance Test (OGTT) or 2) the “Two-step” approach with a 50-g (non- fasting)
screen followed by a 100-g OGTT for those who return a screen positive result. (1)
The International Association of the Diabetes and Pregnancy Study Groups (IADPSG)
statement presents the following screening and diagnostic strategies:
A 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h should be conducted
between the 24–28 weeks of gestation in women who have not been diagnosed with
preceding overt diabetes. The OGTT should be performed in the morning after an overnight
fast of at least 8 h. The diagnosis of GDM is confirmed when any of the subsequent plasma
glucose values are surpassed: Fasting: ≥ 92 mg/dL (5.1 mmol/L), 1 h: ≥ 180 mg/dL (10.0
mmol/L), 2 h: ≥ 153 mg/dL (8.5 mmol/L). (18)
On the other hand, The American Congress of Obstetrics and Gynecology (ACOG) suggests
that screening for GDM should be performed with the use of a random 50-g 1-hour glucose
load test, accompanied by a diagnostic fasting 100-g 3-hour OGTT, if screening test result is
positive. (19) There are two sets of criteria for this diagnostic test: The National Diabetes Data
Group (NDDG) criteria and the Carpenter-Coustan (CC) criteria. The NDDG criteria use fasting,
1-h, 2-h, and 3-h plasma glucose levels of 105 mg/dL, 190 mg/dL, 165 mg/dL, and 145 mg/dL
consequently for the diagnosis of GDM. (20) The Carpenter-Coustan (CC) criteria present
lower threshold values of 95 mg/dL, 180 mg/dL, 155 mg/dL, and 140 mg/dL. (21)
Suggested follow-up for women with GDM is a visit every one or two weeks during pregnancy,
determined by disease gravity and any complications manifested. (22)
Although it is a pregnancy complication that usually resolves after birth, GDM has been
majorly associated with a vast number of short- and long-term health consequences for both
the fetus and mother. (23)(24) Among the most common short- term fetal and neonatal
complications of GDM are the elevated risk of birth trauma and the higher prevalence of
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cesarean section, fetal macrosomia, incidents of neonatal hypoglycemia, respiratory distress
syndrome (RDS) and premature birth, enhancing the likelihood of perinatal death. (25)
Longitudinally, children of women diagnosed with GDM, are more prone to manifest obesity
and metabolic syndrome. (26)(27) In addition, GDM is associated with a variety of both short
and long-term maternal adverse effects such as pregnancy- induced hypertension, pre-
eclampsia, hemolysis, increased liver enzymes, low platelets (HELLP) syndrome and
impairment of any degree of a preceding renal insufficiency or retinopathy. (28) Findings of a
recent case control study conducted in Bangladesh demonstrated that GDM in pregnancy can
be defined responsible for a considerable proportion of cases of Autism Spectrum Disorder
(ASD). (29)
Although pre-eclampsia is an adverse effect of a GDM-complicated pregnancy, a Korean study
has demonstrated that a history of pre-eclampsia in previous pregnancies can be considered
as an important risk factor for the manifestation of GDM in a following pregnancy. (30)
Therefore, women with history of pre-eclampsia who are expecting to give birth to more
children in the future should be thoroughly screened for GDM and they should also undergo
lifestyle counseling. (30)
The neonate of a mother with GDM during pregnancy needs to receive special care. Full
physical examination, assessment of congenital anomalies such as congenital heart defects,
presence of tracheoesophageal fistula and central nervous system abnormalities and birth
trauma assessment are utterly required. Continuous observation is also required for the
identification of possible hypoglycemia, polycythemia, hyperbilirubinemia and presence of
electrolyte abnormalities. Circulating glucose levels have to be assessed within 1 hour from
birth, then assessment needs to be conducted every hour for the next 6 to 8 hours and based
on the results following assessment is defined. Mothers with GDM should preferably
breastfeed their neonates, starting as soon as possible. In cases where oral feeding is not
enough, an intravenous infusion of glucose is considered requisite. (31)
A variety of lifestyle and pharmacological interventions have been proven effective for the
management of GDM. (32) The implementation of a diet, usually followed by exercise is
suggested as a first-line therapy for GDM. (33) It has been suggested that ideal aerobic
exercise during pregnancy, especially for the prevention and administration of GDM, has to
last for a minimum of 15 minutes per session, 3 times a week, and has to be increased
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