Determining the Effect of Food Ordering on Blood Glucose In Gestational Diabetes Mellitus (DEFI-GDM) - a Randomised Crossover Study
Phase: NA
Conditions: Gestational Diabetes Mellitus (GDM)
Sponsor: Queen's University, Belfast

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
Project Title: Determining the Effect of Food ordering on blood glucose In Gestational 
Diabetes Mellitus (DEFI-GDM) - a randomised crossover study 
Dr Hannah O’Hara1, Dr Danielle Logan1, Christina O’Neill1, Rebecca McKenzie1, Professor 
Kevin Murphy2, Dr Ciara Mulligan3, Professor Christopher Cardwell1 and Professor Jayne 
Woodside1 
1Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Queen’s 
University Belfast 
2Department of Metabolism, Digestion and Reproduction - Faculty of Medicine, Imperial 
College London, Hammersmith Campus, London 
3South Eastern Health and Social Care Trust, Trust Headquarters Ulster Hospital, Belfast  
 
Introduction 
Gestational diabetes mellitus (GDM) is glucose intolerance with onset or first diagnosis during 
pregnancy, affecting around 1 in 10 pregnancies in the UK. A major risk factor for GDM is 
obesity and, with ever increasing rates of obesity, GDM prevalence is also rising. Gestational 
diabetes increases the risk of adverse perinatal outcomes including macrosomia, preterm 
delivery, need for caesarean section and even stillbirth. Women with GDM are also 10 times 
more likely to develop T2DM and twice as likely to develop cardiovascular disease in later life 
than women without GDM (1,2). Dietary modification, involving incorporating complex 
carbohydrates into the diet at the expense of refined carbohydrates, is recommended as first 
line management to optimise blood glucose control and reduce the risk of adverse pregnancy 
outcomes including neonatal hypoglycaemia and caesarean section (3). However, this often 
fails, necessitating the use of adjunctive pharmacological agents such as metformin and 
insulin. There are significant disadvantages to pharmacological management, including 
hypoglycaemia, weight gain, and raised BMI in offspring (4,5). Low/no carbohydrate diets are 
gaining popularity among women aiming to improve glucose control by dietary means. 
However, the safety of these diets is uncertain (6). Furthermore, evidence suggests that post-
natal adherence to such diets may actually increase risk of T2DM (7). There is a pressing 
need to find safe and effective dietary approaches to optimise glycaemic control in GDM which 
can be easily adhered to in order to improve perinatal and longer-term outcomes. 
The impact of the sequence of ingestion of macronutrients on glycaemic control is an emerging 
area of interest. Compared to carbohydrate, protein and fat induce greater satiety and reduce 
postprandial glycaemia. Several mechanisms likely mediate this, including influencing gastric 
emptying and secretion of insulin and incretin hormones such as glucagon like peptide-1 
(GLP-1) (8). Recent evidence suggests that the effect magnitude is greater when non-
carbohydrate macronutrients are consumed first; in patients with diabetes, consumption of the 
fat/protein components of a meal prior to the carbohydrate components reduces the post-
prandial peak by around 40% (9). Furthermore, overall post-prandial glucose excursion is 
reduced by around 50-70% (9,10). It has also been demonstrated that sustained non-
carbohydrate first meal consumption is beneficial for longer term glycaemic control in patients 
with T2DM: patients encouraged to eat vegetables before carbohydrate achieved better 
glycaemic control than patients offered traditional dietary advice over a 2-year period (11). 
In women with GDM, sustained consumption of a protein/fat preload before meals improves 
glucose tolerance compared to an isocaloric carbohydrate preload, with glucose levels 
approximately 15% lower following a glucose load (12). However, preloads may increase 
overall energy intake, and acceptability is uncertain. Altering the sequence of macronutrient 
ingestion within a normal diet, as demonstrated to be effective in T2DM and non-diabetic 
individuals (13,14), could offer an alternative approach to optimising glucose control in women 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
with GDM. This could improve acceptability and adherence, whilst ensuring a balanced diet 
without energy or macronutrient restriction. This study will evaluate the effect of consumption 
of non-carbohydrate components of a breakfast meal before carbohydrate components on 
post-prandial glycaemia compared to carbohydrate-first consumption in women with GDM. It 
will also explore potential mechanisms mediating any observed effect, examining subjective 
satiety and food intake over the following 24 hours in women with GDM as well as changes in 
insulin, C-peptide, glucagon, acylated-ghrelin, peptide tyrosine (PYY) and GLP-1, hormones 
which are involved in glucose homeostasis and appetite regulation. The test meal represents 
a commonly eaten breakfast in the real world, and results are likely to be repeatable with other 
meal types. 
 
Aims and Objectives 
Aims 
Using a randomized crossover study of a breakfast meal in women with GDM: 
1. To determine whether the sequence of macronutrient consumption affects post-
prandial glycaemia  
2. To determine whether the sequence of macronutrient consumption affects post-
prandial gut hormone release  
3. To determine whether the sequence of macronutrient consumption affects subsequent 
satiety and food intake 
Objectives 
Using a randomized crossover study of a breakfast meal in women with GDM: 
1. To determine whether the sequence of macronutrient consumption affects the 
magnitude of the post-prandial rise in plasma glucose as measured by Flash Glucose 
Monitoring (FGM) 
2. To determine whether the sequence of macronutrient consumption affects the pattern 
of post-prandial glucose excursion as measured by FGM 
3. To determine whether the sequence of macronutrient consumption affects changes in 
pre- to post-prandial serum insulin, C-peptide and glucagon levels  
4. To determine whether the sequence of macronutrient consumption affects changes in 
pre- to post-prandial ghrelin, GLP-1 and PYY release 
5. To determine whether the sequence of macronutrient consumption affects satiety 
scores as measured by Visual Analogue Scales (VAS) 
6. To determine whether the sequence of macronutrient consumption affects subsequent 
calorie and macronutrient intake as detailed in self-recorded 24-hour food diaries 
 
Project design 
The proposed study is a randomized crossover study involving women with current GDM. 
 
Subjects 
Thirty-five pregnant women with GDM, aged 18-50 years old, will be eligible to be recruited 
for the study.  

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
Exclusion criteria include: 
• 
History of type 1 or type 2 diabetes mellitus 
• 
Dietary restrictions or clinically confirmed food allergies that may affect study 
requirements 
• 
Pharmacologically managed GDM at the point of study entry 
• 
Hyperemesis gravidarum at the point of study entry (i.e. prolonged/severe nausea and 
vomiting)  
• 
Using antiemetic medication (e.g. dimenhydrinate, prochlorperazine, promethazine) 
• 
Any other problems or medical conditions that would substantially limit their ability to 
complete the study requirements 
Participants can be recruited onto the study if they have previously had GDM in another 
pregnancy. Participants can also be recruited if they are involved in other research studies, 
but this will depend on the study type and the decision will be made by the CI. 
Research methods 
Recruitment 
Participants will be recruited from endocrine antenatal clinics within the South-Eastern Health 
and Social Care Trust (SEHSCT) via different methods. Following a positive diagnosis from 
the oral glucose tolerance test (OGTT), patients are routinely referred to the Ulster Hospital 
for further care. A member of the direct care team in the SEHSCT antenatal clinic will be 
required to screen their patient database (i.e. age, history of type 1 or type 2 diabetes mellitus, 
and pharmacologically managed GDM) to determine whether patients meet the main 
inclusion/exclusion criteria for the study. Other criteria will be checked during a screening call 
with the researcher as this information may not be within medical records (i.e. Dietary 
restrictions or clinically confirmed food allergy that may affect study requirements, 
prolonged/severe nausea and vomiting at point of study entry and use of antiemetic 
medication). At the participants first appointment, a member of the direct care team will provide 
study details and contact details for the research team to those patients who may be eligible 
for the study. This will either be given verbally (if it is a remote consultation) or in person by 
the clinical care team, with the additional provision of the participant information sheet being 
emailed or given in person if the patient is happy to receive this.  
Study posters will also be on display in the waiting rooms at locations where OGTTs are being 
carried out across the SEHSCT (i.e. Ulster Hospital, Newtownards Hospital, Lagan Valley 
Hospital and Downe Hospital). Any interested patients will be asked to speak to their 
healthcare professionals in the antenatal clinic, who will be able to provide information on the 
study and contact details for the research team if they are potentially eligible.  
The SEHSCT locations are only involved in identifying potentially eligible participants and in 
advertising the study via displaying posters in areas where OGTTs are being conducted. It will 
only be the direct care team at the Ulster Hospital approaching patients about the study. 
Interested participants will contact the research team to discuss the study and determine their 
eligibility. They will be emailed a copy of the participant information sheet if they haven’t 
already received this from the antenatal clinic and given at least 48 hours to decide whether 
they wish to take part. The researcher will follow up after 48 hours to answer any questions. If 
they are still interested in being involved in the study, the researcher will complete screening 
to confirm their eligibility which should last no longer than 30 minutes. If they are eligible and 
provide their consent, a letter of participation will be sent to their antenatal team in the 
SEHSCT as their healthcare provider to inform them of participation in the intervention. 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
Within the study population, 60-70% of women commence pharmacological management, 
usually within 4 weeks of diagnosis. The study is designed to allow visits in close succession, 
allowing sufficient time for the visits to occur before medication is likely to be started. With 
approximately 400 women diagnosed with GDM in SEHSCT each year, 35 participants 
represents a recruitment rate of less than 9%. The timeline for recruitment, and other study 
activities is depicted in the below Gantt chart. 
 
 
Data collection 
Eligible participants will be invited to attend the research facility in the Centre for Public Health 
at Queen’s University Belfast on two mornings, following an overnight fast, with an interval of 
at least two days between the visits to ensure the participant has a break before the next 
fasting period. The maximum number of days between the visits should ideally be no more 
than 2 weeks. At each visit, participants will be asked to consume a 440Kcal breakfast meal 
approximately 1.5 hours after arrival on their first study visit and approximately 30 minutes 
after arrival on their second study visit. This time may increase to 1.5 hours after arrival if the 
flash glucose monitor needs to re-inserted on the participants arm. The breakfast meal should 
be consumed within 10 minutes, under different conditions at each visit. On one visit they will 
be asked to eat the protein/fat-based component of the meal (scrambled egg) before the 
carbohydrate-based component (wholemeal toast) and on the other visit they will be asked to 
eat the meal in the reverse order. 
Scrambled egg was chosen as the protein and fat will be homogenously distributed (compared 
to boiled egg, for example). Wholemeal toast was chosen as, although lower glycaemic index 
and therefore less likely to expeditiously raise blood glucose than toasted white bread, it will 
be more consistent with the participants’ existing dietary needs. Meals will be prepared by 
members of the research team who have completed Food Safety training. The scrambled egg 
will be prepared in the microwave without additional cooking fat and the toast will be prepared 
with a single serving of low-fat vegetable oil-based spread (see Table 1 for nutritional 
information). The order of the meals will be randomly allocated using block randomization.  
Table 1: Nutritional information for breakfast components 
 
Scrambled 
egg 
Wholemeal 
toast (Hovis 
wholemeal thick  
sliced) 
Vegetable oil-
based spread (I 
can’t believe it’s 
not butter ‘light’) 
Total 
Quantity 
140 g (2 large 
eggs) 
2 slices (100g) 
14 g 
254 g 
Energy (kcal) 
183 
222 
35 
440 
Fat (g) 
12.6 
1.8 
4 
18.4 
Protein (g) 
17.6 
10 
Trace 
27.6 
Carbohydrate (g) 
Trace 
37.8 
Trace 
37.8 
 
 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
 
Study Design  
The following activities will occur at the time points indicated in Figure 1 (following calibration 
of the device at the first study visit and second study visit if required): 
• 
Anthropometry:  
o Height and weight will only be measured at the start of visit 1 using calibrated 
scales and stadiometer respectively.  
 
• 
Self-administered questionnaires: 
o Screening/background information – socio-demographics, lifestyle and 
medical history 
o Self-reported appetite – VAS, 100mm in length with words anchored at each 
end, expressing the most positive and the most negative rating, will be used to 
assess hunger, satiety, fullness, prospective food consumption and desire to 
eat both pre- and post-consumption and palatability (at 10 and 40 minutes). 
 
• 
Flash glucose monitoring:  
o Serum glucose levels will be obtained using FreeStyle Libre 2 (Abbott), a FGM 
device allowing for multiple sampling without multiple blood draws. Following 
participant consent, a researcher will follow manufacturer’s instructions and 
apply the device to the back of the participant’s arm. The researcher will then 
dispose of the needle (that is discharged from the device) into a sharps bin. 
The participant will then wait for 1 hour to allow the device to calibrate. 
o Glucose levels will be recorded by the researcher 5 minutes prior to 
consumption of the breakfast meal and every 5 minutes thereafter until the end 
of the study visit, using a reader connected to the device. Participants will be 
informed that the use of the device and reader are only for study purposes. 
They will also be informed that glucose readings from the device cannot be 
provided by the researcher, and that they should continue with their usual 
clinical care method for glucose monitoring readings.  
 
• 
Intravenous blood sampling:  
o This will be carried out pre- and post-consumption (at 20 and 50 minutes) to 
allow measurement of serum and/or plasma glucose, insulin, C-peptide, 
glucagon, ghrelin, GLP-1 and PYY. At each blood draw, 13ml of blood will be 
collected (i.e. 26ml blood sample in total at each study visit).  
o Samples will be centrifuged and stored at -80 degrees Celsius until analysis in 
the CPH laboratory. All samples will be batch analysed using validated assays 
(16–18). Hormone analysis will take place at Imperial College London, whilst 
glucose, insulin and C-peptide will be analysed in the CPH, QUB. This will take 
place once all participants have completed the study.  
 
• 
Food diaries:  
o Participants will be asked to document the remainder of their food and drink 
consumption for the day of their study visits in food diaries (i.e. two 1-day food 
diaries) (19). The first diary may be returned at the second study visit and the 
second food diary may be returned by post in a pre-paid envelope. If the 
participant prefers to send the completed food diary back via email this will be 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
facilitated. Energy and nutrient intakes will be estimated using Nutritics dietary 
assessment software. 
Participants will be paid an honorarium of £200 to cover time and travel costs on completion 
of the visits. 
 
Figure 1: Timeline of study activities  
Patient and public involvement 
The research question was formulated following discussions with women with a history of 
GDM, particularly those who had required medication after dietary modifications were 
ineffective. They described frustration that the recommended dietary advice hadn’t helped 
them to control their blood sugars, despite feeling restricted in what they ate. There was a high 
level of interest in research that might help women and clinicians better understand how to 
control blood sugars with diet alone. 
The study design was co-constructed with Patient and Public Involvement and Engagement 
(PPIE) representatives with experience of a pregnancy affected by GDM, with key elements 
of the study design informed by their involvement. The use of FGM was felt to be an attractive 
component of taking part in the study. However, it was felt that only having access to FGM 
devices for the duration of the study was unsatisfactory. After discussion with Research 
Governance and QUB contracts, it was not considered possible to provide devices to 
participants after the study ends due to indemnity and insurance issues. This is because using 
devices provided during a study for standard care in the antenatal clinics would not be 
covered.  
 
Study Outcomes  
Primary outcome:  
• 
The difference in the magnitude of postprandial rise in blood glucose between the two 
test meals.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants 
(n=35) are 
randomly 
assigned to eat 
one of two test 
meals 
Consume 
assigned 
breakfast meal 
within ten minutes 
End of 
experiment 
Complete 
appetite 
questionnaire  
0 min 
10 min 
20 min 
40 min 
Complete 
appetite 
questionnaire  
50 min 
30 min 
Height and 
weight 
measurements 
150 min 
FGM every 5 minutes 
Start of 
experiment 
2nd blood 
sample  
1st blood 
sample  

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
Secondary outcomes:   
• 
The difference in the magnitude of postprandial change in serum levels of gut 
hormones between the two test meals.  
• 
The difference in mean change in pre-post ingestion satiety scores between the two 
test meals. 
• 
The difference in 24 hour energy and macronutrient intake following the two test meals. 
 
Power Calculation 
A simplified sample size calculation was conducted based upon a paired samples t-test using 
PASS (PASS 2009, NCSS LLC, Kaysville, Utah). In this sample size a standard deviation of 
0.9 mmol/L was used, based upon the standard deviation of the plasma glucose peak from a 
crossover study which evaluated glucose levels following consumption of a rice-first or rice-
last meal in non-diabetic individuals (15). This will be an over-estimate of the within-person 
standard deviation which wasn’t available. This study was used as it evaluated the difference 
in glucose peaks following consumption of a carbohydrate-first or carbohydrate-last meal, as 
opposed to total post-prandial glucose excursion. This calculation indicated that, with 28 
individuals, the study would have over 80% power to detect as statistically significant, a 
difference in mean of 0.5 mmol/L peak glucose between the two groups (carbohydrate-last 
versus carbohydrate-first). This is smaller than seen in a previous study for the carbohydrate-
last group compared to the carbohydrate-first group (15). As this is based on a study of a non-
diabetic cohort, it is anticipated that there will likely be a higher divergence in tolerance to 
carbohydrate in the cohort in the current study. Recruitment of 35 women will allow for a 20% 
drop-out rate. 
 
Statistical Analysis 
The primary objective is to determine whether the sequence of macronutrient consumption 
affects the magnitude of the post-prandial rise in plasma glucose. We do not anticipate any 
carry over effect. The height and time after consumption of the glucose peak will be compared 
between groups using a paired t-test to calculate a difference in mean and 95% Confidence 
Interval (CI) (20). The total AUC will also be compared between the two groups using a paired 
t-test to calculate a difference in mean and 95% Confidence Interval (CI).  
To explore potential mechanisms by which any observed effects occur, the following 
exploratory analyses will be carried out using paired t-tests: differences in the mean pre- to 
post-prandial change in insulin, C-peptide, glucacon, PYY, GLP-1 and ghrelin compared 
between groups, the mean change in hunger, satiety, fullness, prospective food consumption 
and desire to eat ratings between pre- and post-consumption as recorded by VAS compared 
between groups, and subsequent caloric and macronutrient intake compared between groups. 
Probability values <0.05 will be considered statistically significant. 
 
Confidentiality and Data Storage 
The data collected will be treated securely and with the strictest confidence as necessary 
under the General Data Protection Regulations and stored as required by QUB. All data 
collected will be kept in a pseudonymised format so that participant results can be linked to 
the study ID. Participant ID numbers will be used to keep the identity of the participants 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
anonymised.  
 
Documents including questionnaires and blood results will be stored securely in a locked filing 
cabinet in a locked office within CPH at QUB. The document containing individual names and 
contact telephone numbers that will be needed throughout the study will be stored on a QUB 
encrypted password protected computer held at QUB and will be destroyed on completion of 
the study. Consent forms will be stored securely in a locked filing cabinet in a locked office, 
separate to where the research data is stored. When outcome data has been collected and 
entered in Nutritics, the research team will export it and this will also be stored on a QUB 
encrypted password protected computer held at QUB. The reader is only used alongside the 
FGM device to obtain glucose results during the study visits. These results are recorded by 
the researcher for each participant. Personal information will not be shared with Abbott (device 
and reader supplier).  
 
All such files will be password protected and stored on devices only with sign in password 
protection and fully updated security software. Only encrypted password protected external 
storage devices will be used if needed and all data will be backed-up on the QUB server. 
Personal data will be stored over 3 years is in line with QUB policy. For example, consent 
forms containing personal data will be retained. Research data generated by the study will be 
stored for 5 years based on University Policy. Long term arrangements for the storage of 
research data after the study has ended will involve the data being stored by the data 
custodian, Professor Jayne Woodside, on QUB password protected computers and within 
QUB locked offices in keypad access buildings that are not accessible to the public. Samples 
will also be stored in the Laboratory in CPH, QUB. 
 
 
Ethical and Regulatory Considerations 
Queen’s University Belfast (QUB) will act as Sponsor for the study and the CI will take overall 
responsibility for the conduct of the study.  
The study will comply with the requirements and standards set out in the UK Policy Framework 
for Health and Social Care Research. Prior to initiating the study, a favourable opinion will be 
sought from and NHS/HSC Research Ethics Committee for the study protocol, informed 
consent forms and other relevant documents. Approval will also be sought from the South 
Eastern HSC Trust to act as a Participant Identification Centre in the study. 
Substantial amendments that require review by NHS REC and approval from the sponsor will 
not be implemented until that review is in place and other mechanisms are in place to 
implement at site.  The CI will notify the REC of the end of the study, which is defined as 
completion of data analysis. If the study is ended prematurely, the Chief Investigator will notify 
the REC and sponsor, including the reasons for the premature termination. Within one year 
after the end of the study, the Chief Investigator will submit a final report with the results, 
including any publications/abstracts, to the REC and Sponsor. 
 
Indemnity 
QUB as Sponsor will provide indemnity for the management, design and conduct of the study.  
 
Dissemination 
Dissemination of the overall study results will occur via multiple avenues with target audiences 
including the women who took part in the study, women with current, or a history of, GDM 
throughout the UK, health care professionals, academics and policy makers. Dissemination 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
will occur via publication in relevant peer-reviewed publications, presentation at regional 
scientific meetings and relevant national / international scientific conferences (e.g. Diabetes 
in Pregnancy conference). The research team also regularly promote their research activities 
via social media, media interviews and newspaper articles etc. It is anticipated that similar 
approaches will be utilised in dissemination of this work via press releases, relevant social 
media and additional streams as identified by PPIE contributors.  No one will be identifiable in 
any data produced from this study. 
Potential of research for patient care 
The primary objective of this study is to determine whether the order of consumption of 
macronutrients within a meal influences blood glucose levels post-prandially in women with 
GDM. If consumption of non-carbohydrate components of the meal first was shown to reduce 
post-prandial glucose excursion in women with GDM, it would have significant implications for 
women and their babies. Well controlled blood sugars in GDM are associated with a reduction 
in perinatal complications, including pre-eclampsia, macrosomia, shoulder dystocia and 
neonatal hypoglycaemia (3). Data from this study could inform investigation of the effects of 
sustained non-carbohydrate first eating patterns on glucose control throughout pregnancy, the 
requirement for pharmacological treatment and the risk of adverse perinatal outcomes. If 
demonstrated to be beneficial, it would empower women with GDM to eat a balanced diet, 
without restricting individual food groups or macronutrients. It would represent an opportunity 
to offer simple advice, applicable to a large cohort of women at little cost to beneficial effect, 
and could inform future health policy. 
The reduced glucose excursion associated with non-carbohydrate first meal plans has also 
been demonstrated in normoglycaemic and pre-diabetic individuals. It is possible that this 
dietary approach could have a subsequent effect on the risk of future T2DM in this at-risk 
population. During pregnancy and the post-partum period, women are particularly receptive to 
dietary and lifestyle changes and so this would also be an opportunity to instil dietary habits 
that could have a prolonged beneficial effect on health. 

 
 
IRAS Number: 346910                                                                          Version 2.0 11/02/2025 
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