Pre-meal Consumption of Whey in Gestational Diabetes Mellitus From Diagnosis to Delivery

Study Overview
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Brief Summary
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The main objective of the study is to investigate the metabolic effects of whey protein (whey protein isolate, WPI, (Lacprodan® ISO.Water. from Arla Foods Ingredients) compared with placebo when consumed by women with gestational diabetes mellitus (GDM) from diagnosis (around gestational week 28) to delivery. Any changes in substrate metabolism and energy expenditure using indirect calorimetry will also be investigated. Differences in hunger and satiety parameters as well as blood pressure and gestational weight gain will also be assessed. Furthermore, analysis on the glucose response when the women consume the intervention (whey or placebo) at home in their own environment 30 minutes before breakfast at time of diagnosis (earliest week 28) and week 36 (four days following each time point) will be made. The women will be monitored with continuous glucose monitors, activity monitors and all meals will be provided for two days following the study days in the laboratory. At delivery cord blood will be sampled for analysis on metabolic parameters and investigations on epigenetics/DNA methylations. Complications to the delivery, neonatal outcomes, anthropometrics of the child will also be assessed. Breast milk composition will also be analyzed.

Official Title
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Pre-meal Consumption of Whey in Gestational Diabetes Mellitus From Diagnosis to Delivery

Conditions
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Gestational Diabetes

Intervention / Treatment
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* Dietary Supplement: Whey
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: GDM (OGTT level of blood glucose ≥ 9 mmol/L) Normal blood pressure Age > 18 years Exclusion Criteria: Special dietary regimes > 1 month at time of inclusion e.g. ketogenic diet Daily intake of protein supplements Milk allergy or phenylketonuria Medication with effect on glucose metabolism e.g. steroids Do not speak or understand Danish Twin pregnancy PCOS PI finds the patient unfit (like mental illness, too nervous or other) Severe chronic illness Severe nausea/vomiting Non-breakfast eaters Celiac disease The initiation of insulin treatment during the trial will not lead to exclusion from the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Whey<br>Whey protein isolate WPI (Lacprodan® ISO.Water. from Arla Foods Ingredients). 20 g of whey protein will be ingested 30 min. prior to breakfast from diagnosis of GDM (around week 28) and until delivery. | Dietary Supplement: Whey<br>* 20 g protein of whey protein isolate WPI (Lacprodan® ISO.Water. from Arla Foods Ingredients)<br>|
| Placebo Comparator: Placebo<br>The placebo will be ingested 30 min. prior to breakfast from diagnosis of GDM (around week 28) and until delivery. | Dietary Supplement: Placebo<br>* The placebo contains <1 kcal and 0 g protein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal glycemic variability (GV) | The Coefficient of Variation, power: n = 50 | 24 hours | 
| Maternal glycemic variability (GV) | Interquartile range (IQR), power n = 40 | 24 hours | 
| Maternal glycemic variability (GV) | Standard deviation (SD), power n = 18 | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hours interstitial fluid glucose measures | Continuous glucose monitoring | 24 hours | 
| mean glucose | Continuous glucose monitoring | 24 hours | 
| maximum glucose | Continuous glucose monitoring | 24 hours | 
| Interstitial fluid glucose concentrations | Continuous glucose monitoring | 3 hours following breakfast | 
| Total energy expenditure | Measured with a combined accelerometer and heart rate monitor, reported in kcal | 24 hours | 
| Activity energy expenditure | Measured with a combined accelerometer and heart rate monitor, reported in kcal | 24 hours | 
| Activity count | Measured with a combined accelerometer and heart rate monitor, reported in counts | 24 hours | 
| Heart rate | Measured with a combined accelerometer and heart rate monitor, reported in beats per minute | 24 hours | 
| Resting energy expenditure (REE) (Resting Metabolic Rate) | Indirect calorimetry | Performed for 20 minutes | 
| Respiratory quotient (RQ) | Indirect calorimetry | Performed for 20 minutes | 
| Oxidation rates of lipid, carbohydrate and protein | Indirect calorimetry | Performed for 20 minutes | 
| Diet diary | Total energy intake, composition of macronutrients | 24 hours | 
| Self-reported appetite | Questionnaire: A numerical rating scale ranging from not at all = 0 to extremely = 10 will be used to assess Hunger, Fullness, Satiety, Desire, Prospective consumption (Quantity). | 3,5 hours following intake of whey/placebo at diagnosis, week 32 and week 36 | 
| Body Mass Index | weight and height will be combined to report BMI in kg/m^2 | at diagnosis, week 32 and week 36 | 
| Gestational weight change |  | at diagnosis, week 32 and week 36 | 
| Medications | number of participants prescribed insulin, dose of insulin, time to insulin. Methyldopa, nifidipin or labetalol (medication to lower blood pressure) | from diagnosis to delivery | 
| Pregnancy data | Number of participants with hypertension, preeclampsia, maternal weight gain | from diagnosis to delivery | 
| Delivery data | Number of patients with cesarean section, shoulder dystocia, induction of labour | at delivery | 
| Non-targeted metabolomics will be performed on a sample of breast milk using Nuclear Magnetic Resonance | Analysis generating metabolites from pathways on amino acids, peptides, carbohydrates and lipids measured in folds increase/decrease when comparing placebo with whey | Day 1 postpartum | 
| Blood pressure | Systolic and diastolic blood pressure | at diagnosis, week 32 and week 36 | 
| Concentration differences in Insulin like growth factor I (IGF-1) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in IGF-binding protein 3 (IGFBP-3) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in IGF-binding protein 1 (IGFBP-1) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in FGF-21 (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Leptin (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Adiponectin (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in CRP (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Prolactin (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Cortisol (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Insulin (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Free Fatty Acids (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in lactate (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in grehlin (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in inflammatory markers (IL-6, IL-10, IL-1α, IFN-γ, TNF-α)(mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in glucose independent peptide (GIP) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in glucagon like peptide 1 (GLP-1) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in glucagon (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in c-peptide (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in amino acids (AA) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in progesterone (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in steroid hormone binding protein (SHBP) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in carboxy-terminal collagen crosslinks (CTx) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in osteocalcin (OCN) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Pro-collagen I, N-term. pro-peptide (PINP) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Human chorionic gonadotropin (HCG) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in CD163 (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in estradiol (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in hb1ac (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in lipids (cholesterol, triglyceride) (mother) |  | at diagnosis, week 32 and week 36 | 
| Concentration differences in Insulin (cord blood, offspring) |  | at delivery | 
| Concentration differences in c-peptide (cord blood, offspring) |  | at delivery | 
| Concentration differences in glucagon (cord blood, offspring) |  | at delivery | 
| Concentration differences in glucose (cord blood, offspring) |  | at delivery | 
| Concentration differences in lactate (cord blood, offspring) |  | at delivery | 
| Differences in pH (cord blood, offspring) | Measurement of acidity of the blood. Standard measurement performed on a sample of cord blood when a baby is delivered to evaluate possible oxygen deficiency during delivery. | at delivery | 
| non-targeted metabolomics analysis (cord blood, offspring) | Analysis generating metabolites from pathways on amino acids, peptides, carbohydrates, lipids and energy measured in folds rise/fall in when comparing placebo with whey | at delivery | 
| DNA methylations measured with 850K-Illumina Infinium assay. | Differentially methylated sites or regions associated with the intervention will be assessed. | at delivery | 
| RNA-Seq transcriptome profiling | Up and down-regulated genes associated with the intervention will be assessed | at delivery | 
| Body fat (offspring) | Sum of skinfolds measured with a caliper | at delivery | 
| Birth weight (offspring) |  | at delivery | 
| Head circumference (offspring) |  | at delivery | 
| abdominal circumference (offspring) |  | at delivery | 
| Length (offspring) |  | at delivery | 
| Number of infants with icterus |  | through hospital admission immediately after delivery | 
| Apgar-score | Apgar score, range from 0-10, with the higher score the better outcome. | at delivery | 
| number of patients needing early feeding |  | through hospital admission immediately after delivery | 
| Number of days admitted immediately after delivery |  | through hospital admission immediately after delivery | 
| Number of infants with hypoglycemia |  | at delivery | 
| Weight of placenta |  | at delivery |