Maternal ExeRcIse Timing to Optimise Postprandial Glucose in Type 1 Diabetes

Study Overview
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Brief Summary
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Poor glycaemic control in pregnancy is a major factor leading to obstetric complications and future maternal-offspring diseases. This phenomenon is evidenced in women with type 1 diabetes (T1DM), and is worrisome since it is aggravating the disease burden of this and next generations. Exercise is a promising tool to improve glucose control during pregnancy and thus avoid adverse consequences. The MERIT1D study will explore when is exercise (before or after lunch) more effective to improve postprandial glycaemic control in pregnant and non-pregnant women (of reproductive age) with T1DM, and the mechanisms underlying these metabolic responses.

Detailed Description
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Poor glycaemic control in pregnancy is a major factor leading to obstetric complications and future maternal-offspring diseases (e.g., macrosomia, diabetes). This phenomenon is evidenced in women with type 1 diabetes (T1DM), and is worrisome since it is aggravating the disease burden of this and next generations. Therefore, to find strategies aimed at breaking this intergenerational cycle has become a high-priority. Exercise is a promising tool to improve short-term glycaemic responses such as postprandial glucose peaks and glucose variability, and thus reduce adverse maternal-neonatal outcomes. However, it is unknown which timing of exercise is more effective to optimise postprandial glycaemic control in pregnant women with T1DM, and non-pregnant women (of reproductive age) with T1DM. The mechanisms underlying these benefits in T1DM and pregnancy are also to be established. The MERIT1D project will unravel which timing of exercise (before or after a meal at lunchtime) is more effective to optimise postprandial glycaemic control in pregnant and non-pregnant women with T1DM, and the mechanisms underlying these metabolic responses. Ten pregnant women with T1DM and ten non-pregnant women with T1DM will be involved in this randomised controlled crossover trial. Pregnant women at gestational week 16 and 35 (experimental phases 1 and 2, respectively), and non-pregnant peers once after recruitment (experimental phase 1), will undergo 3 experimental conditions within 10 days (random order): pre-meal exercise, post-meal exercise, and non-exercise meal. Each experimental phase will entail participants attending 4 times to the research centre. Therefore, pregnant women will come to the research centre for a total of 8 study visits, while non-pregnant women will come only to 4 study visits. The acute exercise stimulus will consist of a well-controlled submaximal walking test. The standardised meal provided will consist of a mixed milkshake equivalent to the 35 % of their resting energy expenditure, being made up of approximately 45% carbohydrates, 35% fat, and 20% proteins. Postprandial glycaemic responses will be continuously monitored using last-generation glucose monitoring systems during the 10-day period. Immunometabolic markers (e.g., lipids, cytokines) will be determined in maternal blood and placenta samples. The MERIT1D study will contribute to the understanding of exercise timing in T1DM and pregnancy, and its underlying mechanisms. This will translate into a better clinical prediction, diagnosis, prognosis and treatment of glycaemic dysregulations, and into more effective exercise programmes for pregnant and non-pregnant women with T1DM.

Official Title
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Maternal ExeRcIse Timing to Optimise Postprandial Glucose in Type 1 Diabetes

Conditions
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Pregnancy in Diabetic, Type 1 Diabetes

Intervention / Treatment
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* Other: Exercise and meal testing (acute stimuli)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women and non-pregnant women with T1DM aged 20-40 years Having a BMI of 18-29.9 kg/m2 at pre-pregnancy (pregnant women) or recruitment (non-pregnant) Clinical diagnosis of T1DM, or/and multiple daily insulin injections for >1 year, and/or using insulin pump therapy (open-loop). Willingness to provide informed consent to participate in the MERIT1D study. Being able to read and speak German, English or Spanish well enough to completely understand the instructions, provide informed consent and conduct the experimental procedures. Exclusion Criteria: Having poor glycaemic control HbA1c>10% (86 mmol/mol). Recurrent severe hypoglycaemia; hospitalisation for diabetic ketoacidosis during the last year. Women who smoke or drink alcohol frequently, or require complex diets. Having polycystic ovarian syndrome, poorly controlled asthma/allergy, uncontrolled thyroid diseases or hypertension, diabetic ketoacidosis, hepatitis B, hepatitis C, HIV. Having severe autoimmune/immunodeficiency, macrovascular, renal, or neuromuscular disease, or severe retinopathy or neuropathy. Having any other cardiovascular, pulmonary, orthopaedic, neurologic, psychiatric, or terminal disease, or any other acute/chronic disorder that, in the opinion of the local clinician/researcher, would preclude participation and successful completion of the protocol, or that would directly influence the study results. Use of any medication (e.g., steroids), that, in the opinion of local clinician/researcher, would negatively impact or mitigate full participation and completion, or could influence the study results. Any condition that would interfere with compliance or the results, as judged by the Investigator Pregnant women: having multiple pregnancy Pregnant women: evidence of incompetent cervix, ruptured membranes, placenta previa, foetal malformation, or foetal death.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomised, single-centre, controlled crossover in parallel groups (pregnant and non-pregnant women with type 1 diabetes)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregnant women with type 1 diabetes<br>Participants will undergo 3 experimental conditions in random order at week of gestation 16 and 35 (experimental phases 1 and 2): pre-meal exercise, post-meal exercise, and non-exercise meal. | Other: Exercise and meal testing (acute stimuli)<br>* Pre-meal exercise: 1º milkshake intake + 2º exercise test Post-meal exercise: 1º exercise test + 2º milkshake intake Non-exercise meal: Only milkshake intake<br>|
| Experimental: Non-pregnant women with type 1 diabetes<br>Participants will undergo 3 experimental conditions in random order after recruitment (experimental phase 1): pre-meal exercise, post-meal exercise, and non-exercise meal. | Other: Exercise and meal testing (acute stimuli)<br>* Pre-meal exercise: 1º milkshake intake + 2º exercise test Post-meal exercise: 1º exercise test + 2º milkshake intake Non-exercise meal: Only milkshake intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time spent in the euglycemic range for the 24 hours after each experimental condition | T1DM non-pregnant women, euglycemic range: 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women, euglycemic range: 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Percentage of time spent in the euglycemic range for the 24 hours after each experimental condition | T1DM non-pregnant women: 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women: 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time spent in hypoglycemia for the 24 hours after each experimental condition | T1DM non-pregnant women - range: < 3.9 mmol/L (< 70 mg/dL). T1DM pregnant women - range: < 3.5 mmol/L (< 63 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Percentage of time spent in hypoglycemia for the 24 hours after each experimental condition | T1DM non-pregnant women - range: < 3.9 mmol/L (< 70 mg/dL). T1DM pregnant women - range: < 3.5 mmol/L (< 63 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Percentage of time spent in hyperglycemia for the 24 hours after each experimental condition | T1DM non-pregnant women - range: > 10 mmol/L (> 180 mg/dL). T1DM pregnant women - range: > 7.8 mmol/L (> 140 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Percentage of time spent in hyperglycemia for the 24 hours after each experimental condition | T1DM non-pregnant women - range: > 10 mmol/L (> 180 mg/dL). T1DM pregnant women - range: > 7.8 mmol/L (> 140 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Differences in postprandial glucose levels 1-, 2-, and 4-hours post-experiment | Within-change in glucose values (mmol/L) from pre-experiment (before starting exercise/meal testing) to post-experiment (i.e., 1-, 2-, and 4-hours after starting exercise/meal intake) in each experimental day | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 4 h/day) | 
| Differences in postprandial glucose levels 1-, 2-, and 4-hours post-experiment | Within-change in glucose values (mmol/L) from pre-experiment (before starting exercise/meal testing) to post-experiment (i.e., 1-, 2-, and 4-hours after starting exercise/meal intake) in each experimental day | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 4 h/day) | 
| Number of hypoglycaemic events for the 24 hours after each experimental condition | T1DM non-pregnant women - range: < 3.9 mmol/L (< 70 mg/dL). T1DM pregnant women - range: < 3.5 mmol/L (< 63 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Number of hypoglycaemic events for the 24 hours after each experimental condition | T1DM non-pregnant women - range: < 3.9 mmol/L (< 70 mg/dL). T1DM pregnant women - range: < 3.5 mmol/L (< 63 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Number of hyperglycaemic events for the 24 hours after each experimental condition | T1DM non-pregnant women - range: > 10 mmol/L (> 180 mg/dL). T1DM pregnant women - range: > 7.8 mmol/L (> 140 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Number of hyperglycaemic events for the 24 hours after each experimental condition | T1DM non-pregnant women - range: > 10 mmol/L (> 180 mg/dL). T1DM pregnant women - range: > 7.8 mmol/L (> 140 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Percentage of time spent in nocturnal euglycemia within each experimental day | T1DM non-pregnant women - range: euglycemia 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women - range: euglycaemia 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 00:00 am - 05:59 am) | 
| Percentage of time spent in nocturnal euglycemia within each experimental day | T1DM non-pregnant women - range: euglycemia 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women - range: euglycaemia 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 00:00 am - 05:59 am ) | 
| Percentage of time spent in diurnal euglycemia within each experimental day | T1DM non-pregnant women - range: euglycemia 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women - range: euglycaemia 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 6.00 am - 23:59 am) | 
| Percentage of time spent in diurnal euglycemia within each experimental day | T1DM non-pregnant women - range: euglycemia 3.9 - 10 mmol/L (70 - 180 mg/dL). T1DM pregnant women - range: euglycaemia 3.5 - 7.8 mmol/L (63 - 140 mg/dL). | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 6.00 am - 23:59 am) | 
| Area under the curve of glycaemic exposure | Area under the curve of glycaemic exposure during the 2, 4 and 8 hours after meal intake at each experimental condition. | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 8 hours/day) | 
| Area under the curve of glycaemic exposure | Area under the curve of glycaemic exposure during the 2, 4 and 8 hours after meal intake at each experimental condition. | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 8 h/day) | 
| Glycaemic variability (standard deviation) | Standard deviation (SD) of the mean continuous glucose monitoring levels over the 24 hours after each experimental condition | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Glycaemic variability (standard deviation) | Standard deviation (SD) of the mean continuous glucose monitoring levels over the 24 hours after each experimental condition | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Glycaemic variability (coefficient of variation) | Coefficient of variation of glucose levels over the 24 hours after each experimental condition | assessed in the study phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 24 hours/day) | 
| Glycaemic variability (coefficient of variation) | Coefficient of variation of glucose levels over the 24 hours after each experimental condition | assessed in the study phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 24 h/day) | 
| Maternal glucose metabolism | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to the glucose-insulin axis will be analysed (i.e., glucose, insulin, C-peptide and HbA1c). | assessed in the phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 3 h/day) | 
| Maternal glucose metabolism | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to the glucose-insulin axis will be analysed (i.e., glucose, insulin, C-peptide and HbA1c). | assessed in the phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 3 h/day) | 
| Maternal lipid profile | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to the lipid profile will be analysed (i.e., total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL-cholesterol, triglycerides and free fatty acids). | assessed in the phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 3 h/day) | 
| Maternal lipid profile | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to the lipid profile will be analysed (i.e., total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL-cholesterol, triglycerides and free fatty acids). | assessed in the phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 3 h/day) | 
| Maternal inflammatory markers | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to inflammatory-immunological responses will be analysed (e.g., IL-6, IL-8, IL-1β, TNFα, C-reactive protein, IFNγ) | assessed in the phase 1 (10 days) - at visit nº 2, 3, 4 (3 days, 3 h/day) | 
| Maternal inflammatory markers | Fasting and post-experiment blood samples will be collected using venous puncture in the antecubital vein. Metabolic markers related to inflammatory-immunological responses will be analysed (e.g., IL-6, IL-8, IL-1β, TNFα, C-reactive protein, IFNγ) | assessed in the phase 2 (only pregnant women, 10 days) - at visit nº 6, 7, 8 (3 days, 3 h/day) | 
| Placenta weight | Placenta weight (grams) | assessed at birth - 30 minutes | 
| Placenta biopsies | Eight biopsies will be collected, four on the maternal site and four on the fetal side. Relevant placental proteins (growth factors and cytokines) related to insulin signalling, glucose metabolism, and inflammation will be analysed (e.g., GM-CSF, GCSF, MCP1, TNF-α, IL-6, EGF, IFN-γ, IL-8, IL-10, IL-1β). | collected at birth - 1 hour | 
| Neonate weight | Neonate weight (grams) | assessed at birth - 5 minutes | 
| Placenta efficiency | Neonate weight divided by placenta weight | estimated after birth - 3 minutes |