Clinical trial NCT04924504: Mechanisms Behind Severe Insulin Resistance During Pregnancy in Women With Glucose Metabolic Disorders (SIR-MET)
Official title: Mechanisms Behind Severe Insulin Resistance During Pregnancy in Women With Glucose Metabolic Disorders (SIR-MET)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Diabetes Mellitus, Type 2
Gestational Diabetes
Overweight and Obesity
Pregnancy in Diabetic
Insulin Resistance
Insulin Sensitivity
Pregnancy, High Risk
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Aalborg University Hospital
name: The University of Queensland
First posted: 2021-06-14
Enrollment: 24
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population consist of pregnant women followed at The Department of Gynaecology and Obstetrics at Aarhus University Hospital or Aalborg University Hospital. Cases are diagnosed with gestational diabetes or pregestational type 2 diabetes and are treated with a total daily insulin dose \>= 100 units/day. Controls are either healthy without pregestational or gestational diabetes or diagnosed with gestational diabetes or pregestational type 2 diabetes and are treated with a total daily insulin dose \<= 75 units/day

Brief summary: The aim of this study is to describe the metabolic changes during pregnancy in women with type 2 diabetes or gestational diabetes in order to detect the pathophysiological mechanisms behind severe insulin resistance during pregnancy as well as the short- and long term consequences for mother and child.

Included pathophysiological mechanisms potentially associated with severe insulin resistance are: Maternal hormonal, inflammatory and metabolic markers in the blood, as well as the level, content and bioactivity of exosomes and genetic variants associated with overweight and diabetes.

In addition to the analysis on maternal blood, the same analysis will be performed on umbilical cord blood in order to determine the correlation between markers associated with insulin sensitivity in maternal and umbilical blood. Furthermore, fetal metabolic changes influence on fetal growth and development will be evaluated. Postpartum, the breast milk will also be examined for metabolic active substances that could influence the newborns growth and metabolism.

Investigating one potential short-term consequence of diabetes during pregnancy, the association between insulin resistance and structural and functional changes in the placenta will be examined as well as the consequences of such changes on fetal growth and development.

Investigating one potential long-term consequence of diabetes during pregnancy, the association between treatment with high doses of insulin during pregnancy and the future risk of developing cardiovascular diseases and heart failure will be examined.

Detailed description: This is a prospective observational study including app. 24 pregnant women from the outpatient clinics at Department of Obstetrics and Gynecology at Aalborg and Aarhus University Hospital.

The study includes 8 healthy women without pregestational or gestational diabetes, 8 women with gestational diabetes or type 2 diabetes with a total daily insulin dose \<= 75 units/day and 8 women with gestational diabetes or type 2 diabetes with a total daily insulin dose \>= 100 units/day.

There are three study days: One in gestational week 28-36 (day 1), one during labour (day 2) and one 6 months postpartum (day 3).

Hormonal profiles and inflammatory markers will be measured at all three study days. During labour both maternal and umbilical blood will be collected. The blood sample analysis will include HbA1c, glukose, insulin, C-peptid, human anti-insulin antibody, lipid profile, liver enzymes, creatinine, FGF-21, TSH, Cortisol, human chorionic gonadotropin, estradiol, progesterone, SHBG, prolactin, human placental lactogen, placental growth hormone, PAPP-A, sFlt-1, PP13, IGF-1, IGF-BP's, Leptin, Adiponectin, hs-CRP, IL-6, IL-10, IL-1α, IFN-ɣ, TNF-α, ICAM1, VCAM and CD163. In addition to this, exosomes will be isolated precisely and profiling of the content of exosomes will be performed using in vitro assays. Proteomics and miRNAs sequencing will be employed. Furthermore, whole genome analysis will be applied to find genetic variants associated with overweight and diabetes (genetic analysis will not be performed on umbilical cord blood). Insulin sensitivity will be estimated using the homeostasis model assessment, IS-HOMA, based on fasting C-peptid and glucose concentrations.

In addition to the blood samples, the following examinations will be performed at day 1:

* Height, weight and bioelectrical impedance analysis
* Urine sample (Albumin-to-creatinine ratio)
* Blood pressure and 24-hour ambulatory blood pressure monitoring
* Central arterial pressure waveform analysis (SphygmoCor)
* Echocardiography
* Fetal ultrasound
* MRI scan of the placenta and heart

In addition to the blood samples, the following examinations will be performed at day 2:

* Placenta will be collected for a postpartum histopathological examination
* Breast milk (analyzed for lipid profile, leptin, adiponectin, prolactin, prolactin-binding protein, oxytocin, ghrelin, insulin, hs-CRP, IL-6, IL-10, IL-1α, IFN-ɣ, TNF-α, ICAM1, VCAM, CD163 and untargeted metabolomics)
* Skinfold measurement of the newborn with a caliper

In addition to the blood samples, the following examinations will be performed at day 3:

* Height, weight and bioelectrical impedance analysis
* Urine sample (Albumin-to-creatinine ratio)
* Blood pressure and 24-hour ambulatory blood pressure monitoring
* Central arterial pressure waveform analysis (SphygmoCor)
* Echocardiography
* Breast milk (analyzed for lipid profile, leptin, adiponectin, prolactin, prolactin-binding protein, oxytocin, ghrelin, insulin, hs-CRP, IL-6, IL-10, IL-1α, IFN-ɣ, TNF-α, ICAM1, VCAM, CD163 and untargeted metabolomics)

Eligibility criteria: Inclusion Criteria:

* Pregnant women at The Department of Gynaecology and Obstetrics at Aarhus University Hospital or Aalborg University Hospital.
* Women have to be in 1 of 3 categories: Healthy without pregestational or gestational diabetes, type 2 diabetes treated with insulin or gestational diabetes treated with insulin.

Exclusion Criteria:

* Age \< 18 years
* Not able to read and understand danish
* Previous bariatric surgery
* Treatment with systemic corticosteroids
* Other severe chronic diseases such as inflammatory bowel disease, cystic fibrosis and type 1 diabetes

Primary outcomes:
measure: Association between insulin sensitivity Versus structural and functional changes in the placenta
timeFrame: Gestational week 28-36
Secondary outcomes:
measure: Association between structural and functional changes in the placenta Versus fetal growth and development
timeFrame: Gestational week 28-36
measure: Changes from baseline in serum or plasma concentration of metabolic, hormonal and inflammatory markers
timeFrame: Gestational week 28-36, at labour and 6 months postpartum
measure: Assocation between the serum or plasma concentration of metabolic, hormonal and inflammatory markers Versus Insulin sensitivity
timeFrame: Gestational week 28-36, at labour and 6 months postpartum
measure: Assocation between the serum or plasma concentration of metabolic, hormonal and inflammatory markers in maternal blood Versus the serum or plasma concentrations of the same markers in umbilical cord blood
timeFrame: At labour
measure: Changes from baseline in the level, content and bioactivity of exosomes in serum and plasma.
timeFrame: Gestational week 28-36, at labour and 6 months postpartum
measure: Association between the level, content and bioactivity of exosomes in serum and plasma Versus Insulin sensitivity
timeFrame: Gestational week 28-36, at labour and 6 months postpartum
measure: Association between the level, content and bioactivity of exosomes in serum and plasma in maternal blood Versus the level, content and bioactivity of exosomes in serum and plasma in umbilical cord blood
timeFrame: At labour
measure: Association between genetic variants related to overweight and diabetes Versus Insulin sensitivity
timeFrame: Gestational week 28-36
measure: Changes from baseline in body weight and body composition.
timeFrame: Gestational week 28-36 and 6 months postpartum
measure: Changes from baseline in 24-hour ambulatory blood pressure (systolic and diastolic)
timeFrame: Gestational week 28-36 and 6 months postpartum
measure: Changes from baseline in cardiac function
timeFrame: Gestational week 28-36 and 6 months postpartum
measure: Changes from baseline in the central aortic pressure waveform
timeFrame: Gestational week 28-36 and 6 months postpartum
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Aarhus N
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
Study officials:
affiliation: Aarhus University, Aarhus University Hospital
name: Anna S Koefoed, MD
role: PRINCIPAL_INVESTIGATOR
References: