Mechanisms Behind Severe Insulin Resistance During Pregnancy in Women With Glucose Metabolic Disorders (SIR-MET)

Sponsor

University of Aarhus (Other)

Overall Status

Recruiting

CT.gov ID

NCT04924504

Collaborator

Aarhus University Hospital (Other), Aalborg University Hospital (Other), The University of Queensland (Other)

Enrollment

Locations

Anticipated Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2 Gestational Diabetes Overweight and Obesity Pregnancy in Diabetic Insulin Resistance Insulin Sensitivity Pregnancy, High Risk	Other: No interventions

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)

Study Design

Study Type:

Observational

Anticipated Enrollment :

24 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Mechanisms Behind Severe Insulin Resistance During Pregnancy in Women With Glucose Metabolic Disorders (SIR-MET)

Actual Study Start Date :

May 1, 2021

Anticipated Primary Completion Date :

Nov 30, 2022

Anticipated Study Completion Date :

Nov 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Type A Healthy pregnant women without pregestational or gestational diabetes	Other: No interventions No interventions
Type B Pregnant women with type 2 diabetes or gestational diabetes with a total daily insulin dose <= 75 units/day	Other: No interventions No interventions
Type C Pregnant women with type 2 diabetes or gestational diabetes with a total daily insulin dose >= 100 units/day	Other: No interventions No interventions

Arm

Intervention/Treatment

Type A

Healthy pregnant women without pregestational or gestational diabetes

Other: No interventions

No interventions

Type B

Pregnant women with type 2 diabetes or gestational diabetes with a total daily insulin dose <= 75 units/day

Other: No interventions

No interventions

Type C

Pregnant women with type 2 diabetes or gestational diabetes with a total daily insulin dose >= 100 units/day

Other: No interventions

No interventions

Outcome Measures

Primary Outcome Measures

Association between insulin sensitivity Versus structural and functional changes in the placenta [Gestational week 28-36]
Structural and functional changes in the placenta will be evaluated using a functional T2-weighted MRI scan. Specifically the function of placenta will be evaluated using a T2-value. Furthermore, structural and functional changes in the placenta will be evaluated through a postpartum histopathological examination of the placenta. Insulin sensitivity will be estimated using the homeostasis model assessment (HOMA-IR) based on fasting C-peptid and glucose concentrations.

Secondary Outcome Measures

Association between structural and functional changes in the placenta Versus fetal growth and development [Gestational week 28-36]
Structural and functional changes in the placenta will be evaluated using a functional T2-weighted MRI scan. Specifically the function of placenta will be evaluated using a T2-value. Furthermore, structural and functional changes in the placenta will be evaluated through a postpartum histopathological examination of the placenta. Fetal growth will be evaluated through a fetal ultrasound measuring biometric parameters and bloodflow.
Changes from baseline in serum or plasma concentration of metabolic, hormonal and inflammatory markers [Gestational week 28-36, at labour and 6 months postpartum]
Serum concentration of IGF-1, IGFBP-3, IGFBP-1, FGF-21, Leptin, Adiponectin, CD163, Human Chorionic Gonadotropin, Progesterone, C-peptide, Cortisol, Prolactin, Sex Hormone Binding Globulin, Estradiol, Free fatty acids, Human Placental Lactogen, Human Placental Growth Hormone, PAPP-A, sFlt-1, PP13 and human anti-insulin antibody. Plasma concentrations of IL-6, IL-10, IL-1alpha, IFN-gamma, TNF-alpha, ICAM1, VCAM, LDL, HDL, Triglyceride, Gamma-Glutamyl Transferase, Thyrotropin, glucose and HbA1c.
Assocation between the serum or plasma concentration of metabolic, hormonal and inflammatory markers Versus Insulin sensitivity [Gestational week 28-36, at labour and 6 months postpartum]
Association between the metabolic, hormonal and inflammatory markers listed as Outcome 2 and the Insulin sensitivity. Insulin sensitivity will be estimated using the homeostasis model assessment (HOMA-IR) based on fasting C-peptid and glucose concentrations.
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 [At labour]
Association between the metabolic, hormonal and inflammatory markers listed as Outcome 2 in maternal and umbilical cord blood
Changes from baseline in the level, content and bioactivity of exosomes in serum and plasma. [Gestational week 28-36, at labour and 6 months postpartum]
Exosomes will be isolated and profiling of the content will be performed using SWATH mass spectrometry and miRNA sequencing.
Association between the level, content and bioactivity of exosomes in serum and plasma Versus Insulin sensitivity [Gestational week 28-36, at labour and 6 months postpartum]
Exosomes will be isolated and profiling of the content will be performed using SWATH mass spectrometry and miRNA sequencing. Insulin sensitivity will be estimated using the homeostasis model assessment (HOMA-IR) based on fasting C-peptid and glucose concentrations.
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 [At labour]
Exosomes will be isolated and profiling of the content will be performed using SWATH mass spectrometry and miRNA sequencing.
Association between genetic variants related to overweight and diabetes Versus Insulin sensitivity [Gestational week 28-36]
Genetic variants will be examined using whole genome analysis (Illumina Novaseq System). Insulin sensitivity will be estimated using the homeostasis model assessment (HOMA-IR) based on fasting C-peptid and glucose concentrations.
Changes from baseline in body weight and body composition. [Gestational week 28-36 and 6 months postpartum]
Body weight measured in kilograms. Body composition: Body fat percentage and muscle mass
Changes from baseline in 24-hour ambulatory blood pressure (systolic and diastolic) [Gestational week 28-36 and 6 months postpartum]
Blood pressure includes the measurement of both systolic and diastolic blood pressure (mmHg).
Changes from baseline in cardiac function [Gestational week 28-36 and 6 months postpartum]
Cardiac function will be evaluated through an echocardiography and a MRI scan of the heart
Changes from baseline in the central aortic pressure waveform [Gestational week 28-36 and 6 months postpartum]
Central aortic pressure waveform will be evaluated through a noninvasive measurement with SphygmoCor technology

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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