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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Insulin Resistance; Pregnancy, High Risk; Overweight and Obesity; Insulin Sensitivity; Gestational Diabetes; Pregnancy in Diabetic
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Anticipated): 24

Contacts and Locations

• Study Contact: Name: Anna S Koefoed, MD; Phone Number: +45 93 50 80 69; Email: annask@clin.au.dk
• Study Contact Backup: Name: Per G Ovesen, Prof., MD; Email: perovese@rm.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9100
    • Recruiting
    • Aalborg University Hospital
    • Contact: Anne W Sørensen, M.D.; Phone Number: +45 93 50 80 69; Email: anns@rn.dk
  • Aarhus N
    • Aarhus, Aarhus N, Denmark, 8200
      • Recruiting
      • Aarhus University Hospital
      • Contact: Anna S Koefoed, M.D.; Phone Number: +45 25 32 35 38; Email: annask@clin.au.dk
      • Contact: Per G Ovesen, Prof., M.D.; Email: perovese@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• 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

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between insulin sensitivity Versus structural and functional changes in the placenta	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.	Gestational week 28-36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between structural and functional changes in the placenta Versus fetal growth and development	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.	Gestational week 28-36
Changes from baseline in serum or plasma concentration of metabolic, hormonal and inflammatory markers	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.	Gestational week 28-36, at labour and 6 months postpartum
Assocation between the serum or plasma concentration of metabolic, hormonal and inflammatory markers Versus Insulin sensitivity	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.	Gestational week 28-36, at labour and 6 months postpartum
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	Association between the metabolic, hormonal and inflammatory markers listed as Outcome 2 in maternal and umbilical cord blood	At labour
Changes from baseline in the level, content and bioactivity of exosomes in serum and plasma.	Exosomes will be isolated and profiling of the content will be performed using SWATH mass spectrometry and miRNA sequencing.	Gestational week 28-36, at labour and 6 months postpartum
Association between the level, content and bioactivity of exosomes in serum and plasma Versus Insulin sensitivity	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.	Gestational week 28-36, at labour and 6 months postpartum
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	Exosomes will be isolated and profiling of the content will be performed using SWATH mass spectrometry and miRNA sequencing.	At labour
Association between genetic variants related to overweight and diabetes Versus Insulin sensitivity	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.	Gestational week 28-36
Changes from baseline in body weight and body composition.	Body weight measured in kilograms. Body composition: Body fat percentage and muscle mass	Gestational week 28-36 and 6 months postpartum
Changes from baseline in 24-hour ambulatory blood pressure (systolic and diastolic)	Blood pressure includes the measurement of both systolic and diastolic blood pressure (mmHg).	Gestational week 28-36 and 6 months postpartum
Changes from baseline in cardiac function	Cardiac function will be evaluated through an echocardiography and a MRI scan of the heart	Gestational week 28-36 and 6 months postpartum
Changes from baseline in the central aortic pressure waveform	Central aortic pressure waveform will be evaluated through a noninvasive measurement with SphygmoCor technology	Gestational week 28-36 and 6 months postpartum

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; Aalborg University Hospital; The University of Queensland
• Investigators: Principal Investigator: Anna S Koefoed, MD, Aarhus University, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: June 7, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): November 23, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Body Weight; Hyperinsulinism; Pregnancy Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Overweight; Metabolic Diseases; Diabetes, Gestational; Pregnancy in Diabetics; Glucose Metabolism Disorders
• Other Study ID Numbers: PADME

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No