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

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04924504
• Other study ID #: PADME
• Status: Recruiting
• Start date: May 1, 2021
• Est. completion date: December 2023

Study information

• Verified date: November 2022
• Source: University of Aarhus
• Contact: Anna S Koefoed, MD
• Phone: +45 93 50 80 69
• Email: annask[@]clin.au.dk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diabetes, Gestational
• Gestational Diabetes
• Glucose Metabolism Disorders
• Insulin Resistance
• Insulin Sensitivity
• Metabolic Diseases
• Overweight
• Overweight and Obesity
• Pregnancy in Diabetic
• Pregnancy in Diabetics
• Pregnancy, High Risk

Intervention

Other:
• No interventions
No interventions

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus	Aarhus N

Sponsors (4)

Lead Sponsor	Collaborator
University of Aarhus	Aalborg University Hospital, Aarhus University Hospital, The University of Queensland

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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