The Role of Pregnancy-induced Gallbladder Dysmotility in the Pathophysiology of Gestational Diabetes Mellitus

The primary aim of the study is to evaluate postprandial gallbladder emptying and plasma concentrations of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1) during third trimester of pregnancy in women with gestational diabetes mellitus (GDM) compared with age and body mass index (BMI)-matched pregnant control women with normal glucose tolerance (NGT).

Study Overview

• Status: Completed
• Conditions: Gestational Diabetes Mellitus

Detailed Description

Gestational diabetes mellitus (GDM) defined as glucose intolerance first detected during pregnancy is a strong predictor of future type 2 diabetes. Patients with GDM exhibit severely reduced postprandial responses of the insulinotropic and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1), which normalise alongside remission of GDM after delivery. Ingested nutrients and bile acids constitute potent stimulators of GLP-1 secretion. Reduced postprandial GLP-1 responses likely contribute to the pathophysiology of GDM, but the mechanisms are unknown. Based on previous studies studying gallbladder emptying during pregnancy, we hypothesize that reduced postprandial GLP-1 responses in GDM is due to incomplete gallbladder emptying during third trimester. If our hypothesis proves right, reduced gallbladder emptying and ensuing attenuation of postprandial GLP-1 secretion will constitute an obvious and druggable target for the treatment of GDM.

Fifteen women with gestational diabetes mellitus and 15 age and body mass index (BMI)-matched pregnant women with normal glucose tolerance will be enrolled in the study. For each subject, the study encompasses one screening visit and two experimental days; one during third trimester of pregnancy and one 3-9 months post partum. On experimental days, a standardised liquid mixed meal test (added 1.5 g of paracetamol for evaluation of gastric emptying according to paracetamol absorption) with repeated ultrasonographic gallbladder scans and blood samples will be performed.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Fifteen women with gestational diabetes mellitus and 15 age and body mass index (BMI)-matched pregnant women with normal glucose tolerance will be enrolled in the study. Only pregnant women who have been tested for gestational diabetes mellitus will be enrolled in the study.

Description

Inclusion criteria - women with gestational diabetes mellitus (GDM):

• GDM diagnosed according to current Danish guidelines (plasma glucose (PG) concentration at 120 min after a 75 g oral glucose tolerance test (OGTT) ≥9.0 mM)
• Caucasian ethnicity
• Age >18 years
• Pre-pregnancy BMI <30 kg/m2 and third trimester BMI <35 kg/m2
• Informed oral and written consent

Exclusion criteria - women with gestational diabetes:

• Anaemia (haemoglobin <7.5 mM)
• Previous preeclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and/or pregnancy-induced intrahepatic cholestasis
• Gastrointestinal disease, previous gastric or intestinal resection, cholecystectomy and/or any major intra-abdominal surgery
• Previous pancreatic disease and/or neoplasia
• Postpartum use of hormonal contraception including intrauterine device
• Any condition the investigator group suspect would interfere with trial participation

Inclusion criteria - control group:

• Normal glucose tolerance (fasting plasma glucose (PG) concentration ≤6.0 mM and PG concentration at 120 min after a 75 g-OGTT <7.8 mM)
• Caucasian ethnicity
• Age >18 years
• Pre-pregnancy BMI <30 kg/m2 and third trimester BMI <35 kg/m2
• Informed oral and written consent

Exclusion criteria - control group:

• Anaemia (haemoglobin <7.5 mM)
• Previous preeclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and/or pregnancy induced intrahepatic cholestasis
• Gastrointestinal disease, previous gastric or intestinal resection, cholecystectomy and/or any major intra-abdominal surgery
• Previous pancreatic disease and/or neoplasia
• Postpartum use of hormonal contraception including intrauterine device
• Verified prior GDM

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients with gestational diabetes mellitus (GDM); GDM diagnosed according to current Danish guidelines (plasma glucose (PG) concentration at 120 min after a 75 g oral glucose tolerance test (OGTT) ≥9.0 mM)
Pregnant women with normal glucose tolerance (control group); Pregnant women with normal glucose tolerance (fasting plasma glucose (PG) concentration ≤6.0 mM and PG concentration at 120 min after a 75 g-OGTT <7.8 mM)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GLP-1 response	Postprandial GLP-1 response (as assessed by area under curve (AUC) within 240 minutes after meal ingestion) during third trimester compared to 3-9 months postpartum.	240 minutes
Gallbladder emptying	Postprandial gallbladder emptying (evaluated as repeated measures of gallbladder volumes using bed-side ultrasonography within 240 minutes after meal ingestion) during third trimester compared to 3-9 months postpartum.	240 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responses of glucose, insulin, C-peptide, glucagon, GIP	Postprandial responses of glucose, insulin, C-peptide, glucagon (as assessed by area under curve (AUC) during third trimester compared to 3-9 months postpartum.	240 minutes
Gastric emptying	Postprandial responses of paracetamol (as assessed by area under curve (AUC) during third trimester compared to 3-9 months postpartum.	240 minutes
Bile acid and gallbladder physiology	Postprandial responses of GLP-2, CCK, total bile acids, C4 and FGF-19 (as assessed by area under curve (AUC) during third trimester compared to 3-9 months postpartum.	240 minutes
Oxytocin	Postprandial responses of oxytocin (as assessed by area under curve (AUC) during third trimester compared to 3-9 months postpartum.	240 minutes
GDF15	Postprandial responses of GDF-15 (as assessed by area under curve (AUC) during third trimester compared to 3-9 months postpartum.	240 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2019
• Primary Completion (Actual): October 30, 2020
• Study Completion (Actual): October 30, 2020

Study Registration Dates

• First Submitted: September 25, 2019
• First Submitted That Met QC Criteria: September 25, 2019
• First Posted (Actual): September 27, 2019

Study Record Updates

• Last Update Posted (Actual): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 18, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: pregnancy; gestational diabetes mellitus; glp-1; gallbladder motility
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pregnancy Complications; Diabetes Mellitus; Diabetes, Gestational
• Other Study ID Numbers: H-19036095

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