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

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.

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