Glucagon Resistance in Patients With MASLD and T2DM

Mechanisms for Glucagon Resistance as Driver of Metabolic Associated Steatotic Liver Disease and Cardiovascular Disease in Humans With Type 2 Diabetes

The goal of this clinical trial is to investigate the sensitivity to glucagon in patients with type 2 diabetes mellitus (T2DM), with and without metabolic associated fatty liver disease (MASLD).

The main questions it aims to answer are:

1. Is the sensitivity to glucagon with respect to hepatic FA oxidation and suppression of VLDL-TG secretion impaired in humans with T2DM and MASLD?
2. Is glucagon resistance and MASLD reflected in an aberrated lipidomic/metabolomic profile in blood and adipose tissue?

Researchers will compare patients with T2DM with and without MASLD to see if the response to basal and high levels of glucagon differs between the groups.

Participants will attend 2 short visits and 1 full-day visit, including:

• Body scan (DXA) to check fat and bone composition
• MRI to measure liver fat.
• Blood tests.
• Ultrasound to check liver stiffness and scarring.
• Fat biopsies
• 8-hour hormone (including glucagon) and tracer infusion
• PET-CT scans

Inclusion Criteria:

• BMI > 26 kg/m²
• confirmed diagnosis of Type 2 Diabetes Mellitus (T2DM) min. 6 months prior enrollment
• steatosis FF% > 5,6% on MR spectroscopy for MAFLD group

Exclusion Criteria:

• Alcohol abuse (>10 units per week for both sexes) or other substance abuse

• Smoking

• Current or previous malignant disease

• Blood donation within the last 3 months prior to the study day

• Participation in studies involving radioactive isotopes within the past 3 months

• Pregnancy

• Severely dysregulated type 2 diabetes mellitus (haemoglobin A1c ≥ 100 mmol/mol)

• C-peptide < 200 pmol/L

• Previous acute myocardial infarction (AMI)

• Clinical symptoms of heart failure

• Current or previous malignant disease

• Known ongoing systemic disease, except for dyslipidaemia and hypertension

• Regular use of medication that may affect lipid and glucose metabolism, including insulin treatment, regular use of over-the-counter medications, and hormonal contraception. Exceptions:

  1. Participants treated with statins may be included following a 2-week washout period prior to the experimental study day.
  2. Participants receiving oral glucose-lowering therapy for T2DM and antihypertensive medication may be included provided that medication is withheld on the study day only.
  3. Participants receiving weekly injectable glucagon-like peptide-1 receptor agonists (GLP-1 analogues) may be included following a 1-week washout period prior to the study day.