NAFLD - Non-Alcoholic Fatty Liver Disease, Type 2 Diabetes
Conditions
Brief summary
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum from simple reversible hepatic steatosis to inflammation and fibrosis termed steatohepatitis (NASH) and cirrhosis. Accumulating evidence indicates that NAFLD is associated with development of heart failure, abnormal ventricular glucose and fatty acid (FA) utilisation and cardiac steatosis. The mechanisms behind why some subjects progress from NAFLD to NASH and the link between cardiac involvement and NAFLD are poorly understood, but must include altered cardiac and intrahepatic lipid handling. Investigators plan comprehensive kinetic studies of heart and liver FA uptake and oxidation, ventricular function and substrate utilisation, and hepatic triglyceride (TG) secretion in order to assess mechanisms governing cardiac and hepatic lipid and glucose trafficking in subjects with type 2 diabetes with and without NAFLD and NASH and the relationship with heart function. In addition, the investigators will assess skeletal muscle and adipose tissue enzyme activities, gene expression and protein concentrations in type 2 diabetic subjects to define mechanisms involved in the cross-talk between heart, liver, muscle and adipose tissues. Investigators will address these questions using tracer techniques (11Cpalmitate PET tracers and triglyceride (TG) tracers) to study cardiac and liver substrate trafficking, as well as MR spectroscopy, echocardiography, muscle and fat biopsies in combination with state-of-the art muscle and adipose tissue enzyme kinetics, gene- and protein expression. The overarching goals are to define abnormalities and differences between NAFLD and NASH in hepatic lipid (FA and TG) metabolism.
Interventions
OTHERHyperinsulinemic euglycaemic clamp
Infusion of constant intravenous insulin to achieve hyperinsulinemia and concomitant infusion of glucose to maintain euglycemia (plasma glucose at 5 mM). Infusion of palmitate and VLDL-triglyceride tracer. PET/CT scans of heart and liver, both in basal period and during intervention.
Sponsors
Danish Diabetes Academy
University of Aarhus
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects with Type 2 Diabetes with and without NAFLD (steatosis FF% \> 5,6% on MR spectroscopy for NAFLD and NASH groups)
Exclusion criteria
* Active smoking * Comorbidity other than hypertension and hyperlipidemia * Fixed medical drug consumption (including insulin) except statins and anti-diabetic medications. However, statins and weekly based GLP-1 agonist must be paused 1 week before the examination date and other antidiabetic medication 3 days before the study date. * Patients with cancer or former cancer patients * Blood donation within the last 3 months prior to the study * Participation in experiments involving radioactive isotopes within the last 3 months * Alcohol abuse (over 21 items per week for men and over 14 for women) * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fatty acid uptake in Heart (mg/kg/min) | 1 day | Infusion of \[11-C\] palmitate and measured by PET/CT scan. |
| Fatty acid oxidation in Heart (µmol/min) | 1 day | Infusion of \[11-C\] palmitate and measured by PET/CT scan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fatty acid uptake in liver (mg/kg/min) | 1 day | Infusion of \[11-C\] palmitate and measured by PET/CT scan. |
| Fatty acid oxidation in liver (µmol/min) | 1 day | Infusion of \[11-C\] palmitate and measured by PET/CT scan. |
| VLDL-triglyceride secretion (µmol/min) | 1 day | Ex vivo labeled VLDL \[14C\]-triolein tracer technique. |
| VLDL-triglyceride uptake in adipose tissue (percent) | 1 day | Measurement of fatty acid concentration and specific activity in adipose tissue biopsies |
| VLDL-triglyceride uptake in muscle (percent) | 1 day | Measurement of fatty acid concentration and specific activity in muscle biopsies |
| VLDL-triglyceride oxidation (µmol/min) | 1 day | Oxidation is measured by specific activity in exhaled air. |
Countries
Denmark
Outcome results
None listed