Glucose Metabolism Disorders, Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis
Conditions
Brief summary
The investigators propose that the sensitivity to glucagon in hepatic lipid metabolism is impaired in subjects with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Moreover, they propose a dys-coordinated, reduced glucagon sensitivity in hepatic lipid metabolism and endogen glucose production in patients with NAFLD and NASH compared with healthy subjects and patients with simple steatosis. This reduced sensitivity may be the basis of a more severe dyslipidemia and the production of increased concentrations of toxic lipid intermediates in plasma and muscle tissue. The study will include healthy subjects with obesity and subjects with simple steatosis and NASH, tested at basal glucagonemia and moderate hyperglucagonemia to mimic insulin resistant levels during simultaneous somatostatin infusion and replacement doses of insulin and growth hormone. Infusion of palmitate, VLDL-triglyceride and glucose tracers in combination with indirect calorimetry as well as skeletal and adipose tissue biopsies will be employed to assess free fatty acid and VLDL-triglyceride kinetics (turnover, and oxidation) and hepatic fatty acid-esterification.
Interventions
OTHERglucagon
Infusion of low dose glucagon and high dose glucagon during simultaneous somatostatin infusion and replacement doses of insulin and growth hormone. Infusion of palmitate, VLDL-triglyceride and glucose tracers.
Sponsors
Danish Council for Independent Research
University of Aarhus
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
38 Years to 68 Years
Healthy volunteers
Yes
Inclusion criteria
* BMI \> 28 kg/m2 * steatosis FF% \> 5,6% on MR spectroscopy for NAFLD and NASH groups
Exclusion criteria
* active smoking * pregnancy * comorbidity other than hypertension and hyperlipidemia * participation in other radioactive isotope studies within the past 3-5 months (depending on radiation dose) * blood donation (within 3 months)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min)) | 30 minutes at steady-state | Ex vivo labeled VLDL \[14C\]-triolein tracer technique. Oxidation is measured by specific activity in exhaled air. |
| Endogen glucose production (mmol/kg/min) | 30 minutes at steady-state | 3-3H glucose tracer technique |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LPL-activity (lipoprotein lipase, µmol/h) | 30 minutes at steady-state | Measured by the 'glycerol-stabilized substrate' method |
| VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%) | 30 minutes at steady-state | Measurement of fatty acid concentration and specific activity in muscle- and adipose tissue biopsies |
| Expression of relevant genes in tissues | 30 minutes at steady-state | PCR in muscle- and adipose tissue biopsies |
| Fatty acid turnover (µmol/min) | 30 minutesat steady-state | Infusion af \[9,10-3H\] palmitate and measurement of specific activity in muscle and adipose tissue |
Countries
Denmark
Outcome results
None listed