Glucagon Resistance in Patients With NAFLD

Study Overview
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Brief Summary
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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.

Official Title
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In-depth Studies of Glucagon Resistance on Hepatic Glucose, Fatty Acid and Triglyceride Kinetics and Generation of Toxic Lipid Intermediates in NAFLD and NASH.

Conditions
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Non-Alcoholic Fatty Liver Disease, Non-alcoholic Steatohepatitis, Glucose Metabolism Disorders

Intervention / Treatment
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* Other: glucagon


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 38 Years
Maximum Age: 68 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Healthy overweight subjects<br>MR spectroscopy verified no steatosis | Other: glucagon<br>* 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.<br>|
| Active Comparator: Subjects with non-alcoholic fatty liver disease<br>MR spectroscopy verified steatosis, no steatohepatitis on liver biopsy | Other: glucagon<br>* 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.<br>|
| Active Comparator: Subjects with non-alcoholic steatohepatitis<br>MR spectroscopy verified steatosis, steatohepatitis on liver biopsy | Other: glucagon<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VLDL-triglyceride kinetics (appearance rate (µmol/min) and oxidation (µmol/min)) | Ex vivo labeled VLDL [14C]-triolein tracer technique. Oxidation is measured by specific activity in exhaled air. | 30 minutes at steady-state | 
| Endogen glucose production (mmol/kg/min) | 3-3H glucose tracer technique | 30 minutes at steady-state | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LPL-activity (lipoprotein lipase, µmol/h) | Measured by the 'glycerol-stabilized substrate' method | 30 minutes at steady-state | 
| VLDL-triglyceride-fatty acid uptake in muscle and fatty tissue (%) | Measurement of fatty acid concentration and specific activity in muscle- and adipose tissue biopsies | 30 minutes at steady-state | 
| Expression of relevant genes in tissues | PCR in muscle- and adipose tissue biopsies | 30 minutes at steady-state | 
| Fatty acid turnover (µmol/min) | Infusion af [9,10-3H] palmitate and measurement of specific activity in muscle and adipose tissue | 30 minutesat steady-state |