Involvement of Steatosis-induced Glucagon Resistance in Hyperglucagonaemia

Study Overview
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Brief Summary
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The purpose of this study is to examine whether non-alcoholic fatty liver disease (NAFLD) is associated with hepatic glucagon resistance and hyperglucagonemia.

Detailed Description
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Hyperglucagonemia is a common condition in obesity, prediabetes and type 2 diabetes. It increases the hepatic glucose production, thus contributing to type 2-diabetic hyperglycemia. In the current study we wish to examine whether non-alcoholic fatty disease (NAFLD) results in hepatic glucagon resistance. This could result in hyperglucagonemia through a feedback mechanism acting on the level of pancreatic alpha cells. Cirrhosis and type 1 diabetes, respectively, has previously been shown to be associated with hepatic glucagon resistance but it has not been examined in relation to NAFLD in humans so far.

Official Title
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Involvement of Steatosis-induced Glucagon Resistance in Hyperglucagonaemia

Conditions
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Non-alcoholic Fatty Liver Disease

Intervention / Treatment
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* Procedure: Liver biopsy
* Other: Pancreatic clamp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal fasting plasma glucose and HbA1c < 6.0% Between 18.5 and 25 kg/m2 or between 30 and 40 kg/m2 Normal haemoglobin Normal coagulation factor II, VII and X, INR and thrombocytes Age above 25 years Informed consent Exclusion Criteria: Diabetes Prediabetes (impaired glucose tolerance and/or impaired fasting plasma glucose) First-degree relatives with diabetes Nephropathy (eGFR < 60ml/min and/or albuminuria) Liver disease (ALAT and/or serum ASAT >2x normal values) Use of anticoagulative medicine like Clopidogrel og Warfarin Pregnancy and/or breastfeeding Age above 80 years Any condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 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 |
| --- | --- |
| Experimental: Healthy, lean<br>15 healthy, lean subjects. Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed. | Procedure: Liver biopsy<br>* One ultrasound guided liver biopsy<br>Other: Pancreatic clamp<br>* I.v. infusions of somatostatin and insulin (basal rate) for will be adminstered for 3 hours. Glucagon will administered for 3 hours in total with infusion rates at a basal and a high physiological rate for 1.5 hours each.<br>|
| Experimental: Obese, otherwise healthy<br>15 obese, otherwise healthy subjects Will have a liver biopsy, and on the experimental day a pancreatic clamp will be performed. | Procedure: Liver biopsy<br>* One ultrasound guided liver biopsy<br>Other: Pancreatic clamp<br>* I.v. infusions of somatostatin and insulin (basal rate) for will be adminstered for 3 hours. Glucagon will administered for 3 hours in total with infusion rates at a basal and a high physiological rate for 1.5 hours each.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous glucose production |  | 0-180 min | 
| Amino acid metabolism |  | 0-180 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Degree of steatosis |  | baseline | 
| Total RNA sequencing of liver biopsies |  | baseline |