Hepatic Metabolic Changes in Response to Glucagon Infusion

Study Overview
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Brief Summary
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The objective of the study is to investigate how exogenously administered glucagon affects hepatic lipid, glucose and protein metabolism as well as appetite, food intake and resting energy expenditure.

Detailed Description
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Most research has focused on the role of the pancreatic hormone, insulin, and insulin signalling (or lack of) in the development of NAFLD. However, increasing evidence suggest that the other major gluco-regulatory pancreatic hormone glucagon is also implicated in lipid metabolism and recent human data from studies investigating the effect of glucagon receptor antagonism suggest that glucagon signalling may be essential for maintaining a fat-free liver. This, combined with observations of increased degree of hepatic steatosis in patients after total pancreatectomy, who are devoid of pancreatic glucagon and typically are lean and peripherally insulin sensitive, suggests that glucagon may play a hitherto unrecognised role in the pathophysiology of NAFLD. The hypothesis of the study is that exogenously delivered glucagon will drive hepatic metabolism in a lipolytic direction and increase resting energy expenditure without affecting appetite and food intake. The acute effects of exogeneous glucagon infusion on hepatic lipid metabolism will be evaluated in patients after total pancreatectomy (no endogenous pancreatic hormones), in patients with type 1 diabetes (no endogenous insulin production) and in healthy controls (preserved endogenous pancreatic hormones).

Official Title
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Hepatic Metabolic Changes in Response to Glucagon Infusion

Conditions
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Non-Alcoholic Fatty Liver Disease, Total Pancreatectomy, Diabetes Mellitus

Intervention / Treatment
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* Drug: Glucagon
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pancreatectomised patients Patients who have undergone total pancreatectomy Caucasian between 30-80 Blood haemoglobin >7.0 mmol/l for males and >6.5 mmol/l for females Informed consent Patients with type 1 diabetes Patients with C-peptide negative type 1 diabetes Caucasian between 30-80 Blood haemoglobin >7.0 mmol/l for males and >6.5 mmol/l for females Informed consent Healthy controls Normal fasting plasma glucose (< 7 mmol/l) and normal HbA1c (< 6.5 %) (30,31) Normal blood haemoglobin (>8.3 mmol/l for males and >7.3 mmol/l for females) Caucasian between 30-80 Informed consent Exclusion Criteria: All subjects Inflammatory bowel disease Gastrointestinal resection (other than the gastro-duodenectomy performed in connection with total pancreatectomy) and/or ostomy Nephropathy (eGFR < 60 ml/min/1.73 m² and/or urine albumin > 20 mg/L) Known liver disease (excluding non-alcoholic fatty liver disease) Severe lung disease Pregnancy and/or breastfeeding Uncontrolled hypertension and/or significant cardiovascular disease Treatment with drugs with potential steatogenic side-effects within three months prior to inclusion Alcohol consumption above 21 units/week for men and 14 units/week for women Any condition that the investigator feels would interfere with the safety of the trial participation or the safety of the subject.

Ages Eligible for Study
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Minimum Age: 30 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: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glucagon<br>3 hours i.v. infusion of Glucagon (4 ng/kg/min). | Drug: Glucagon<br>* Glucagon (4 ng/kg/min)<br>* Other names: GlucaGen;|
| Placebo Comparator: Saline<br>3 hours i.v. infusion of saline | Drug: Saline<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic lipid metabolism | evaluated using isotopic labelled tracer kinetics: lipolysis, ketogenesis, very low-density lipoprotein (VLDL) secretion and free fatty acid (FFA) re-esterification rate | -120,-30,-15,0,30,60,90,120,135,150 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma concentration of lipids | Total cholesterol, VLDL, LDL, HDL, FFA | 0, 60,150 minutes | 
| Changes in plasma concentration of amino acids |  | 0, 60, 120, 150 minutes | 
| Changes in plasma concentration of fibroblast growth factor 21 (FGF-21) |  | -120,0,150 minutes | 
| Endogenous glucose production | Measured by glucose tracer | -120,-30,-15,0,30,60,90,120,135,150 minutes | 
| Changes in resting energy expenditure and oxidation rate | Measured by indirect calorimetry | 0, 150 minutes | 
| Food intake | Ad libitum meal | 30 minutes (150-180) minutes | 
| Changes in appetite sensation | Visual analogue scale | 0,30,60,90,120,150 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon, Stable isotope, Energy expenditure, Lipid metabolism, Glucose metabolism, Appetite