Hepatic Metabolic Changes in Response to Glucagon Infusion

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Total Pancreatectomy
• Intervention / Treatment: Drug: Saline; Drug: Glucagon

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Glucagon; 3 hours i.v. infusion of Glucagon (4 ng/kg/min).	Drug: Glucagon; Glucagon (4 ng/kg/min); Other Names: GlucaGen
Placebo Comparator: Saline; 3 hours i.v. infusion of saline	Drug: Saline; Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: University of Copenhagen
• Investigators: Study Director: Filip Krag Knop, Prof., Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): June 12, 2019
• Study Completion (Actual): June 12, 2019

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: May 3, 2018
• First Posted (Actual): May 16, 2018

Study Record Updates

• Last Update Posted (Actual): August 6, 2019
• Last Update Submitted That Met QC Criteria: August 5, 2019
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Energy expenditure; Appetite; Glucagon; Lipid metabolism; Glucose metabolism; Stable isotope
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: H-18003696

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No