Hepatic Metabolic Changes in Response to Glucagon Infusion

Not Applicable

Completed

• Conditions: Diabetes Mellitus; Non-Alcoholic Fatty Liver Disease; Total Pancreatectomy
• Interventions: Drug: Saline; Drug: Glucagon

• Registration Number: NCT03526445
• Lead Sponsor: Steno Diabetes Center Copenhagen

Brief Summary

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

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 Timeline

• Status Verified: 2018-05
• Study Start: 2018-05-01
• Study First Submitted: 2018-05-03
• Study First Submitted QC: 2018-05-03
• Study First Posted: 2018-05-16
• Primary Completion: 2019-06-12
• Study Completion: 2019-06-12
• Last Update Submitted: 2019-08-05
• Last Update Posted: 2019-08-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 27

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Saline	Saline	3 hours i.v. infusion of saline
Glucagon	Glucagon	3 hours i.v. infusion of Glucagon (4 ng/kg/min).

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen; 🇩🇰 Hellerup, Denmark