Hepatic Metabolic Changes in Response to Glucagon Infusion

Sponsor

Steno Diabetes Center Copenhagen (Other)

Overall Status

Completed

CT.gov ID

NCT03526445

Collaborator

University of Copenhagen (Other)

Enrollment

Location

Arms

13.4

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Alcoholic Fatty Liver Disease Total Pancreatectomy Diabetes Mellitus	Drug: Glucagon Drug: Saline	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

Hepatic Metabolic Changes in Response to Glucagon Infusion

Actual Study Start Date :

May 1, 2018

Actual Primary Completion Date :

Jun 12, 2019

Actual Study Completion Date :

Jun 12, 2019

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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]
Changes in plasma concentration of fibroblast growth factor 21 (FGF-21) [-120,0,150 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

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.