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Hepatic Metabolic Changes in Response to Glucagon Infusion

Primary Purpose

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

Status

Completed

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Glucagon

Saline

About this trial

This is an interventional basic science trial for Non-Alcoholic Fatty Liver Disease focused on measuring Glucagon, Stable isotope, Energy expenditure, Lipid metabolism, Glucose metabolism, Appetite

Eligibility Criteria

30 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Glucagon

Saline

Arm Description

3 hours i.v. infusion of Glucagon (4 ng/kg/min).

3 hours i.v. infusion of saline

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Changes in plasma concentration of lipids

Total cholesterol, VLDL, LDL, HDL, FFA

Changes in plasma concentration of amino acids

Changes in plasma concentration of fibroblast growth factor 21 (FGF-21)

Endogenous glucose production

Measured by glucose tracer

Changes in resting energy expenditure and oxidation rate

Measured by indirect calorimetry

Food intake

Ad libitum meal

Changes in appetite sensation

Visual analogue scale

Full Information

NCT ID

NCT03526445

First Posted

May 3, 2018

Last Updated

August 5, 2019

Sponsor

Steno Diabetes Center Copenhagen

Collaborators

University of Copenhagen

1. Study Identification

Unique Protocol Identification Number

NCT03526445

Brief Title

Hepatic Metabolic Changes in Response to Glucagon Infusion

Official Title

Hepatic Metabolic Changes in Response to Glucagon Infusion

Study Type

Interventional

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Completed

Study Start Date

May 1, 2018 (Actual)

Primary Completion Date

June 12, 2019 (Actual)

Study Completion Date

June 12, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Steno Diabetes Center Copenhagen

Collaborators

University of Copenhagen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Glucagon, Stable isotope, Energy expenditure, Lipid metabolism, Glucose metabolism, Appetite

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

27 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Glucagon

Arm Type

Active Comparator

Arm Description

3 hours i.v. infusion of Glucagon (4 ng/kg/min).

Arm Title

Saline

Arm Type

Placebo Comparator

Arm Description

3 hours i.v. infusion of saline

Intervention Type

Drug

Intervention Name(s)

Glucagon

Other Intervention Name(s)

GlucaGen

Intervention Description

Glucagon (4 ng/kg/min)

Intervention Type

Drug

Intervention Name(s)

Saline

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

Hepatic lipid metabolism

Description

evaluated using isotopic labelled tracer kinetics: lipolysis, ketogenesis, very low-density lipoprotein (VLDL) secretion and free fatty acid (FFA) re-esterification rate

Time Frame

-120,-30,-15,0,30,60,90,120,135,150 minutes

Secondary Outcome Measure Information:

Title

Changes in plasma concentration of lipids

Description

Total cholesterol, VLDL, LDL, HDL, FFA

Time Frame

0, 60,150 minutes

Title

Changes in plasma concentration of amino acids

Time Frame

0, 60, 120, 150 minutes

Title

Changes in plasma concentration of fibroblast growth factor 21 (FGF-21)

Time Frame

-120,0,150 minutes

Title

Endogenous glucose production

Description

Measured by glucose tracer

Time Frame

-120,-30,-15,0,30,60,90,120,135,150 minutes

Title

Changes in resting energy expenditure and oxidation rate

Description

Measured by indirect calorimetry

Time Frame

0, 150 minutes

Title

Food intake

Description

Ad libitum meal

Time Frame

30 minutes (150-180) minutes

Title

Changes in appetite sensation

Description

Visual analogue scale

Time Frame

0,30,60,90,120,150 minutes

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Filip Krag Knop, Prof.

Organizational Affiliation

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

Official's Role

Study Director

Facility Information:

Facility Name

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

City

Hellerup

ZIP/Postal Code

2900

Country

Denmark

12. IPD Sharing Statement

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Hepatic Metabolic Changes in Response to Glucagon Infusion

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