Hepatic Metabolic Changes in Response to Glucagon Infusion

• ClinicalTrials.gov Identifier: NCT03526445
• Recruitment Status: Completed
• First Posted: May 16, 2018
• Last Update Posted: August 6, 2019
• Sponsor: Steno Diabetes Center Copenhagen
• Collaborator: University of Copenhagen
• Information provided by (Responsible Party): Steno Diabetes Center Copenhagen

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	Not Applicable

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 (Clinical Trial)
• 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: June 12, 2019
• Actual Study Completion Date: June 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 Name: GlucaGen
Placebo Comparator: Saline; 3 hours i.v. infusion of saline	Drug: Saline; Placebo

Outcome Measures

Primary Outcome Measures :

1. Hepatic lipid metabolism [ Time Frame: -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 :

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

Eligibility Criteria

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

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.

Contacts and Locations

Locations

Denmark

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

Hellerup, Denmark, 2900

Sponsors and Collaborators

Steno Diabetes Center Copenhagen

University of Copenhagen

Investigators

• Study Director: Filip Krag Knop, Prof.; Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen

More Information

• Responsible Party: Steno Diabetes Center Copenhagen
• ClinicalTrials.gov Identifier: NCT03526445
• Other Study ID Numbers: H-18003696
• First Posted: May 16, 2018
• Last Update Posted: August 6, 2019
• Last Verified: May 2018

• 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

Keywords provided by Steno Diabetes Center Copenhagen:

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

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Digestive System Diseases; Glucagon; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs