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Hepatic Metabolic Changes in Response to Glucagon Infusion

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

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

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




Primary Outcome Measures :
  1. Hepatic lipid metabolism [ Time Frame: -120,-90,-60,-30,-15,0,30,60,90,120,135,150,180 min ]
    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: -120,0,150 min ]
    Total cholesterol, VLDL, LDL, HDL, FFA

  2. Changes in plasma concentration of amino acids [ Time Frame: -120,0,150 min ]
  3. Changes in plasma concentration of fibroblast growth factor 21 (FGF-21) [ Time Frame: -120,0,150 min ]
  4. Endogenous glucose production [ Time Frame: -120,-90,-60,-30,-15,0,30,60,90,120,135,150,180 min ]
    Measured by glucose tracer

  5. Changes in resting energy expenditure and oxidation rate [ Time Frame: 0, 150 min ]
    Measured by indirect calorimetry

  6. Liver fat content and stiffness [ Time Frame: 0, 150 min ]
    Fibroscan

  7. Food intake [ Time Frame: 30 minutes (150-180) min ]
    Ad libitum meal

  8. Changes in appetite sensation [ Time Frame: -120,-90,-60,-30,0,30,60,90,120,150,180 min ]
    Visual analogue scale



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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03526445


Contacts
Contact: Iben Rix Petersen, MD +45 24917125 iben.rix.petersen@regionh.dk

Locations
Denmark
Steno Diabetes Center Copenhagen Recruiting
Hellerup, Denmark, 2900
Contact: Iben Rix Petersen, MD    +45 24917125    iben.rix.petersen@regionh.dk   
Sponsors and Collaborators
Steno Diabetes Center
University of Copenhagen
Investigators
Study Director: Filip Krag Knop, Prof. Steno Diabetes Center Copenhagen, Clinical Metabolic Physiology

Responsible Party: Steno Diabetes Center
ClinicalTrials.gov Identifier: NCT03526445     History of Changes
Other Study ID Numbers: H-18003696
First Posted: May 16, 2018    Key Record Dates
Last Update Posted: June 6, 2018
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:
Glucagon
Stable isotope
Energy expenditure
Lipid metabolism
Glucose metabolism
Appetite

Additional relevant MeSH terms:
Diabetes Mellitus
Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Digestive System Diseases
Glucagon
Glucagon-Like Peptide 1
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Incretins