Hepatic Metabolic Changes in Response to Glucagon Infusion

Diabetes Mellitus Clinical Trial

Official title:

Hepatic Metabolic Changes in Response to Glucagon Infusion

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03526445
• Other study ID #: H-18003696
• Status: Completed
• Phase: N/A
• Start date: May 1, 2018
• Est. completion date: June 12, 2019

Study information

• Verified date: May 2018
• Source: Steno Diabetes Center Copenhagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: June 12, 2019
• Est. primary completion date: June 12, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Fatty Liver
• Liver Diseases
• Non-Alcoholic Fatty Liver Disease
• Total Pancreatectomy

Intervention

Drug:
• Glucagon
Glucagon (4 ng/kg/min)
• Saline
Placebo

Locations

Country	Name	City	State
Denmark	Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen	Hellerup

Sponsors (2)

Lead Sponsor	Collaborator
Steno Diabetes Center Copenhagen	University of Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

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