Diabetes Mellitus, Non-Alcoholic Fatty Liver Disease, Total Pancreatectomy
Conditions
Keywords
Glucagon, Stable isotope, Energy expenditure, Lipid metabolism, Glucose metabolism, Appetite
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).
Interventions
DRUGGlucagon
Glucagon (4 ng/kg/min)
DRUGSaline
Placebo
Sponsors
University of Copenhagen
Steno Diabetes Center Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 plasma concentration of lipids | 0, 60,150 minutes | Total cholesterol, VLDL, LDL, HDL, FFA |
| Food intake | 30 minutes (150-180) minutes | Ad libitum meal |
| Changes in appetite sensation | 0,30,60,90,120,150 minutes | Visual analogue scale |
| Changes in resting energy expenditure and oxidation rate | 0, 150 minutes | Measured by indirect calorimetry |
Countries
Denmark
Outcome results
None listed