Liver hormones are key metabolic regulators and increased in metabolic diseases, including fatty liver disease. The underlying mechanisms driving the elevated levels are currently unknown and presents a major challenge in understanding the interplay between liver hormones and fatty liver disease. The project aims to investigate what stimulates the liver to secrete its hormones and why the secretion is increased in patients with fatty liver disease. The investigator (Associate Prof. Nicolai J Wewer Albrechtsen) will investigate the direct and indirect effects of an amino acid amino infusion on the secretion of hepatokines in individuals with and without metabolic dysfunction-associated steatotic liver disease (MASLD).
The liver secretes signaling molecules, (termed hepatokines) to the blood circulation which are powerful metabolic regulators and biomarkers of liver disease. Some of the more studied hepatokines include follistatin, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) and they have been sown to improve glucose tolerance, reduce liver fat content and regulate appetite. In dysregulated metabolic conditions, including obesity, MASLD and type 2 diabetes, the circulating levels of hepatokines are increased. It could be speculated that the body increases hepatokine levels as a feedback mechanism to combat dysregulated metabolism. However, the underlying mechanisms driving the elevated levels in metabolic disease are currently unknown. The secretion of follistatin, FGF21 and GDF15 from the liver has been suggested to be stimulated by glucagon and amino acids. In dysregulated metabolic diseases, circulating levels of glucagon and amino acids are often increased and are highly dependent on hepatic steatosis. Increased levels of hepatokines observed in dysregulated metabolic individuals could therefore be attributed to an increase in circulating glucagon, amino acids, or a combination of both. The study aims to explore the direct and indirect effect of amino acids on the regulation of hepatokines in individuals with and without MASLD. The study evaluates the acute effect of an amino acid infusion with and without a concomitant infusion of the somatostatin analogue octreotide to eliminate endogenous production of glucagon, thus isolating the direct effect of amino acids. , The investigators hypothesizes that an amino acid infusion will increase the secretion of hepatokines independent of glucagon.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
30
The experimental days consist of four study days: 1. Assessment of liver fat and visceral fat by magnetic resonance imaging (MRI; 6-point Dixon) (study day A) 2. Somatostatin infusion (4 hours) plus amino acid infusion (45 minutes) (study day B) 3. Saline infusion (4 hours) plus amino acid infusion (45 minutes) (study day C) 4. Somatostatin infusion (4 hours) plus saline infusion (45 minutes) (study day D) The subjects will participate in the experimental days (study day B to D) in randomized order on three different days. For study day B to D, at timepoint t = -75, subjects will receive either; a 240-minute intravenous infusion of a somatostatin analogue (at 200 ng/kg/min (infusion rate will not exceed 1000 µg/hour) or saline. After 75 minutes (timepoint t = 0), the subjects will receive a 45-minute intravenous infusion of amino acids or saline at 3.885 ml/kg/hour. In total, blood will be sampled 11 times over a period of 6 hours and 15 minutes.
Bispebjerg University Hospital
Copenhagen, Denmark
The direct (amino acid + somatostatin) versus the indirect (amino acid + placebo) effect of amino acids on circulating levels of follistatin.
Defined as the difference in incremental AUC0-300 min (iAUC) of follistatin between study day B and study day C in healthy individuals.
Time frame: From blood sample at minute 0 until blood sample at minute 300.
The direct (amino acid + somatostatin) versus the indirect (amino acid + placebo) effect of amino acids on circulating levels of FGF21 and GDF15
Defined as the difference in iAUC0-300 min between study day B and study day C in healthy individuals.
Time frame: From blood sample at minute 0 until blood sample at minute 300.
The direct versus the indirect effect of amino acids on circulating levels of hepatokines (follistatin, FGF21 and GDF15).
Defined as the difference in iAUC0-300 min of hepatokines between study day B and study day C in individuals with MASLD.
Time frame: From blood sample at minute 0 until blood sample at minute 300
Differences between healthy and MASLD in the increase in hepatokines during study day B (direct effect of amino acids)
Defined as the differences in iAUC0-300 min of hepatokines between healthy and MASLD
Time frame: From blood sample at minute 0 until blood sample at minute 300
Differences between healthy and MASLD in the increase in hepatokines during study day C (indirect effect of amino acids).
Defined as the differences in iAUC0-300 min of hepatokines between healthy and MASLD
Time frame: From blood sample at minute 0 until blood sample at minute 300
The inhibitory effect of somatostatin versus the stimulatory effect of amino acids on glucagon, insulin and C-peptide levels during study day B in healthy and MASLD.
Defined as the difference between iAUC -75-0 min and iAUC0-45 min in both groups
Time frame: From blood sample at minute -75 until blood sample at minute 45
Differences in glucagon, insulin and C-peptide concentrations between study day B and C in healthy and MASLD
Defined as the difference between iAUC0-300 min during study day B and C in healthy and MASLD
Time frame: From blood sample at minute 0 until blood sample at minute 300
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