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| Name | Class |
|---|---|
| Bispebjerg Hospital | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Evaluating the direct and indirect effect of amino acids on the regulation of hepatokines | Experimental | Participants will be subjected to four experimental days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evaluating 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 | Other | The experimental days consist of four study days:
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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From blood sample at minute 0 until blood sample at minute 300. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From blood sample at minute 0 until blood sample at minute 300. |
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Group 1: (Lean controls)
Inclusion Criteria:
Exclusion Criteria:
Group 2 (individuals with hepatic steatosis):
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bispebjerg University Hospital | Copenhagen | Denmark |
We have not decided to share IPD as this also would require approval from the ethical and data approval committee.
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|
| 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. |
| 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 | 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 | 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 | 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 | From blood sample at minute 0 until blood sample at minute 300 |
| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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