Changes of hepatic metabolism and lipidomic profile with biochemical improvement of acromegaly

Paul Fellinger; Lorenz Pfleger; Hannes Beiglboeck; Clemens Baumgartner; Nara Marella; Alexander Micko; Stefan Wolfsberger; Greisa Vila; Anton Lmger; Alexandra Kautzky-Willer; Martin Krssak; Thomas Scherer; Peter Wolf; Michael Krebs; Yvonne Winhofer

doi:10.1530/endoabs.99.RC5.7

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Endocrine Abstracts (2024) 99 RC5.7 | DOI: 10.1530/endoabs.99.RC5.7

ECE2024 Rapid Communications Rapid Communications 5: Pituitary and Neuroendocrinology | Part I (8 abstracts)

Changes of hepatic metabolism and lipidomic profile with biochemical improvement of acromegaly

Paul Fellinger ¹ , Lorenz Pfleger ² , Hannes Beiglboeck ¹ , Clemens Baumgartner ¹ , Nara Marella ³ , Alexander Micko ⁴ , Stefan Wolfsberger ⁴ , Greisa Vila ¹ , Anton Lmger ¹ , Alexandra Kautzky-Willer ¹ , Martin Krssak ^1,2 , Thomas Scherer ¹ , Peter Wolf ¹ , Michael Krebs ¹ & Yvonne Winhofer ¹

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¹Medical University of Vienna, Endocrinology and Metabolism, Wien, Austria; ²Medical University of Vienna, Biomedical Imaging and Image-Guided Therapy, Hochfeld MR Zentrum (High Field MR Center), Wien, Austria; ³CeMM Forschungszentrum für Molekulare Medizin GmbH, Wien, Austria; ⁴Medical University of Graz, Neurosurgery, Graz, Austria

Overview: Despite marked insulin resistance, patients with active acromegaly have low hepatocellular lipid content (IHL) and an unfavourable hepatic lipid composition (UI). As previously shown, inadequate mitochondrial activity in the liver might counteract lipid accumulation in the liver. The purpose of this study was to understand changes in hepatic metabolism, and lipidomic profile with therapy of acromegaly.

Methods: We prospectively included thirteen subjects (5 female; age: 48.3±12.7 years) with active acromegaly, which was diagnosed by elevated serum IGF-1 concentrations and lack of GH level suppression (>1 ng/ml) after ingestion of 75 mg glucose during a standardized two-hour oral glucose tolerance test (OGTT). For further metabolic characterization, participants underwent 31P/1H-7T-MR-spectroscopy of the liver, an OGTT, as well as plasma metabolomic and lipidomic profiling at baseline and twelve months after inclusion.

Results: As expected IGF-I decreased in all patients after therapy with 7 out of 11 patients reaching biochemical control, defined as IGF-1 below age and sex specific upper limit of normal (IGF-I-ULN) of 120% (IGF-I ULN: before 296.1±119.7%; after 115.3±52.4%; P=<0.001). Two patients were lost to follow up after twelve months. Insulin resistance, measured with HOMA-IR decreased significantly (median difference -20; P<0.01). IHL increased (median difference: 0.92%; P=0.016), whereas UI decreased significantly after twelve months (median difference -3.6%; P=0.016). The hepatic mitochondrial ATP synthase activity parameter relative to the IHL content also decreased significantly after twelve months. The lipid classes of ceramides, sphingomyelins, as well as lysophosphatidylcholines decreased significantly, whereas alkyl-phosphatidyl-ethanolamines increased significantly with improvement of acromegaly.

Conclusion: This study shows that with biochemical improvement of acromegaly, lipid composition as well hepatic mitochondrial activity changes significantly and might therefore indicate a causal relation between growth hormone (GH) excess and hepatic lipid accumulation. Furthermore, a reduction in lipid classes, like ceramides and sphingomyelins, which are associated with insulin resistance gives a more detailed insight into mechanisms of insulin resistance associated with acromegaly. In conclusion, this study offers valuable insight into direct antisteatotic pathways of GH as well as the direct effects of GH on the metabolomic profile.