Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts

Abraham S. Meijnikman, Casper C. van Olden, Ömrüm Aydin, Hilde Herrema, Dorota Kaminska, Dimitra Lappa, Ville Männistö, Valentina Tremaroli, Louise E. Olofsson, Maurits de Brauw, Arnold van de Laar, Joanne Verheij, Victor E.A. Gerdes, Thue W. Schwartz, Jens Nielsen, Fredrik Bäckhed, Päivi Pajukanta, Jussi Pihlajamäki, Tamar Tchkonia, James L. KirklandFolkert Kuipers, Max Nieuwdorp, Albert K. Groen

Research output: Contribution to journalArticlepeer-review


Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors and may contribute to development of type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). In this article, we investigated whether chronically elevated insulin levels are associated with cellular senescence in the human liver. In 107 individuals undergoing bariatric surgery, hepatic senescence markers were assessed by immunohistochemistry as well as transcriptomics. A subset of 180 participants from the ongoing Finnish Kuopio OBesity Surgery (KOBS) study was used as validation cohort. We found plasma insulin to be highly associated with various markers of cellular senescence in liver tissue. The liver transcriptome of individuals with high insulin revealed significant upregulation of several genes associated with senescence: p21, TGFb, PI3K, HLA-G, IL8, p38, Ras, and E2F. Insulin associated with hepatic senescence independently of NAFLD and plasma glucose. By using transcriptomic data from the KOBS study, we could validate the association of insulin with p21 in the liver. Our results support a potential role for hyperinsulinemia in induction of cellular senescence in the liver. These findings suggest possible benefits of lowering insulin levels in obese individuals with insulin resistance.

Original languageEnglish (US)
Pages (from-to)1929-1936
Number of pages8
Issue number9
StatePublished - Sep 2022

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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