Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts
Journal article, 2022
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, TGFβ, 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.
Author
A. S. Meijnikman
Spaarne Hospital
University of Amsterdam
C. C. Van Olden
University of Amsterdam
O. Aydin
Spaarne Hospital
University of Amsterdam
H. Herrema
University of Amsterdam
Dorota Kaminska
University of Eastern Finland
Dimitra Lappa
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Ville Männistö
Kuopio University Hospital
Valentina Tremaroli
Wallenberg Lab.
L. E. Olofsson
Wallenberg Lab.
Maurits de Brauw
Spaarne Hospital
A. W. Van de Laar
Spaarne Hospital
J. Verheij
University of Amsterdam
V. E.A. Gerdes
Spaarne Hospital
University of Amsterdam
Thue W. Schwartz
University of Copenhagen
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Fredrik Bäckhed
University of Copenhagen
Sahlgrenska University Hospital
Wallenberg Lab.
Päivi Pajukanta
University of California at Los Angeles
Jussi Pihlajamäki
Kuopio University Hospital
University of Eastern Finland
Tamar Tchkonia
Mayo Clinic
James L. Kirkland
Mayo Clinic
Folkert Kuipers
University of Groningen
M. Nieuwdorp
University of Amsterdam
A. K. Groen
University of Amsterdam
University of Groningen
Diabetes
00121797 (ISSN) 1939327X (eISSN)
Vol. 71 9 1929-1936Subject Categories
Endocrinology and Diabetes
Gastroenterology and Hepatology
Nutrition and Dietetics
DOI
10.2337/db21-1076
PubMed
35713877