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 1929-1936

Subject Categories

Endocrinology and Diabetes

Gastroenterology and Hepatology

Nutrition and Dietetics

DOI

10.2337/db21-1076

PubMed

35713877

More information

Latest update

1/3/2024 9