American Diabetes Association
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Hyperinsulinemia is highly associated with markers of hepatocytic senescence in two independent cohorts

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posted on 2022-06-17, 15:19 authored by Abraham S. Meijnikman, Casper C. van Olden, Omrum 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. Kirkland, Folkert Kuipers, Max Nieuwdorp, Albert K. Groen


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 and Non-Alcoholic Fatty Liver Disease (NAFLD). Here, 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.


This study was funded by Leducq consortium grant CVD01 and Novo Nordisk Foundation (NNF15OC0016798). DK was supported by the Academy of Finland grant (contract 316458). The Kuopio Obesity Surgery Study (PI J.P.) was supported by Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019) and the Academy of Finland grant (Contract no. 138,006). A.S.M is supported by EFSD/Lilly. FK is supported by the Noaber Foundation. JLK and TT were supported by National Institute of Health grants AG013925, AG062413, and the Translational Geroscience Network (AG061456), Robert and Arlene Kogod, the Connor Group, Robert J. and Theresa W. Ryan, and the Ted Nash Long Life and Noaber Foundations.