TY - JOUR
T1 - Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts
AU - Meijnikman, Abraham S.
AU - van Olden, Casper C.
AU - Aydin, Ömrüm
AU - Herrema, Hilde
AU - Kaminska, Dorota
AU - Lappa, Dimitra
AU - Männistö, Ville
AU - Tremaroli, Valentina
AU - Olofsson, Louise E.
AU - de Brauw, Maurits
AU - van de Laar, Arnold
AU - Verheij, Joanne
AU - Gerdes, Victor E. A.
AU - Schwartz, Thue W.
AU - Nielsen, Jens
AU - Bäckhed, Fredrik
AU - Pajukanta, P. ivi
AU - Pihlajamäki, Jussi
AU - Tchkonia, Tamar
AU - Kirkland, James L.
AU - Kuipers, Folkert
AU - Nieuwdorp, Max
AU - Groen, Albert K.
N1 - Funding Information: Acknowledgments. The authors thank the nursing staff and all participating individuals for making this study possible and Manuela Kr€amer and Robert Jakubowicz (Wallenberg Laboratory, University of Gothenburg) for the preparation of the samples. The authors also thank the CSC–IT Center for Science, Finland, for computational resources and pathologist Vesa K€arj€a for histological characterization in KOBS cohort (Department of Pathology, University of Eastern Finland) and the members of the Dutch Liver Pathology Panel: Carolien M. Bronkhorst (Jeroen Bosch Hospital), Michael Doukas (Erasmus MC), Paul Drillenburg (OLVG Amsterdam), Arantza Farina (Amsterdam University Medical Centers), Natascha N.T. Goemaere (Maasstad Hospital), Mieke Jonker (Gelre Hospitals), Miangela M. Lacle (University Medical Center Utrecht), and Iryna Samarski (Maastricht UMC). Funding. This study was funded by Leducq consortium grant CVD01 and the Novo Nordisk Foundation (NNF15OC0016798). D.K. was supported by Academy of Finland grant (contract 316458). The KOBS study (principal investigator J.P.) was supported by Kuopio University Hospital Project grants (EVO/VTR grants 2005–2019) and an Academy of Finland grant (contract no. 138,006). A.S.M. is supported by EFSD/Lilly. F.K. is supported by the Noaber Foundation. T.T. and J.L.K. were supported by National Institutes of Health grants AG013925 and AG062413 and the Translational Geroscience Network (AG061456), Robert and Arlene Kogod Center on Aging, the Connor Group, Robert J. and Theresa W. Ryan, and the Ted Nash Long Life and Noaber Foundations. Duality of Interest. M.N. is on the Scientific Advisory Board of Caelus Health, Amsterdam, the Netherlands. F.B. is on the board of directors of Me-tabogen AB, Sweden. However, none of these possible conflicts of interest Publisher Copyright: © 2022 by the American Diabetes Association.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Diabetes Mellitus, Type 2/complications
KW - Humans
KW - Hyperinsulinism/complications
KW - Insulin
KW - Insulin Resistance
KW - Liver
KW - Non-alcoholic Fatty Liver Disease/complications
UR - http://www.scopus.com/inward/record.url?scp=85137008651&partnerID=8YFLogxK
U2 - https://doi.org/10.2337/db21-1076
DO - https://doi.org/10.2337/db21-1076
M3 - Article
C2 - 35713877
SN - 0012-1797
VL - 71
SP - 1929
EP - 1936
JO - Diabetes
JF - Diabetes
IS - 9
ER -