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 Kirkland; Folkert Kuipers; Max Nieuwdorp; Albert K Groen

doi:10.2337/db21-1076

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 Kirkland

Folkert Kuipers, Max Nieuwdorp, Albert K Groen

University of Eastern Finland
Chalmers University of Technology
Kuopio University Hospital
Department of Pediatrics, The Queen Silvia Children's Hospital, University of Gothenburg Sweden, Gothenburg, Sweden.
Spaarne Gasthuis Academy, Spaarne Gasthuis Hospital, Hoofddorp, The Netherlands
Danish PCD Centre, Pediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark , Copenhagen, Denmark.
David Geffen School of Medicine at UCLA
Robert and Arlene Kogod Center on Aging
Department of Hematology University Medical Center Groningen University of Groningen Groningen The Netherlands.
Pediatric Intensive Care Unit, Emma Children's Hospital, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Amsterdam University Medical Centers
Spaarneziekenhuis
Amsterdam Cardiovascular Sciences
University of Gothenburg
University of Copenhagen
Mayo Clinic Rochester, MN
University of Groningen

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	1929-1936
Number of pages	8
Journal	Diabetes
Volume	71
Issue number	9
DOIs	https://doi.org/10.2337/db21-1076
Publication status	Published - 1 Sept 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Biomarkers
Diabetes Mellitus, Type 2/complications
Humans
Hyperinsulinism/complications
Insulin
Insulin Resistance
Liver
Non-alcoholic Fatty Liver Disease/complications

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10.2337/db21-1076

Hyperinsulinemia-is-highly-associated-with-markers-of-hepatocytic-senescence-in-two-independent-cohorts.pdfFinal published version, 70.3 MBLicence: Taverne

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Meijnikman, A. S., van Olden, C. C., Aydin, Ö., Herrema, H., Kaminska, D., Lappa, D., Männistö, V., Tremaroli, V., Olofsson, L. E., de Brauw, M., van de Laar, A., Verheij, J., Gerdes, V. E. A., Schwartz, T. W., Nielsen, J., Bäckhed, F., Pajukanta, P., Pihlajamäki, J., Tchkonia, T., ... Groen, A. K. (2022). Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts. Diabetes, 71(9), 1929-1936. https://doi.org/10.2337/db21-1076

@article{257790575d804188979d87518fd0fcfb,

title = "Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts",

abstract = "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.",

keywords = "Biomarkers, Diabetes Mellitus, Type 2/complications, Humans, Hyperinsulinism/complications, Insulin, Insulin Resistance, Liver, Non-alcoholic Fatty Liver Disease/complications",

author = "Meijnikman, \{Abraham S\} and \{van Olden\}, \{Casper C\} and {\"O}mr{\"u}m Aydin and Hilde Herrema and Dorota Kaminska and Dimitra Lappa and Ville M{\"a}nnist{\"o} and Valentina Tremaroli and Olofsson, \{Louise E\} and \{de Brauw\}, Maurits and \{van de Laar\}, Arnold and Joanne Verheij and Gerdes, \{Victor E A\} and Schwartz, \{Thue W\} and Jens Nielsen and Fredrik B{\"a}ckhed and P{\"a}ivi Pajukanta and Jussi Pihlajam{\"a}ki and Tamar Tchkonia and Kirkland, \{James L\} and Folkert Kuipers and Max Nieuwdorp and Groen, \{Albert K\}",

note = "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: {\textcopyright} 2022 by the American Diabetes Association.",

year = "2022",

month = sep,

day = "1",

doi = "10.2337/db21-1076",

language = "English",

volume = "71",

pages = "1929--1936",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "9",

}

Meijnikman, AS, van Olden, CC, Aydin, Ö , Herrema, H, Kaminska, D, Lappa, D, Männistö, V, Tremaroli, V, Olofsson, LE, de Brauw, M, van de Laar, A, Verheij, J , Gerdes, VEA, Schwartz, TW, Nielsen, J, Bäckhed, F, Pajukanta, P, Pihlajamäki, J, Tchkonia, T, Kirkland, JL, Kuipers, F, Nieuwdorp, M & Groen, AK 2022, 'Hyperinsulinemia Is Highly Associated With Markers of Hepatocytic Senescence in Two Independent Cohorts', Diabetes, vol. 71, no. 9, pp. 1929-1936. https://doi.org/10.2337/db21-1076

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, Päivi

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, 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.

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, 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.

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 - https://www.scopus.com/pages/publications/85137008651

U2 - 10.2337/db21-1076

DO - 10.2337/db21-1076

M3 - Article

C2 - 35713877

SN - 0012-1797

VL - 71

SP - 1929

EP - 1936

JO - Diabetes

JF - Diabetes

IS - 9

ER -

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

Abstract

UN SDGs

Keywords

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