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

Author:

Meijnikman Abraham S.12,van Olden Casper C.1,Aydin Ömrüm12,Herrema Hilde1,Kaminska Dorota3,Lappa Dimitra4,Männistö Ville5,Tremaroli Valentina6,Olofsson Louise E.6,de Brauw Maurits2,van de Laar Arnold2,Verheij Joanne7,Gerdes Victor E.A.12,Schwartz Thue W.8,Nielsen Jens4,Bäckhed Fredrik6910,Pajukanta Päivi1112ORCID,Pihlajamäki Jussi35,Tchkonia Tamar13,Kirkland James L.13,Kuipers Folkert14,Nieuwdorp Max1,Groen Albert K.114ORCID

Affiliation:

1. 1Departments of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands

2. 2Department of Surgery, Spaarne Hospital, Hoofddorp, the Netherlands

3. 3Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

4. 4Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden

5. 5Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio Finland

6. 6Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

7. 7Department of Pathology, University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands

8. 8Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

9. 9Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

10. 10Region Västra Götaland, Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden

11. 11Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA

12. 12Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA

13. 13Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN

14. 14Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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