Center for Molecular Medicine Cologne

Niessen, Carien M | Hanßen, Ruth - C 12

Skin insulin resistance in type II diabetes and its associated diseases

Introduction

Obesity and type 2 diabetes mellitus (T2DM) are increasingly prevalent worldwide. T2DM comes with a wide range of co-morbidities including cardiovascular, kidney and skin diseases. Whether these comorbidities are driven by long-term hyperglycemia, chronic inflammation and/or direct insulin resistance in these organs is still largely unclear. Moreover, little is known whether early insulin resistance in non-classical endocrine organs, like the skin, promotes T2DM development. We found that epidermal loss of insulin/IGF-1 signaling (IIS), short term high fat diet (HFD), or genetically obese mice share similar phenotypes including a change in stem cell activity, reduced stratification, impaired barrier function, and sensitized skin inflammatory responses, thus directly linking epidermal insulin resistance to diabetes-associated skin phenotypes. The overall aim of this proposal is to understand whether and how skin insulin resistance promotes T2DM and its associated skin morbidities. We will combine genetic mouse models, human T2DM patients as well as healthy and prediabetic cohorts, multi-omics and imaging to identify how diet-induced changes in epidermal insulin resistance is communicated within the skin and to other organs under normal and high fat diet conditions taking sex and external skin barrier challenges in account, and explore the predictive and therapeutic opportunities of our findings in humans.

Figure 1

Clinical Relevance

Type 2 diabetes Mellitus (T2DM) is increasingly prevalent with rising premature mortality rates. Currently, over 6% of the worldwide population is affected, illustrating a great unmet need for new therapies to counteract this obesity-related pandemic. We will address the hypothesis that diet-induced changes in skin insulin sensitivity directly contribute to T2DM development and to its co-morbidities, and using human cohorts, will explore clinical and therapeutic implications of our findings.

Approach

  • Combine genetic mouse models for epidermal insulin/IGF resistance and/or T2DM with different short term and long-term challenges to skin barrier function in combination with different diets
  • Asses epidermal barrier structure and function and skin structure and function to examine communication within the skin.   Determine changes in central insulin/metabolic tissues including liver, fat and muscle to examine systemic communication
  • assess changes in cell fate, inflammation, lipid signaling and metabolic fate and communication using single cell sequencing, proteomics and lipidomics/metabolomics to identify molecular mediators of insulin resistance.
  • Assess role of stress signaling and stress factors in hyperglycemic and diabetic phenotypes.
  • Use functional barrier tests and identified markers to examine skin phenotypes in human cohorts
  • Use the skin barrier as a sensor to assess effects of interventions in hyperglycemic subjects an T2DM patients

Hanssen R, Rigoux L, Albus K, Kretschmer AC, Thanarajah SE, Chen W, Hinze Y, Giavalisco P, Steculorum S,  Cornely OA,  Brüning JC, Tittgemeyer M. (2023) Circulating uridine dynamically and adaptively regulates food intake in humans. Cell Rep. Med. 4: 100897, doi: 10.1016/j.xcrm.2022.100897

Peskoller M, Bhosale A, Göbel K, Löhr J, Miceli S, Perot S, Persa OD, Rübsam M, Shah J, Zhang H, Niessen, CM. (2022) How to build and regenerate a functional skin barrier: the adhesive and cell shaping travels of a keratinocyte. J. Invest. Dermatol. 42:1020-1025. doi: 10.1016/j.jid.2021.12.034 (https://www.youtube.com/watch?v=bRYX0hJHRS8)

Koester J, Miroshnikova Y, Ghatak S, Chacón-Martínez C, Morgner J, Li X, Atanassov I, Altmuller J, Birk DE, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, and Wickström S. Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters. Nature Cell Biology 23:771-781. doi: 10.1038/s41556-021-00705-x

Hanssen R, Kretschmer AC, Rigoux L, Albus K, Thanarajah SE, Sitnikow T, Melzer C,  Cornely AC, BRuning. JC, Tittgemeyer M (2021)GLP-1 and hunger modulate incentive motivation depending on insulin sensitivity in humans. Mol. Metab. 45: 101163. DOI: 10.1016/j.molmet.2021.101163

Peters F*, Tellkamp F*, Brodesser S, Wachmuth E, Tosetti B, Karow U, Bloch W, Utermohlen O, Krönke M, Niessen CM (2020) Murine epidermal Ceramide Synthase 4 is a key regulator of skin barrier homeostasis. J. Investig. Derm. https://doi.org/10.1016/j.jid.2020.02.006

Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, MetgeF, Boucas J, Vihinen H, Jokitalo E, García Arcos JM, HoffmannB, Merkel R, Niessen CM, Dahl KN, and WickströmSA. (2020) Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181:800-817.e22. doi: 10.1016/j.cell.2020.03.052

OstermannAL, WunderlichCM, Schneiders L, Vogt MC, Woeste M, Belgardt, BF Niessen  CM, MartinyB, SchaussAC, Frommolt P, Nikolaev N, Hövelmeyer RC, Sears RC KochPJ, Gunzel D., BrüningJC, Wunderlich FT.(2019) Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nature Metabolism, 1: 371-389

Clayton RW, Göbel K, Niessen CM, Paus R, van Steensel MAM, and Lim X. (2019) Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis.Br J Dermatol. 2019 May 6. doi: 10.1111/bjd.17981. [Epub ahead of print] Review.

Peters, F, Vorhagen S, Brodesser S, Jacobshagen K, Brüning JC, Niessen CM#, Krönke M.#(2015) Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling. J. Invest. Dermatol. 135:1501-9

Guenschmann, C., Stachelscheid H., Akyüz M.D, Schmitz A., Missero, C., Bruning, J.C. and Niessen CM (2013) IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition. Developmental Cell 26(2): 176-87

  • Kasper JY, Laschke MW, Koch M, Alibardi L, Magin T, Niessen CM, and Del Campo A (2023). Actin-templated Structures: Nature's Way to Hierarchical Surface Patterns (Gecko's Setae as Case Study). Adv Sci (Weinh), e2303816. doi:10.1002/advs.202303816.
     
  • Rubsam M, Pullen R, Tellkamp F, Bianco A, Peskoller M, Bloch W, Green KJ, Merkel R, Hoffmann B, Wickstrom SA, and Niessen CM (2023). Polarity signaling balances epithelial contractility and mechanical resistance. Sci Rep 13, 7743. doi:10.1038/s41598-023-33485-5.
Prof. Dr. Carien M Niessen CMMC Cologne
Prof. Dr. Carien M Niessen

Department Cell Biology of the Skin - CECAD Research Center

CMMC - PI - C 12
Executive Board Member

+49 221 478 89512

+49 221 478 6360

Department Cell Biology of the Skin - CECAD Research Center

Joseph-Stelzmann-Str. 26

50931 Cologne

https://niessen.cecad-labs.uni-koeln.de/home

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Publications - Carien Niessen

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Dr. Ruth Hanßen CMMC Cologne
Dr. Ruth Hanßen

Center for Endocrinology, Diabetes and Preventive Medicine

CMMC - Co-PI - C 12

Center for Endocrinology, Diabetes and Preventive Medicine

Current: Institute of Metabolic Science, Cambridge University, UK

https://endokrinologie.uk-koeln.de/forschung/ag-translationale-stoffwechselforschung/

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Ruth Hanßen

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Group Members

Lab coordinator
Stéphanie Miceli
Senior scientist
Matthias M. Rübsam
PostDoc
Gladiola Goranci-Buzhala
PhD student
Hanyin Zhang, Aishwarya Bhosale
Skyler Perot, Lea Trojahn

Master student
Ta-Chieh Chen
medical student
Lukas Koch, Zirui Yu
Technician
Julia Löhr