Niessen, Carien M | Hanßen, Ruth - C 12

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.

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.

• 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