The skin

: a novel regulator of whole-body glucose metabolism

Abstract

Many epidemiological and clinical studies suggest a link between skin function and glucose homeostasis. For example, the inflammatory skin disease psoriasis is an independent risk-factor for Type 2 diabetes (T2D) development, and presence of psoriasis is a strong predictor of T2D progression and severity. Moreover, some skin-specific transgenic mouse models display altered whole-body glucose homeostasis. This suggests an important role for skin in regulating whole-body glucose metabolism. However, the underlying mechanisms are unclear. We hypothesised that the skin plays an important regulatory role in whole body glucose homeostasis, via the actions of skin-derived proteins and lipids, termed the skin secretome. Secondly, we hypothesised that the skin secretome becomes dysregulated in psoriasis, leading to impaired metabolic homeostasis. To investigate this hypothesis we adopted two main approaches: (1) The imiquimod (IMQ)-mouse model of psoriasis was used to investigate the effects of skin inflammation on whole-body metabolic phenotype in vivo. Glucose and insulin tolerance tests were conducted to assess whole-body glucose metabolism and key metabolic tissues - particularly pancreatic islets and subcutaneous adipose tissue (sAT) - were collected to assess tissue specific effects on skin inflammation. (2) Human explant skin was cultured and treated with imiquimod to induce a psoriasis-like phenotype. Skin conditioned media (CM) was collected and used to treat sAT and pancreatic islets. Islets and adipose tissue were then analysed to assess the regulatory effects of skin-derived factors present in the CM. IMQ-mice displayed signs of systemic and sAT inflammation and insulin resistance. Furthermore, pancreatic β-cells showed signs of compensation to insulin resistance in the form of improved glucose tolerance and increased β-cell function and proliferation. Consistent with a role for the skin secretome in these effects, incubation with skin-CM (IMQ) induced inflammation in healthy sAT. In contrast to the in vivo findings, incubation with skin-CM (IMQ) induced signs of β-cell dysfunction in healthy islets. In conclusion, this data demonstrates that skin inflammation alone can regulate whole-body glucose metabolism, via actions on key metabolic tissues including pancreatic islets and sAT. The effects on sAT appear to occur via direct actions of the skin secretome, whilst the effects on islets are potentially dependent on more complex inter-organ crosstalk. Fully characterising the skin secretome could lead to the identification of novel psoriasis co-morbidity biomarkers and therapeutic targets.

Date of Award	1 Apr 2020
Original language	English
Awarding Institution	King's College London
Supervisor	Paul Caton (Supervisor)