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Inhibition of 11?-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing.

ABSTRACT: Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11?-HSD1) is the key enzyme which controls local GC availability in target tissues such as skin. Since treatment with GCs has detrimental side effects on skin integrity, causing atrophy and delayed wound healing, we asked whether the dysregulated expression of 11?-HSD1 and consequently local GC levels in skin contribute to delayed wound healing in obese, diabetic db/db mice. We found increased expression of 11?-HSD1 during disturbed wound healing and in the healthy skin of obese, diabetic db/db mice. Cell analysis revealed increased expression of 11?-HSD1 in fibroblasts, myeloid cells and dermal white adipose tissue from db/db mice, while expression in keratinocytes was unaffected. Among diabetes- and obesity-related factors, insulin and insulin-like growth factor 1 down-regulated 11?-HSD1 expression in fibroblasts and myeloid cells, while glucose, fatty acids, TNF-? and IL-1? did not affect it. Insulin exerted its inhibitory effect on 11?-HSD1 expression by activating PI3-kinase/Akt-signalling. Consequently, the inhibitory effect of insulin is attenuated in fibroblasts from insulin-resistant db/db mice. We conclude that insulin resistance in obesity and diabetes prevents the down-regulation of 11?-HSD1, leading to elevated endogenous GC levels in diabetic skin, which could contribute to impaired wound healing in patients with DM.

SUBMITTER: Brazel CB

PROVIDER: S-EPMC7760287 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inhibition of 11β-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing.

Brazel Christina B CB Simon Jan C JC Tuckermann Jan P JP Saalbach Anja A

Journal of clinical medicine 20201128 12

Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is the key enzyme which controls local GC availability in target tissues such as sk ...[more]

PMID: 33260645

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Project description:BackgroundExcessive scarring and fibrosis are the most severe and common complications of burn injury. Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin, leading to skin thinning and impaired wound healing. Skin can generate active glucocorticoids locally through expression and activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). We hypothesised that burn injury would induce 11β-HSD1 expression and local glucocorticoid metabolism, which would have important impacts on wound healing, fibrosis and scarring. We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring.MethodsSkin 11β-HSD1 expression in burns patients and mice was examined. The impacts of 11β-HSD1 mediating glucocorticoid metabolism on burn wound healing, scar formation and scar elasticity and quality were additionally examined using a murine 11β-HSD1 genetic knockout model. Slow-release scaffolds containing therapeutic agents, including active and inactive glucocorticoids, were developed and pre-clinically tested in mice with burn injury.ResultsWe demonstrate that 11β-HSD1 expression levels increased substantially in both human and mouse skin after burn injury. 11β-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition, tensile strength and stiffness, features characteristic of excessive scarring. Application of slow-release prednisone, an inactive glucocorticoid, slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation, myofibroblast generation, collagen production and scar stiffness.ConclusionsSkin 11β-HSD1 expression is a key regulator of wound healing and scarring after burn injury. Application of an inactive glucocorticoid capable of activation by local 11β-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury.

Dataset Information

Inhibition of 11?-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing.

Publications

Inhibition of 11β-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing.

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