Impaired skin barrier and advanced skin aging in the long term hyperglycemic condition

Abstract

Type 2 diabetes mellitus (DM) is a prevalent disease that induces many disorders of the skin such as xerosis, pruritus, infection, and delayed wound healing. These are major factors leading to a decreased quality of life in DM patients as well as advanced aged people. Many diabetic skin complications have been speculated from impaired skin barrier homeostasis like an aged skin. However, little is known about the skin barrier state of type 2 DM patients which dysfunction may be a major cause of their skin problems. This study was investigated whether the long standing hyperglycemic condition such as type 2 DM impairs skin barrier homeostasis in proportional to the duration of the hyperglycemia, and the associated pathomechanism of this relationship. For our experiments we utilized the Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rat as an animal model of the long term hyperglycemic condition such as human type 2 DM, which develops DM spontaneously with aging, and Long-Evans-Tokushima-Otsuka (LETO) rats as a control strain. Metabolic changes and skin barrier homeostasis in OLETF and LETO rats were evaluated at ages of 15, 20, 30 and 45 weeks. Body weight and hemoglobin A1c were significantly increased in OLETF rats in proportional to the duration. Likewise, intraperitoneal glucose tolerance tests revealed higher glucose levels in OLETF rats. These results confirmed the OLETF rats as a reliable animal model of human type 2 DM. Long term hyperglycemic condition decreased stratum corneum (SC) hydration and weakened SC integrity. And long term hyperglycemia delayed skin barrier homeostasis which also correlated with hemoglobin A1c levels. OLETF rats also exhibited decreased expression of epidermal lipid synthesis related enzymes and antimicrobial peptide levels with increasing age. Decreased epidermal lipid synthesis accounted for decreased lamellar body production. Dermal collagen density was decreased in the long term hyperglycemic condition due to decreasing tendency of type I procollagen and increased levels of MMP-13, a major collagenase. In addition, OLETF rats had significantly higher serum levels of advanced glycation end products (AGEs) and elevated levels of the receptor for AGEs in the epidermis. In conclusion, the long term hyperglycemic condition impairs skin barrier function including permeability and antimicrobial barriers in proportional to the hyperglycemia duration, which could be a major pathophysiology underlying cutaneous complications of DM. And the long standing hyperglycemia could accelerate skin aging.