Abstract
Diabetes causes skin complications, including xerosis and foot ulcers. Ulcers complicated by infections exacerbate skin conditions, and in severe cases, limb/toe amputations are required to prevent the development of sepsis. Here, we hypothesize that hyperglycemia induces skin barrier dysfunction with alterations of epidermal integrity. The effects of hyperglycemia on the epidermis were examined in streptozotocin-induced diabetic mice with/without insulin therapy. The results showed that dye leakages were prominent, and transepidermal water loss after tape stripping was exacerbated in diabetic mice. These data indicate that hyperglycemia impaired skin barrier functions. Additionally, the distribution of the protein associated with the tight junction structure, tight junction protein-1 (ZO-1), was characterized by diffuse and significantly wider expression in the diabetic mice compared to that in the control mice. In turn, epidermal cell number was significantly reduced and basal cells were irregularly aligned with ultrastructural alterations in diabetic mice. In contrast, the number of corneocytes, namely, denucleated and terminally differentiated keratinocytes significantly increased, while their sensitivity to mechanical stress was enhanced in the diabetic mice. We found that cell proliferation was significantly decreased, while apoptotic cells were comparable in the skin of diabetic mice, compared to those in the control mice. In the epidermis, Keratin 5 and keratin 14 expressions were reduced, while keratin 10 and loricrin were ectopically induced in diabetic mice. These data suggest that hyperglycemia altered keratinocyte proliferation/differentiation. Finally, these phenotypes observed in diabetic mice were mitigated by insulin treatment. Reduction in basal cell number and perturbation of the proliferation/differentiation process could be the underlying mechanisms for impaired skin barrier functions in diabetic mice.
Highlights
Skin complications are relatively common in diabetes
We demonstrated that the skin barrier dysfunction with impaired the proliferation/differentiation processes of keratinocytes in diabetic mice was attributable to hyperglycemia
While precise mechanisms remain unknown, these skin diseases would be associated with increase in the susceptibility to microbial infection in diabetes [39, 40]
Summary
Skin complications are relatively common in diabetes. Xerosis (dry skin) is a skin disease characterized by persistent itchiness and fissures in diabetic patients, and it often delays the process of wound healing, resulting in reduction in the patients’ quality of life [1]. A foot ulcer is a common skin disorder in diabetic patients This skin damage becomes more critical when complicated by a bacterial infection [2]. With respect to the molecular profile of non-wounded skin in diabetes, inconsistent results from studies using even the same type 2 diabetic mouse model, db/db mice, have been reported on commonly assessed skin proliferation/differentiation markers such as keratin 1 [8, 12]. One of the reasons for such contradictory results could be attributed to evidence obtained from various animal models (i.e., type 1 or type 2 diabetes, and mice or rats) as well as from humans, because studies on non-wounded skin in diabetes are relatively fewer compared with those on other complications such as kidney, retina, and peripheral nerves
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