title: Hyperglycemia Induces Skin Barrier Dysfunctions with Impairment of Epidermal Integrity in Non-Wounded Skin of Type 1 Diabetic Mice.
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.
authors.affiliation: Department of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Okano
authors.affiliation: Departments of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Departments of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Katagi
authors.affiliation: Industry-Academia-Government Collaboration Center of Nara Medical University, Nara, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Departments of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakae
authors.affiliation: Departments of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurakane
authors.affiliation: Department of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Internal Medicine, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.affiliation: Department of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Udagawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism; D053550:Keratin-10 / Q000096:biosynthesis / Q000235:genetics; D053547:Keratin-14 / Q000096:biosynthesis / Q000235:genetics; D053555:Keratin-5 / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D007328:Insulin; D053547:Keratin-14; D053555:Keratin-5; C507446:Krt14 protein, mouse; D008565:Membrane Proteins; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C064554:loricrin; D053550:Keratin-10