Glucose Effects on Skin Keratinocytes Implications for Diabetes Skin Complications

Natalia Spravchikov, Galina Sizyakov, Marina Gartsbein, Domenico Accili, Tamar Tennenbaum, Efrat Wertheimer

Research output: Contribution to journalArticlepeer-review

Abstract

Altered skin wound healing is a common cause of morbidity and mortality among diabetic patients. However, the molecular mechanisms whereby diabetes alters skin physiology have not been elucidated. In this study, we investigated the relative roles of hyperglycemia, insulin, and IGF-I, all of which are abnormal in diabetes, in primary murine skin keratinocytes. These cells proliferate and differentiate in vitro in a manner similar to skin in vivo. It was found that in the presence of high glucose (20 mmol/1), the glucose transport rate of primary proliferating or differentiating keratinocytes was down-regulated, whereas at 2 mmol/1 glucose, the transport rate was increased. These changes were associated with changes in the GLUT1 expression and with changes in the affinity constant (Km) of the transport. Exposure to high glucose was associated with changes in cellular morphology, as well as with decreased proliferation and enhancement of Ca2+-induced differentiation of keratinocytes. Furthermore, in the presence of high glucose, ligand-induced IGF-I receptor but not insulin receptor (IR) autophosphorylation was decreased. Consequently, in high glucose, the effects of IGF-I on glucose uptake and keratinocyte proliferation were inhibited. Interestingly, lack of IR expression in IR-null keratinocytes abolished insulin-induced glucose uptake and partially decreased insulin- and IGF-I-induced proliferation, demonstrating the direct involvement of the IR in these processes. Our results demonstrate that hyperglycemia and impaired insulin signaling might be directly involved in the development of chronic complications of diabetes by impairing glucose utilization of skin keratinocytes as well as skin proliferation and differentiation.

Original languageEnglish
Pages (from-to)1627-1635
Number of pages9
JournalDiabetes
Volume50
Issue number7
DOIs
StatePublished - Jul 2001

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