Glucose Effects on Skin Keratinocytes

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/l), the glucose transport rate of primary proliferating or differentiating keratinocytes was downregulated, whereas at 2 mmol/l glucose, the transport rate was increased. These changes were associated with changes in the GLUT1 expression and with changes in the affinity constant (K m ) of the transport. Exposure to high glucose was associated with changes in cellular morphology, as well as with decreased proliferation and enhancement of Ca 2؉ -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.

Severely Impaired Insulin Signaling in Chronic Wounds of Diabetic ob/ob Mice

“…Lack of InsR in keratinocytes led to an abrogation of glucose uptake and an impairment of differentiation. 17,18 Additionally, these findings clearly impact nonwounded diabetic skin that was characterized by a markedly reduced expression of InsR.…”

“…In line, skin keratinocytes have been shown to express the insulin receptor (InsR), which is functionally implicated in keratinocyte differentiation and glucose uptake. 17,18 There is increasing evidence for a functional link between insulin resistance, obesity, and diabetes. Initial studies demonstrated an increase in adipocyte-derived tumor necrosis factor (TNF)-␣ in obese rodents that was functionally connected to insulin resistance.…”

Molecular factors involved in skin dryness in diabetic patients

“…Keratynocyty na powierzchni mają m.in. transporter glukozy GLUT1, którego ekspresja obniża się w odpowiedzi na hiperglikemię [9]. Powoduje to powstanie swoistego błędnego koła -mniej glukozy przechodzi do keratynocytów, wzrasta natomiast jej stężenie pozakomórkowe i obniża się ekspresja GLUT1.…”

“…Powoduje to powstanie swoistego błędnego koła -mniej glukozy przechodzi do keratynocytów, wzrasta natomiast jej stężenie pozakomórkowe i obniża się ekspresja GLUT1. Podobna zależność została opisana także dla komórek łożyska, mięśni gładkich i szkieletowych oraz endotelium [9][10][11][12]. W kilku badaniach stwierdzono, że insulina i insulinopodobny czynnik wzrostu 1 (ang.…”

The percutaneous permeability and absorption of dexamethasone esters in diabetic rats: a preliminary study

“…Moreover, the exposure of keratinocytes to high glucose conditions could lead to an inhibition of the proliferation and autophosphorylation of insulin-like growth factor. Therefore, the skin cells proliferation-differentiation balance could be altered by high glucose (Spravchikov et al, 2001), which might affect the functions of the SC (Seirafi et al, 2008). Besides, microcirculation and dysmetabolism are also involved in the diabetic skin damage.…”