Abstract
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Highlights
Diabetes mellitus has seen an extensive global increase, which had been predicted nearly a decade ago [1]
The observed impaired glucose tolerance in high fat diet (HFD)-treated mice was accompanied by a hyperinsulinaemic state and markedly raised levels of circulating leptin (Figure 1(c)), which both represent welldescribed features of a developing HFD-induced type 2 Diabetes mellitus in mice [27]
Using the endothelial marker CD31 to detect wound angiogenesis, we showed that wound vascular endothelial growth factor (VEGF) signals appeared to be translated into a robust angiogenic response only in chow diet (CD) mice (Figure 6(c), left panel)
Summary
Diabetes mellitus has seen an extensive global increase, which had been predicted nearly a decade ago [1]. Diabetic skin ulcerations represent a severe complication of the disease, and more important, a still unmet medical problem associated with significant mortality [2, 3]. The lifetime risk for any diabetic patient to develop this complication is about 15% [4]. Diabetic ulcers have a poor prognosis and the 3-year survival rate after amputations are only between 50 and 59% [5, 6]. Predisposing factors (neuropathy, ischemia), which lead to foot ulceration [7], are all but impossible to imitate using the respective animal models of wound healing. Diabetic and obese rodents have long been used as animal models to unravel molecular and cellular mechanisms that might form the basis of or at least contribute to diabetes-disturbed wound conditions
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