Blood glucose fluctuation affects skin collagen metabolism in the diabetic mouse by inhibiting the mitogen-activated protein kinase and Smad pathways

Background. We recently reported that in mice, blood glucose fluctuations (BGF) produced more detrimental effects on skin structure and function than did diabetes alone. Aim. To determine whether treatment of BGF changes the collagen metabolism in the skin of diabetic mice, and to explore its possible molecular mechanism further. Methods. The study used diabetic and BGF animal models. Immunohistochemistry, western blotting and real-time PCR analysis were used to detect the expression of type I collagen, matrix metalloproteinase (MMP)-1, MMP-2 and MMP-13, tissue inhibitor of metalloproteinase (TIMP)-1, extracellular signal-regulated kinase, p38, and Smad2/3. The activities of mitogen-activated protein kinase (MAPK) and Smad signal molecules were also detected by western blotting, and the skin fibroblast ultrastructure was examined using an electron microscope. Results. BGF treatment produced a twofold reduction in type I collagen synthesis compared with diabetes-only mice. Expression of MMP-1, MMP-2 and MMP-13 increased markedly in the BGF-treated mice, but TIMP-1 expression was strongly downregulated by the BGF treatment. There was also evidence of higher levels of apoptosis of skin fibroblasts after BGF treatment. Conclusions. BGF treatment can affect collagen production in the skin of diabetic BGF mice by inhibiting collagen synthesis and increasing collagen degradation. Furthermore, both MAPK and Smad signalling pathways seem to play a role in the inhibition of collagen production in diabetic mice treated with BGF.