Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors.
Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors.
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DOI：
10.1038/jid.2013.532
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发表时间：
2014-05
影响因子：
6.5
通讯作者：
Paller, Amy S.
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Qi;Lee, Sarah;Wilson, Heather;Seeger, Mark;Iordanov, Hristo;Gatla, Nandita;Whittington, Adam;Bach, Daniel;Lu, Jian-yun;Paller, Amy S.
神经节苷脂GM3介导脂肪细胞胰岛素抵抗，但GM3在糖尿病伤口愈合中的作用尚不清楚，这是发病率的主要原因。确定GM3消耗是否促进糖尿病伤口愈合并直接激活角质细胞胰岛素通路信号。GM3合成酶（GM3S）在人糖尿病足皮肤、ob/ob和饮食诱导的肥胖糖尿病小鼠皮肤以及葡萄糖升高的小鼠角质形成细胞中表达增加。饮食诱导的肥胖小鼠GM3S敲除可防止糖尿病创面愈合缺陷。在野生型细胞中，过量的葡萄糖抑制了角质形成细胞的增殖、迁移和胰岛素受体（IR）和胰岛素生长因子-1受体（IGF-1R）的激活，但在补充葡萄糖的GM3S - / -角质形成细胞中增加了。IR、IR底物-1 （IRS-1）和IGF-1R的共免疫沉淀，伴随着受体激活，IRS-1和Akt磷酸化增加。补充GM3或抑制IGF-1R或PI3K可逆转GM3S - / -角质形成细胞迁移的增加，而IR敲低仅部分抑制迁移。皮肤GM3积累可能通过抑制角质细胞胰岛素/IGF-1轴信号参与饮食诱导的糖尿病伤口愈合受损。消耗GM3S/GM3的策略可能会改善糖尿病伤口愈合。
Ganglioside GM3 mediates adipocyte insulin resistance, but the role of GM3 in diabetic wound healing, a major cause of morbidity, is unclear. Determine whether GM3 depletion promotes diabetic wound healing and directly activates keratinocyte insulin pathway signaling. GM3 synthase (GM3S) expression is increased in human diabetic foot skin, ob/ob and diet-induced obese diabetic mouse skin, and mouse keratinocytes exposed to increased glucose. GM3S knockout in diet-induced obese mice prevents the diabetic wound healing defect. Keratinocyte proliferation, migration, and activation of insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R) are suppressed by excess glucose in wild type cells, but increased in GM3S −/− keratinocytes with supplemental glucose. Co-immunoprecipitation of IR, IR substrate-1 (IRS-1), and IGF-1R, and increased IRS-1 and Akt phosphorylation accompany receptor activation. GM3 supplementation or inhibition of IGF-1R or PI3K reverses the increased migration of GM3S−/− keratinocytes, whereas IR knockdown only partially suppresses migration. Cutaneous GM3 accumulation may participate in the impaired wound healing of diet-induced diabetes by suppressing keratinocyte insulin/IGF-1 axis signaling. Strategies to deplete GM3S/GM3 may improve diabetic wound healing.
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