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神经节苷脂 GM3 耗竭通过激活 IGF-1 和胰岛素受体逆转糖尿病小鼠的伤口愈合受损。

Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors.

机构信息

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

出版信息

J Invest Dermatol. 2014 May;134(5):1446-1455. doi: 10.1038/jid.2013.532. Epub 2013 Dec 10.

DOI:10.1038/jid.2013.532
PMID:24326453
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3989402/
Abstract

Ganglioside GM3 mediates adipocyte insulin resistance, but the role of GM3 in diabetic wound healing, a major cause of morbidity, is unclear. The purpose of this study was to determine whether GM3 depletion promotes diabetic wound healing and directly activates keratinocyte (KC) insulin pathway signaling. GM3 synthase (GM3S) expression is increased in human diabetic foot skin, ob/ob and diet-induced obese diabetic mouse skin, and in mouse KCs exposed to increased glucose. GM3S knockout in diet-induced obese mice prevents the diabetic wound-healing defect. KC 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 (-/-) KCs 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(-/-) KCs, whereas IR knockdown only partially suppresses migration.

摘要

神经节苷脂 GM3 介导脂肪细胞胰岛素抵抗，但 GM3 在糖尿病创面愈合中的作用尚不清楚，而糖尿病创面愈合不良是发病率的主要原因。本研究旨在确定 GM3 耗竭是否能促进糖尿病创面愈合，并直接激活角质细胞（KC）胰岛素通路信号。人糖尿病足皮肤、ob/ob 肥胖和饮食诱导肥胖的糖尿病小鼠皮肤以及暴露于高糖环境中的小鼠 KC 中 GM3 合成酶（GM3S）表达增加。饮食诱导肥胖的 GM3S 敲除小鼠可预防糖尿病创面愈合缺陷。在野生型细胞中，过量葡萄糖会抑制 KC 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（-/-）KC 中则会增加。IR、IR 底物 1（IRS-1）和 IGF-1R 的共免疫沉淀以及 IRS-1 和 Akt 的磷酸化增加伴随受体激活。GM3 补充或 IGF-1R 或 PI3K 抑制可逆转 GM3S（-/-）KC 的迁移增加，而 IR 敲低仅部分抑制迁移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/70824dabaa46/nihms546938f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/fb63bd3013b5/nihms546938f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/1847adedbecc/nihms546938f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/6e6868531ad5/nihms546938f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/d78c2f79c354/nihms546938f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/70824dabaa46/nihms546938f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/fb63bd3013b5/nihms546938f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/1847adedbecc/nihms546938f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/6e6868531ad5/nihms546938f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/d78c2f79c354/nihms546938f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ae69/3989402/70824dabaa46/nihms546938f5.jpg

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