title: Ganglioside GM3 depletion reverses impaired wound healing in diabetic mice by activating IGF-1 and insulin receptors.
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.
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Xiao-Qi
authors: XQ
authors: Wang
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Sarah
authors: S
authors: Lee
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Heather
authors: H
authors: Wilson
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Mark
authors: M
authors: Seeger
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Hristo
authors: H
authors: Iordanov
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Nandita
authors: N
authors: Gatla
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Adam
authors: A
authors: Whittington
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Daniel
authors: D
authors: Bach
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Jian-Yun
authors: JY
authors: Lu
authors: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: apaller@northwestern.edu.
authors: Amy S
authors: AS
authors: Paller
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005679:G(M3) Ganglioside / Q000172:deficiency / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
chemical_list: D005679:G(M3) Ganglioside; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D012799:Sialyltransferases; C021343:haematoside synthetase; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin