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

Background—Ganglioside GM3 mediates adipocyte insulin resistance, but the role of GM3 in diabetic wound healing, a major cause of morbidity, is unclear. Purpose—Determine whether GM3 depletion promotes diabetic wound healing and directly activates keratinocyte insulin pathway signaling. Results—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. Conclusions—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