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.