Gangliosides in Diabetic Wound Healing

An organized series of complicated biological and molecular phenomena is required for normal skin wound healing. These processes depend on normal cellular responses to cytokines, growth factors, and other mediators, such as clotting factors, prostaglandins, free radicals, and nitric oxide. In diabetic ulcers, impaired responses to these molecules lead to abnormalities in vascularization, innervation, matrix reconstruction, and reepithelialization of wounds. keratinocyte migration and proliferation on an extracellular matrix is critical in reepithelialization, but the response to growth factors is blunted in diabetes, including the insulin/IGF-1signaling axis. Ganglioside GM3, a sialylated epidermal glycosphingolipid, has been identified as a key mediator of the inhibition of insulin/IGF-1 signaling in response to factors, such as tumor necrosis factor-alpha (TNF-alpha) and hyperglycemia. Decreased expression of GM3 and the enzyme required for its synthesis, GM3 synthase (GM3S), leads to increased insulin/IGF-1 receptor signaling and accelerated keratinocyte migration, even in the presence of high glucose levels. GM3 depletion in GM3S knockout diabetic mice and diet-induced diabetic mice treated topically with nanoconstruct-mediated GM3S-targeting gene regulation also accelerates wound healing. These recent observations, coupled with evidence that GM3 depletion reverses distal innervation abnormalities in diabetic mice, suggest that GM3-depleting strategies are a promising new approach for human diabetic wounds.