Ganglioside GM3 Depletion Reverses Impaired Wound Healing in Diabetic Mice by Activating IGF-1 and Insulin Receptors

Abstract

BackgroundGanglioside GM3 mediates adipocyte insulin resistance, but the role of GM3 in diabetic wound healing, a major cause of morbidity, is unclear.PurposeDetermine whether GM3 depletion promotes diabetic wound healing and directly activates keratinocyte insulin pathway signaling.ResultsGM3 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.ConclusionsCutaneous 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.

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

“…6) (28). As the literature shows, IGF-I has strong adipogenic and anti-inflammatory properties (21,24,30,32,66,70,75,80), as does adiponectin (14,47,63,68), whereas leptin is known to be proinflammatory and adipolytic (7,14,47). IL-6, another cytokine known to have proinflammmatory and adipolytic properties (34,40,42), was also consistently decreased following BAT transplants.…”

“…2) (27), adiponectin and IGF-I are likely to exert stronger effects on the overall equilibrium. Other reported benefits of IGF-I include repair of damaged tissue, inhibition of apoptosis, improved wound healing, angiogenesis, and cell proliferation (4,12,21,30,32,39,66,70,75), all of which are important in the regeneration of healthy adipose tissue in T1D.…”

The Roles of Growth Factors in Keratinocyte Migration

“…41 The insulin/IGF-1 signaling axis in KCs has recently been shown to be regulated by GM3 ganglioside, which is increased in diabetic epidermis, suggesting a direct link between KC membrane lipid components and insulin/IGF-1-induced KC migration. 43 IGF-1 signaling is also regulated extracellularly by IGF binding proteins (IGFBP), which bind and restrict IGF-1 from interacting with IGF1R. The IGFBPs, in turn, are regulated by the activity of matrix metalloproteinases (MMP), indicating multiple levels of regulation for IGF-1 signaling in KCs.…”

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

“…Ganglioside-monosialic acid 3 (GM3), the predominant sialylated glycosphingolipid in skin, has recently been recognized to be a critical mediator of insulin resistance (4)(5)(6)(7)(8)(9)(10)(11)(12). Indeed, we have recently shown three-and fourfold more GM3 synthase (GM3S; also known as SAT-I or ST3Gal-V), which is required for the synthesis of GM3, in diabetic human plantar skin than in site-and age-matched control skin (4).…”

“…Indeed, we have recently shown three-and fourfold more GM3 synthase (GM3S; also known as SAT-I or ST3Gal-V), which is required for the synthesis of GM3, in diabetic human plantar skin than in site-and age-matched control skin (4). Similarly, skin samples from the backs of diet-induced obese (DIO) and ob/ob mouse diabetic models show increased GM3S mRNA expression and GM3 levels.…”