SPHK1 and diabetic retinopathy: In addition, S1P has been proposed to signal through S1PRs, in a paracrine fashion, upregulating the transcription of SphK1 and thus activating the S1P/SphK1 axis; this “outside-in” signaling pathway has been shown to contribute to the progression of diabetic retinopathy (Huang et al., 2014).