The major results of the present study were; 1) In T2D subjects plasma S1P was significantly increased in response to the anti-diabetic drug, rosiglitazone; 2) Plasma S1P correlated with measures of improved glucose homoeostasis; 3) Glucose homeostasis was exacerbated in HFD-fed S1PR3−/− mice compared to HFD-fed WT counterparts; 4) The worsened metabolic phenotype of HFD-fed S1PR3−/− mice was mechanistically related to inflammation in the adipose and liver and increased hepatic steatosis; 5) S1P promoted adipogenesis in 3T3-L1 preadipocytes, potentially via S1P3. This evidence concerns the gene S1PR3 and type 2 diabetes mellitus.