Reduced insulin sensitivity is the putative defect in the onset of type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) can restore euglycemia and improve insulin sensitivity in individuals with T2D. However, the mechanisms contributing to surgical remission of T2D are not fully understood. Growth Differentiating Factor 15 (GDF15) is a circulating stress-responsive cytokine with appetite suppressive properties and therapeutic potential for treating obesity and T2D. However, the effect of GDF15 on insulin sensitivity is not known. The purpose of this investigation was to assess the role of GDF15 in insulin sensitivity in type 2 diabetic populations and to evaluate the effect of exogenous GDF15 treatment in obese diabetic mice. Twelve human volunteers with T2D (age: 40±2, BMI: 46.2±1.7) underwent RYGB surgery. Glucose tolerance and fasting plasma GDF15 levels were assessed prior to and 3-month post-surgery. Additionally, 8-week-old db/db mice were injected every other day for 4 weeks with saline or rhGDF15. After 4 weeks of treatment, body composition, insulin tolerance, and blood metabolites were assessed. Plasma GDF15 significantly increased after RYGB (PRE: 581.6±93.0 POST: 910.1±137.4 pg/ml, P<0.001). Change in GDF15 in humans with T2D correlated with improvements in insulin sensitivity based on the Matsuda index (R=0.6, P=0.05). Supporting our human data, 4 weeks of GDF15 treatment in db/db mice increased insulin sensitivity (P<0.05) while body weight (P<0.01), fasting blood glucose (P<0.05) and plasma insulin (P<0.05) were reduced. In conclusion, GDF15 is associated with improved insulin sensitivity in humans with T2D, and increases insulin sensitivity in db/db mice. These data support a role for GDF15 as a therapeutic target for type 2 diabetes. Disclosure H. Zhang: None. W. Dantas: None. W.T. King: None. C.L. Axelrod: None. S. Gil: None. I. Murai: None. H. Roschel: None. B. Gualano: None. J.P. Kirwan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; Louisiana Clinical & Translational Science Center