Dapagliflozin Treatment Impacts ß, but Not a, Cell Function in Normal Human Islets

Dapagliflozin (DAPA), a selective Sodium Glucose Cotransporter-2 (SGLT2) inhibitor, is widely used for the treatment of type 2 diabetes (T2D). In T2D individuals, DAPA increases plasma glucagon, decreases insulin secretion, and improves muscle insulin sensitivity. DAPA has been reported to increase glucagon secretion in cultured normal human islets possibly because SGLT2 was more highly expressed in α cells. To investigate DAPA effect on human islets in vivo, we transplanted normal human islets (n=3 donors) into immunodeficient mice and treated them with DAPA (2mg/kg/day) or NaCl by oral gavage for 4 weeks. Basal blood glucose (NaCl vs. DAPA: 101±8 vs. 85±5 mg/dL, p=0.0858), glucagon (199.5±24.4 vs. 169.9±15.9 pg/mL, p=0.3107), and human insulin (1.15±0.17 vs. 0.99±0.14 ng/mL, p=0.4626) levels were similar in both groups. However, 15 minutes after glucose challenge, DAPA-treated mice had lower blood glucose (375±21 vs. 287±16 mg/dL, p=0.003), unchanged glucagon (86±14 vs. 75±8 pg/mL, p=0.4883), but lower human insulin levels (2.05±0.24 vs. 0.96±0.ng/mL, p Disclosure C. Dai: None. A. Shostak: None. Y.H. Bouchi: None. N. Hart: None. G. Poffenberger: None. D.C. Saunders: None. R. Haliyur: None. D. Dean: None. R. Aramandla: None. M. Brissova: None. M. Shiota: None. D.L. Greiner: Consultant; Self; The Jackson Laboratory, Allakos, Inc. L.D. Shultz: None. R. Bottino: None. A.C. Powers: None.