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

Abstract

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<0.0001). The ratio of human insulin/blood glucose was lower in the DAPA group (0.52±0.07 vs. 0.36±0.04, p=0.0322). Ultrastructure of transplanted human islets showed that the DAPA treatment decreased the % immature granules (52±2% vs. 43±2%, p=0.0109) but increased the % empty granules (5.7±0.6% vs. 13.7±0.7%, p<0.0001) in β cells. To investigate if these changes were a consequence of improved insulin sensitivity or DAPA’s direct effect on β cells, we assessed insulin secretion by culturing human islets (n=3 donors) in 3.3 mM and 16.7 mM glucose with DAPA (0.5 μM) or NaCl for 1 hour. DAPA treatment had no effect on glucagon secretion at both glucose concentrations but reduced insulin secretion by 30% at 16.7 mM glucose (p=0.0259). By transcriptional profiling SGLT2 was expressed equally in α and β cells. These data suggest that DAPA does not directly affect glucagon secretion but has a direct impact on human β cell function. 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.