Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction

Sodium‐glucose cotransporter 2 inhibitors ( SGLT 2i) exert their antidiabetic effects by promoting urinary glucose excretion. Nutrition therapy is obviously important, but little is known about the interactions between SGLT 2i agents and carbohydrate restriction. Therefore, we studied these interactions using an obese diabetic animal model. KK ‐A y mice were pair‐fed normal chow [ NC ; carbohydrate: fat: protein = 65:15:20], low carbohydrate [ LC ; 43:42:15] or severely carbohydrate restricted diets [ SR ; 12:45:43] for 12 weeks. Tofogliflozin (Tofo) was administered as the SGLT 2i in the NC and LC diet groups. Blood glucose levels were significantly increased in the SR group. Tofo reduced blood glucose levels significantly in the NC group during the experiment and in the LC group at 2‐6 weeks. Plasma triglycerides were markedly elevated in the SR group without Tofo, but decreased in response to Tofo administration. Hepatic triglyceride contents were not changed by the LC or the SR diet alone. However, Tofo ameliorated hepatosteatosis in NC ‐fed animals. Consistent with the downregulation of stearoyl‐CoA desaturase 1, the ratio of plasma monounsaturated to saturated fatty acids was significantly reduced in the LC with Tofo and in the SR alone groups, but was not altered in the NC with Tofo group. In summary, metabolism of glucose and lipids was improved by Tofo but not by the SR diet. Furthermore, Tofo improved these parameters more effectively in the NC than in the LC diet group. These data suggest that the effects of SGLT 2i are distinct from those of carbohydrate restriction and that a nonrestricted dietary carbohydrate composition is essential for SGLT 2i treatment to be effective.