Sodium glucose co-transporter 2 inhibitors (SGLT2i) show promise as an add-on to insulin therapy in patients with type 1 diabetes (T1D), however their effect on glucagon secretion in T1D is not yet known. Increases in glucagon have the potential to protect against hypoglycemia that may develop from insulin overtreatment or exercise. We investigated whether 8 days of SGLT2i treatment (10mg/kg empagliflozin, 2x/day) altered plasma glucagon concentrations in response to voluntary running wheel activity and insulin-induced hypoglycemia in male and female Wistar rats with streptozotocin-induced T1D. SGLT2 inhibition did not alter basal or post-exercise glucagon concentrations and did not affect exercise-associated changes in blood glucose (BG) levels. Additionally, SGLT2 inhibition did not alter voluntary activity levels. However, in males, SGLT2 inhibition lowered plasma glucagon response during an insulin tolerance test (+22.7±30.8 pg/mL vs. +40.4±48.6 pg/mL, p=0.02) and decreased the time taken to reach hypoglycemia (30±13.4 min vs. 63.8±17.2 min, p<0.0001), as compared to placebo. We also observed novel sex differences in the response of BG and glucagon concentrations to voluntary exercise. In female rats alone, voluntary exercise decreased BG concentrations (-2.9±2.6 mM vs. +1.7±1.8 mM, p=0.0003) and led to lower post-exercise glucagon concentrations (37.3±47.9 pg/mL vs. 117.9±86.0 pg/mL, p=0.01), as compared to inactive animals. On average, voluntary activity levels were higher in females than in males (539.2±199.4 m vs. 308.4±215.6 m, p=0.02), however running distances were not correlated with changes in BG levels during exercise (r2=0.02). Our finding of increased hypoglycemia risk with SGLT2i has concerning implications for its use as an adjunct to insulin therapy in T1D. The novel sex differences that we observed should be investigated in individuals with T1D to determine their human applicability and potential mechanisms.


C.A. Greenberg: None. E.R. Mandel: None. A.M. Pasieka: None. M. Jahangiriesmaili: None. J. Tremblay: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc.

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