Non-carbohydrate anaplerotic therapy counters empagliflozin-induced diabetic ketosis

Background: SGLT2 inhibitors (SGLTi) confer significant cardiometabolic benefits in diabetes, but are associated with increased risk of diabetic ketoacidosis (DKA). We hypothesized that supporting anaplerosis with glycerol could mitigate SGLTi-induced ketosis, enhance insulin-mediated resolution of severe diabetic ketosis, and lower the risk of DKA when used as a dietary supplement. Methods: Insulin-dependent diabetes was induced in yearling sheep using alloxan. The animals subsequently developed severe hyperglycemia (glucose > 500 mg/dL) and hyperketonemia (β-hydroxybutyrate [BHB] > 5 mM), requiring daily insulin therapy for metabolic control and survival. Ketosis was induced by partial insulin withdrawal and with the administration of 10 mg of the SGLT2 inhibitor empagliflozin. Animals were randomly assigned in a cross-over trial to evaluate the effects of intravenous 5% glycerol infusions for the treatment of moderate diabetic ketosis (1.5 mM < BHB < 3.0 mM), and as an insulin-adjunct therapy in cases of severe diabetic ketosis (BHB > 3.0 mM). Longer-term effects of dietary glycerol were assessed by supplementing 5% glycerol in the drinking water of the diabetic sheep under empagliflozin treatment. Data were analyzed using repeated measures ANOVA with a standard least squares fit model in JMP. Results: Intravenous glycerol administration decreased moderate ketosis by 28.5% (P = 0.03), increased glucose by 63.3% (P = 0.04), and enhanced insulin-mediated resolution of severe diabetic ketosis (P = 0.001). Nightly dietary glycerol intake suppressed empagliflozin-induced morning elevations in blood BHB (P = 0.002). Conclusions: Intravenous glycerol reduced empagliflozin-induced ketosis and provided protection against hypoglycemia. When used as an insulin adjunct, it enhanced insulin resolution of severe diabetic ketosis induced by empagliflozin. Dietary glycerol supplementation improved the energetic state and reduced the risk of ketosis in diabetic sheep undergoing SGLTi therapy. These findings may have clinical relevance for DKA management and nutritional prevention, particularly but not necessarily under SGLTi therapy.