Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes.
Level 3 - non-randomized controlled study
Controlled clinical comparative study evaluating mechanistic metabolic responses in non-diabetic individuals alongside a previously reported cohort with type 2 diabetes.
PubMed 26861783 · doi:10.2337/db15-1356
What was done
Investigators evaluated the metabolic consequences of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in 25 subjects without diabetes and compared them with 66 previously reported patients with type 2 diabetes (T2D). Fasting and postmeal glucose fluxes were measured using a double glucose tracer technique. Lipolysis was estimated via [2H5]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides; lipid oxidation was measured using indirect calorimetry; and ketogenesis was assessed via circulating β-hydroxybutyrate levels following acute (first dose) and chronic (4 weeks) administration.
What was found
In both non-diabetic individuals and patients with T2D, empagliflozin increased endogenous glucose production (EGP), decreased tissue glucose disposal (TGD), and stimulated lipolysis, lipid oxidation, and ketogenesis. The response pattern in non-diabetic participants mirrored that in T2D patients but was quantitatively smaller. Compared to acute dosing, 4 weeks of chronic treatment attenuated glucose flux responses while enhancing lipid responses; fasting β-hydroxybutyrate concentrations in patients with T2D rose from 246 ± 288 to 561 ± 596 µmol/L (P < 0.01).
Why it matters
This study demonstrates that glycosuria induced by SGLT2 inhibition causes a fundamental shift in fuel metabolism from carbohydrate to fatty substrate utilization and ketogenesis, driven in part by a lowered insulin-to-glucagon ratio, irrespective of diabetes status.
Limits
The study includes a modest non-diabetic sample size (n = 25) and relies on historical/previously published data for the 66 T2D comparators rather than a single concurrently randomized trial. The abstract reports specific numerical values for β-hydroxybutyrate in T2D patients only, omitting exact numerical values and confidence intervals for non-diabetic lipid and glucose flux changes.
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