Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes

Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [¹⁸F]FDG positron emission tomography/computed tomography (PET/CT) and [¹¹C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, μmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, μmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, μmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10⁻⁹ min⁻¹, p < 0.01) and glucose effectiveness (2.6 × 10⁻² ± 0.3 × 10⁻² vs. 2.4 × 10⁻² ± 0.3 × 10⁻², dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.