Introduction: SGLT2-inhibitors improve beta-cell glucose sensitivity (BGS) and insulin sensitivity in patients with type 2 diabetes (T2D) . This effect has been attributed to relief of glucotoxicity, but very few studies have controlled for differences in glycemia. Here, we explore the effects of empagliflozin on BGS and secondarily, peripheral insulin sensitivity (IS) , compared to similar glycemic control with insulin treatment.
Materials and Methods: 17 subjects with T2D (13 males, 58±3 years (mean±sem) , BMI 32.9±0.9 kg/m2, HbA1c 52.4±2.4 mmol/L, T2D duration 8.9±1.3 years) were treated with empagliflozin (E) and NPH-insulin (I) for 5 weeks in a randomized cross-over study design with 3 weeks of washout. Insulin was titrated to obtain similar glycemic control as with empagliflozin. An OGTT with stable iv and oral glucose tracers was performed prior to and at the end of each treatment.
Results: Glycemia was similarly reduced on both treatments (Δfasting glucose: E: -1.3±0.2, p<0.01; I: -0.8±0.2, p<0.01; E vs. I: p=NS) . Fasting insulin concentrations were lower with empagliflozin and higher with insulin (E: 92±12 vs. 180±27 pmol/L, p<0.001) . Fasting hepatic glucose production (HGP) was increased with empagliflozin compared to insulin (19.5±0.8 vs. 16.6±0.6 µmol/kg/min, p<0.001) , but postprandial HGP did not differ between treatments. BGS was greater with empagliflozin compared to insulin (0.82±0.1 vs. 0.59±0.pmol/ (kg·min·mM) , p=0.001) . IS (AUC Glucose Rd, tissue /AUC Insulin) was unchanged with empagliflozin, but decreased with insulin compared to washout (0.09±0.vs. 0.11±0.02 µmol/ (kg FFM·pM·min) , p=0.025) . Fatty tissue insulin resistance (Adipo-IR: fasting FFA x fasting insulin) was lower with empagliflozin compared to insulin (77±vs. 110±17 mmol/L x pmol/L, p=0.012) .
Conclusion: Improved beta-cell function during empagliflozin treatment is not a result of reduced glucotoxicity. Peripheral hyperinsulinemia may induce insulin resistance.
R.Thirumathyam: None. E.A.Richter: None. J.Goetze: Consultant; Novo Nordisk A/S. P.L.Madsen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. S.Madsbad: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S.
Boehringer Ingelheim Gmbh Investigator initiated study grant