Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

Abstract

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.

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

“…20 Furthermore, no alterations in glucose uptake between the intervention group and the placebo group were identified. Comparable findings were reported by both Sato et al and Kern et al, showing the constancy of unaltered glucose uptake in skeletal muscle during a hyperinsulinemic-euglycemic clamp in humans 21 and mice. 22 Conversely, a recent study animal study reported decreased [ 18 F]FDG uptake in skeletal muscle within a diabetic mice model treated with dapagliflozin compared to controls.…”

“…Empagliflozin did not affect LPL activity 10.1 (CI95% 7.1-15.2) versus 12.6 (CI95% 8.9-18.0) μmol FFA/hour/g tissue, p = 0.10 (Figure 3E). In addition, empagliflozin did not change protein content of GLUT4 (30 ± 12 vs. 33 ± 13%, p = 0.30), HK-II (16)(17)(18)(19)(20)(21)(22)(23)(24)…”

“…Therefore, our estimates may have been affected by changes in c-peptide clearance or extrahepatic insulin clearance. However, no effect of SGLT2 inhibition on whole-body insulin clearance was recently observed in a study by Sato et al 21 The potential consequences of an increased hepatic insulin clearance remain to be fully understood, but studies consistently show that hepatic insulin clearance is reduced to the degree of the prevalent glucose intolerance (insulin resistance) in humans. 30,31 Therefore, the observed increase in hepatic insulin extraction could represent a reversal of one of the pathophysiological abnormalities observed with insulin resistance.…”

The sodium–glucose cotransporter 2 inhibitor ipragliflozin improves liver function and insulin resistance in Japanese patients with type 2 diabetes

“…All patients in our study were Japanese; therefore, our results contribute to everyday clinical work in the Asian population. A recent Japanese study indicated that the SGLT2i tofogliflozin did not change whole-body insulin clearance 30 . According to these results, SGLT2i treatment mainly increases hepatic insulin clearance, not whole-body insulin clearance.…”