Association of increased hepatic insulin clearance and change in serum triglycerides or β-hydroxybutyrate concentration via the sodium/glucose-cotransporter 2 inhibitor tofogliflozin

Abstract

Aims: Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose-cotransporter 2 inhibitors (SGLT2-is) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2-is on hepatic insulin clearance. We examined the impact of an SGLT2-i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2-i and the mechanism of the effects of SGLT2-i. Materials and methods: Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2-i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C-peptide and insulin levels derived from oral meal tolerance test data (C-peptide AUC0-120 min/insulin AUC0-120 min: HICCIR). The correlation of HICCIR via the SGLT2-i with other clinical variables was analysed using multivariate analysis. Results: HICCIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P < 0.001) and β-hydroxybutyrate (BHB) was significantly elevated (P < 0.001). Changes in HICCIR were significantly correlated with changes in TG and BHB via TOFO. Conclusions: Increased HICCIR was significantly associated with reduced TG via TOFO and contributed to the greater increase in BHB compared with placebo in addition to the correction of hyperinsulinaemia.