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Association of increased hepatic insulin clearance and change in serum triglycerides or ?-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 AUC_{0-120 min} /insulin AUC_{0-120 min} : HIC_CIR ). The correlation of HIC_CIR via the SGLT2-i with other clinical variables was analysed using multivariate analysis.

Results: HIC_CIR was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P CIR were significantly correlated with changes in TG and BHB via TOFO.

Conclusions: Increased HIC_CIR 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.

SUBMITTER: Matsubayashi Y

PROVIDER: S-EPMC7318197 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Matsubayashi Yasuhiro Y Yoshida Akihiro A Suganami Hideki H Osawa Taeko T Furukawa Kazuo K Suzuki Hiroshi H Fujihara Kazuya K Tanaka Shiro S Kaku Kohei K Sone Hirohito H Sone Hirohito H

Diabetes, obesity & metabolism 20200214 6

<h4>Aims</h4>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 ...[more]

PMID: 31984623

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Project description:ObjectiveTofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models.MethodsDiet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated.ResultsIn DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC-UGE-energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone.ConclusionBody weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential to prevent obesity, hepatic steatosis and improve insulin resistance as well as hyperglycemia.

Dataset Information

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

Publications

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

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