Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models.

M Suzuki,A Kito,M Yamane,Y Kawabe,M Yamamoto,K Honda,T Yata,T Nagata,Y Suzuki,T Fukuzawa,M Takeda,M Fukazawa

doi:10.1038/nutd.2014.20

Abstract

Objective:Tofogliflozin, 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.Methods:Diet-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.Results:In 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.Conclusion:Body 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.

Highlights

More than 340 million people worldwide have diabetes mellitus,[1] B90% of whom have Type 2 diabetes (T2D)
We assumed that the calorie loss (B13 kcal per day) was greater than the increase in calorie intake (B10 kcal per day), and the deduced total calorie balance decreased by B3 kcal per day in the TOFO group as compared with the high-fat diet (HFD) group
Excess body weight gain was attenuated with tofogliflozin in both obese Diet-induced obese (DIO) rats and diabetic KKAy mice

Summary

Introduction

More than 340 million people worldwide have diabetes mellitus,[1] B90% of whom have Type 2 diabetes (T2D). Epidemiological studies identify obesity as a major risk factor for T2D,2,3 and intraabdominal adiposity is profoundly associated with the pathogenesis of T2D via inflammation in adipose tissues, insulin resistance and impaired glucose regulation caused by fat accumulation.[4,5] diet and exercise are regarded as an important strategy to prevent and delay progression of T2D.6. It is difficult to control body weight and plasma glucose solely by diet and exercise.[7,8]. Glucagon-like peptide 1 analogues can reduce body weight,[13] they are used via subcutaneous self-injection and have gastrointestinal side effects. An orally available antidiabetic that can control both plasma glucose and body weight is required for T2D patients

Methods

Results

Conclusion