Mechanism Mediated by S6 Kinase Resulting in both Sufficient Glucose Metabolism Improvement and Insufficient Weight Loss by Glucose Excretion against Fat Load

SGLT2 inhibitors have succeeded in improving prognosis in addition to blood glucose control and weight loss in T2D patients, but the reason is unclear, Systemic metabolic changes when improvement by glucose excretion is not sufficiently elucidated. Here, metabolic respiration balance and insulin signal change were analyzed when the high fat diet-induced insulin resistance was improved with the SGLT2 inhibitor tofogliflozin. 8-week-old male C57/Bl6 mice were divided into 3 groups; normal feed group (N group), 60% high fat (HF) feed group and 3 mg/kg/day tofogliflozin (Tofo) administered group on high fat diet. After 8 weeks of food loading, the body weight increased by 30% in the HF group compared to the N group and by 16% in the Tofo. Both IPGTT and IPITT were improved in the Tofo compared with HF group. In the calorimetric analysis, the heat production increased, the respiratory exchange ratio (RER) decreased, and the RER diurnal variation disappeared in the HF group, while the Tofo reduced the energy consumption to the same level as the N group while maintaining the RER equivalent to the HF group. UCP1 in brown fat was elevated in the HF group and improved in the Tofo. In liver, muscle and fat IRS-1 amount decreased in the HF group and revived in Tofo. Phosphorylation of the basal S6K was enhanced in the HF group and disappeared in the Tofo, while after insulin administration, pAkt and resulting pS6K were accelerated in the Tofo. In conclusion, urinary glucose excretion against high fat load is resulting in improvement of IRS-1 degradation by basal S6Kinase promotes insulin Akt activation. Lipid synthesis is enhanced by insulin while energy expenditure is normalized. Inhibited fat burning compensation leaves weight gain, but since insulin signal has been improved enough, glucose metabolism is improved adequately. This suppression of catabolism might be involved in the improved prognosis by administration of SGLT2 inhibitors. Disclosure T. Kikuchi: None. A. Kushiyama: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Pharmaceutical Co., Ltd, StaGen. Consultant; Self; RIZAP. M. Fujishiro: Research Support; Self; Johnson & Johnson Services, Inc.. H. Sakoda: None. T. Asano: Research Support; Self; Teijin Pharma Limited, Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K. Y. Iwamoto: Board Member; Self; Japan Diabetes Foundation.