Beneficial Effects of Sodium Glucose Cotransporter 2 Inhibition by Canagliflozin Independent of its Glucose Lowering Effects in Type 2 Diabetes Mellitus
Authors: Woods T Cooper , Sato Ryosuke , Miyata Kayoko , Katsurada Akemi , Lightell Daniel , Navar L Gabriel 
Published: November 2023

Type 2 diabetes mellitus (T2DM) is a complex disease where hyperglycemia occurs as a result of the development of insulin resistance. It is often associated with obesity and is characterized by hyperglycemia, hyperinsulinemia, as well as hyperleptinemia. In addition to the problems associated with poor glucose control, T2DM is accompanied by a chronic inflammatory state, leading to a number of associated complications, including renal and cardiovascular injury. The sodium glucose cotransporter 2 (SGLT2) is mainly expressed in renal proximal tubules and is responsible for most of the glucose reabsorption by the tubules. Clinical trials of SGLT2 inhibitors including canagliflozin (CANA) have reported that SGLT2 inhibition lowers systolic blood pressure and attenuates body weight gain in patients with T2DM. However, the mechanisms underlying the beneficial effects of CANA have not been clearly elucidated. This study tested the effects of CANA in a T2DM mouse model which can be used for further studies to investigate the mechanisms. Male New Zealand Obese (NZO) mice were fed with regular fat diet (RFD, 4% fat) or high fat diet (HFD, 40% fat). When the mice fed with HFD exhibited >350 mg/dl blood glucose levels (week 0), both RFD and HFD fed mice were treated with 10 mg/kg/day CANA or vehicle for 6 weeks by daily oral gavage. Systolic blood pressure (SBP) levels were measured by a tail cuff system and 24‐hour urine samples were collected using metabolic cages. Since elevated oxidative stress has been shown to play a crucial role in the development of diabetic nephropathy, urinary 8‐isoprostane levels, a marker of renal oxidative stress, were determined by ELISA. The HFD group achieved significantly increased blood glucose concentrations compared to the RFD group (378.3±27.8 vs. 130.0±14.6 mg/dl, by week 6). CANA treatment resulted in an immediate decrease in blood glucose levels in HFD mice (180.2±7.8 mg/dl by week 1) which was maintained until week 6. CANA treatment did not significantly reduce blood glucose levels in the RFD mice. Mean body weight of RFD and HFD mice on vehicle were 47.8±3.4 and 69.2±2.6 g, respectively. CANA treatment suppressed the body weight gain in both groups (41.0±1.6 and 65.6±2.6 g), suggesting the effect of CANA on body weight gain is independent of blood glucose control. SBP levels in HFD groups were higher than the RFD and RFD+CANA groups (134.7±3.6, 118.7±10.8 and 108.3±7.6 mmHg, respectively) on week 6. The high SBP in HFD was normalized by CANA (110.0±6.0 mmHg). CANA treatment also decreased urinary 8‐isoprostane levels in mice fed with HFD (3.8±1.7 ng/day in HFD group and 1.2±0.3 ng/day in HFD+CANA group on week 1). These results suggest that CANA suppresses the increases in body weight in both healthy and T2DM subjects and attenuates the increased oxidative stress in T2DM subjects. Taken together, these data suggest that some of the cardiovascular benefits of CANA treatment are independent of the glucose lowering mechanisms.

Support or Funding Information

This study is supported by Janssen Pharmaceutica (28431754DIA4010, Navar)