Caloric Restriction combined with SGLT2 Inhibitor Improves Glucose Tolerance Independent of Reduced SBP or Triglycerides in Obese, Insulin Resistant Rats
Authors: Cornejo Manuel Alejandro , Montes Iris Dayana , Asghar Syed Asad , Escobedo Benny , Nishiyama Akira , Ortiz Rudy Martin 
Published: June 2021

Inhibition of sodium‐glucose cotransporter 2 (SGLT2), a transporter highly expressed in the renal proximal tubules, decreases plasma glucose by increasing urinary excretion. For this reason, SGLT2 inhibitors are emerging as a novel therapy for T2DM [1]. When used in monotherapy, these inhibitors present low risk for hypoglycemia, preserved islet mass, and improved insulin sensitivity [2]. Current data suggest improvement in cardiovascular health as well; however, the use of this drug is not advised in the event of low‐carbohydrate diets, extreme insulin deficiency or cachexia [3]. Our hypothesis is that a mild caloric restriction (30%) combined with SGLT2i treatment, will improve metabolic syndrome and SBP without hypoglycemia, insulin deficiency, or cachexia.

Fourteen lean Long Evans Tokushima Otsuka (LETO) rats, and twenty‐eight obese, insulin resistant Otsuka Long Evans Tokushima Fatty rats (OLETF) of 10 weeks of age were fed ad libidum during 4 weeks. After that time, they were randomly assigned into A) LETO (n=14), B) OLETF (n=14) and C) OLETF with SGLT2i (n=14; 10 mg/kg/d of luseogliflozin × 2 wks) groups. After the 2 weeks, the three groups were divided into either ad lib control (n=7) or caloric restriction (CR; n=7; 2 wks), which were given 70% food intake of the control groups. After the 2 wks CR, 24 hr urine samples were collected, rats were subjected to an oral glucose tolerance test (oGTT), and dissected 3 days later.

Mass (Fig. 1) and food intake were recorded daily. Systolic, diastolic, and mean arterial pressure were measured by tail‐cuff plethysmography twice per week (n=6). Blood glucose and plasma insulin were measured at 0, 5, 10, 30, 60 and 120 min during oGTT. Both AUC for glucose and insulin concentrations were multiplied to obtain the IRI (Fig. 2)

Mean mass for OLETF Control and OLETF SGLT2i increased without significant differences, and all CR groups maintained their baseline body mass. Differences in blood pressure were significant between LETO and OLETF, but not among groups. Fasting glucose increased with CR in both LETO (69±3 vs 74±3 mg/dl), and OLETF (93±5 vs 95±3 mg/dl), but decreased in OLETF SGLT2i (105±3 vs 93±6 mg/dl). Mean IRI in OLETF SGLT2i was higher than OLETF fed ad lib (13.1±1.4 vs 12.5±0.8 RI), but significantly lower in CR (14.5±1.0 vs 9.7±0.9 RI). 24h glucose urine excretion decreased 41.3% in CR vs Control in OLETF SGLT2i. Mean plasma triglyceride concentrations were significantly different between strains, but not among OLETF groups.

In conclusion, IR was ameliorated when SGLT2 was combined with CR, but had no profound effect on SBP or plasma triglycerides. CR, concomitant to SGLT2i, resulted in an unexpected decrease in urinary glucose excretion without fasting hypoglycemia. These results suggest the possibility of a relatively safe and more efficient treatment combining SGLT2i and CR.

Support or Funding Information

We thank the graduate students and staff from the Department of Pharmacology at Kagawa University for their assistance during this study. This research was funded by a doctoral fellowship from the University of California Institute for Mexico and the United States and Mexico's National Council for Science and Technology (UC MEXUS‐CONACYT) and a Minorities Health and Health Disparities International Research Training Fellowship.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.