Effects of SGLT-2 Inhibitors and Visceral Fat on Glucose Metabolism

INTRODUCTION: Abdominal obesity and excess visceral adiposity (VAT), have strong associations with insulin resistance, hyperglycemia and type 2 diabetes. A previous pilot study showed that participants with high VAT have less 13C enrichment in glucose reflecting an abundant endogenous substrate pool from adipose turnover for gluconeogenesis, compared with participants with low VAT. This study aims to evaluate the effects of a SGLT-2 inhibitor known to modify markers of VAT on gluconeogenic pathways in the liver. METHODS: Obese adults without diabetes were stratified into high and low VAT groups based on MRI (high n=8, low n=7). After an overnight fast, participants were administered non-radioactive labeled glycerol, and blood samples were collected to calculate glycerol enrichment at sequential time points over 180 minutes. Participants were then randomized to receive empagliflozin 10 mg daily or matching placebo for 3 months and glycerol studies were repeated. RESULTS: High VAT subjects demonstrated a significantly lower enrichment of ingested glycerol in blood glucose, when compared to low VAT individuals for the 60-180 minute interval (p <0.001). During this same time interval, pentose phosphate pathway activity was significantly decreased in high VAT, compared to low VAT subjects (p<0.01). The effects of empagliflozin on these pathways are currently being analyzed. DISCUSSION: SGLT-2 inhibitors inhibit renal glucose reabsorption in the proximal nephron, inducing weight loss and decreasing systolic blood pressure. This medication has been suggested to reduce CVD event rate and lower hemoglobinA1c levels up to 1%. Observed differences in pathways between high visceral fat subjects on a SGLT-2 inhibitor compared to control high visceral fat subjects could provide insight into the physiologic changes provided by SGLT-2 inhibitors.