Effects of Empagliflozin Treatment on Glycerol‐Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial

Abstract

The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol. Methods: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C 3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models. Results: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerolderived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss. Conclusions: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.

Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state

“…During an IR state, the high turnover rate of mesenteric Tg delivers glycerol and NEFAs directly into the portal circulation and provides both energy and a gluconeogenic substrate for liver gluconeogenesis [63,64]. A recent well-organized double-blind randomized study investigated the possible role of empagliflozin, so as to increase blood glucose exogenous glycerol-derived 13 C, by reducing endogenous glycerol-derived hepatic gluconeogenesis from VAT of obese individuals [65]. A total of 35 participants (mean body mass index (BMI): 35 kg/m 2 ) were included in the final analysis (18 received empagliflozin 10 mg daily and 17 matching placebo) for 3 months.…”

“…A VAT-specific mechanism could explain this effect, since glycerol-derived 13 C enrichment in glucose was not associated with meaningful body weight loss. VAT reduction and associated lower levels of endogenous glycerol and/or phosphoenolpyruvate carboxykinase-derived substrates could serve as possible underlying mechanisms [65,66].…”

Do SGLT2 Inhibitors Improve Cardio-Renal Outcomes in Patients With Type II Diabetes Mellitus: A Systematic Review

“…The other beneficial effect of SGLT2 inhibitors is their promotion of sodium excretion in urine that causes osmotic diuresis and reduced blood pressure [4,5]. These drugs reduce endogenous glycerol-derived hepatic gluconeogenesis from visceral adipose tissue causing weight loss [6]. One of the renal protective mechanisms of SGLT2 inhibitors is in albuminuria where it reduces intraglomerular pressure and prevents subsequent tubular cell injury [7].…”

SGLT2 Inhibition, Visceral Adiposity, Weight, and Type 2 Diabetes Mellitus

“…In this issue of Obesity , Neeland et al (5) studied the effects of VAT on glycerol‐derived 13 C enrichment in glucose, and whether such effects are affected by empagliflozin, by performing an eloquent randomized placebo‐controlled trial in individuals with visceral obesity. Thirty‐five individuals with a median BMI of 35 were enrolled.…”

“…The mechanisms through which empagliflozin increases glycerol‐derived 13 C enrichment in glucose are largely unknown; however, the authors have hypothesized that they are mediated by the reduction of the endogenous glycerol‐derived hepatic gluconeogenesis from VAT (5). In conclusion, the results of this study suggest that 1) VAT is associated with increased lipolysis, which results in greater delivery of glycerol to the liver to be used for gluconeogenesis, ultimately resulting in chronic hyperglycemia, especially in a fasting state; and 2) empagliflozin may reduce such by VAT‐induced increase in gluconeogenesis.…”