TY - JOUR

T1 - Effects of SGLT2 inhibition on lipid transport in adipose tissue in type 2 diabetes

AU - Lauritsen, Katrine M

AU - Voigt, Jens Hohwü

AU - Pedersen, Steen Bønløkke

AU - Hansen, Troels K

AU - Møller, Niels

AU - Jessen, Niels

AU - Gormsen, Lars C

AU - Søndergaard, Esben

PY - 2022/4

Y1 - 2022/4

N2 - SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blind, placebo-controlled crossover design of four weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal subcutaneous adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect FFA uptake in abdominal subcutaneous adipose tissue, but increased FFA uptake in visceral adipose tissue by 27% (p<0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (p=0.03) and mRNA content (p=0.01) in abdominal subcutaneous adipose tissue, but without affecting glucose uptake. In addition, SGLT2 inhibition decreased expression of genes involved in insulin signaling in adipose tissue. We concludethat SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal subcutaneous adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

AB - SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blind, placebo-controlled crossover design of four weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal subcutaneous adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect FFA uptake in abdominal subcutaneous adipose tissue, but increased FFA uptake in visceral adipose tissue by 27% (p<0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (p=0.03) and mRNA content (p=0.01) in abdominal subcutaneous adipose tissue, but without affecting glucose uptake. In addition, SGLT2 inhibition decreased expression of genes involved in insulin signaling in adipose tissue. We concludethat SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal subcutaneous adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

U2 - 10.1530/EC-21-0558

DO - 10.1530/EC-21-0558

M3 - Journal article

C2 - 35234661

VL - 11

JO - Endocrine Connections

JF - Endocrine Connections

SN - 2049-3614

IS - 4

M1 - e210558

ER -