Significant increase of serum extracellular vesicle-packaged growth differentiation factor 15 in type 2 diabetes mellitus: a cross-sectional study

Abstract

Background: Growth differentiation factor 15 (GDF15) is a stress-inducible factor involved in the inflammatory progression of many complications, including type 2 diabetes mellitus (T2DM). Growing evidence suggests that molecules in extracellular vesicles (EVs) are associated with diabetes or diabetes-related complications. However, the correlation between serum extracellular vesicle-derived growth differentiation factor15 (EV-GDF15) and T2DM is unknown. The aim of this cross-sectional study is to investigate whether serum EV-GDF15 is associated with T2DM incidence.

Methods: 116 individuals, including 78 T2DM and 38 non-T2DM, were recruited as participants. The concentrations of serum EV-GDF15 and serum GDF15 were determined by Luminex assay. Serum EVs were obtained by ultracentrifugation. Multivariate stepwise regression analysis was used to determine the association between serum GDF15 levels and fasting plasma glucose (FPG) as well as glycated hemoglobin (HbA1c). The association of serum EV-GDF15 levels with T2DM was determined by multivariate logistic regression analysis.

Results: Our data showed that the levels of serum EV-GDF15 and serum GDF15 were significantly increased in T2DM patients compared with non-T2DM subjects (EV-GDF15 levels, 13.68 (6.61-23.44) pg/mL vs. 5.56 (3.44-12.09) pg/mL, P < 0.001; and serum GDF15 levels, 1025.49 (677.87-1626.36) pg/mL vs. 675.46 (469.53-919.98) pg/mL, P < 0.001). There was a linear correlation between EV-GDF15 levels and fasting plasma glucose (FPG) and Hemoglobin A1C (HbA1c) levels (normalized β = 0.357, P < 0.001; normalized β = 0.409, P < 0.001, respectively). Elevated levels of EV-GDF15 were accompanied by an increase in the proportion of patients with T2DM (from 47.5 to 78.9%) and a progressive independent association with the incidence of T2DM (from OR = 3.06, 95% CI 1.02-9.19, P = 0.047 to OR = 3.75, 95% CI 1.14-12.26, P = 0.029). Notably, high levels of serum GDF15 plus high levels of serum EV-GDF15 were significantly associated with T2DM more than either alone.

Conclusion: This study elucidated that increased levels of GDF15 in serum EVs were independently associated with T2DM.

Keywords: Biomarker; Extracellular vesicles; Growth differentiation factor 15; Serum; Type 2 diabetes mellitus.