Background  
Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) superfamily. In people with type 2 diabetes, GDF15 is elevated and related to diabetic complications , such as diabetic retinopathy, and diabetic nephropathy [1-3]. While the association of GDF15 and major adverse cardiovascular events (MACE) is not significant after adjustment of cardiovascular risk factors [1]. A Mendelian randomization study also reported that GDF15 was not associated with type 2 diabetes and coronary artery disease risk factors [4]. Therefore, the relationship between GDF15 and cardiovascular diseases in people with type 2 diabetes still need more studies to confirm.

Aim  
This study aims to investigate the relationship between circulating GDF15 and mortality including all-cause, cardiovascular, and cancer death in Chinese aging people with type 2 diabetes using the long-term follow-up data of the Da Qing Diabetes Study.

Method  
A total of 510 subjects from the Da Qing Diabetes Study with type 2 diabetes were enrolled in the present study. The circulating GDF15 in 2006 or 2009 were assessed. Outcomes of all-cause, cardiovascular, and cancer mortality were followed in 2016 (mean follow-up of 7.5 years). Time-to-event survival curves for each outcome were created using the cumulative incidence method, and comparisons between the groups were performed with log-rank tests. Cox proportional hazards regression was used for the estimation of hazard ratios (HRs) and their 95% confidence intervals (CIs) for death.

Results  
At the end of the follow-up, 143 (28.0%) subjects died and 54.5% (78/143) were cardiovascular death. The cumulative incidence of all-cause death in the third tertile group was higher than that in the lowest level group (58.6% [95% CI 43.7 – 73.6] vs 19.6% [95% CI 12.7 – 26.5], log-rank p &lt; 0.0001). Compared to the first tertile group of GDF15, the risk of all-cause death (HR = 3.27, 95% CI [1.90 – 5.64]), and cardiovascular death (HR = 3.11, 95% [1.45 – 6.67]) in the third tertile group increased more than two folds, even after adjustment of age, sex, smoking, SBP, LDL-c, HbA1c, duration of diabetes, and CVD history. Increased GDF15 level (per 1 SD increase) related to a higher risk of cancer death in all subjects (HR = 2.25, 95%CI [1.34 – 3.80]) and those without CVD (HR = 2.88, 95%CI [1.59 – 5.24]) after adjustment of traditional risk factors.

Discussion  
In the present study, an elevated level of GDF15 is related to the higher risk of all-cause, cardiovascular, and cancer death in Chinese aging people with type 2 diabetes. The results of all-cause and cardiovascular death were consistent regardless of CVD history. Expression of GDF15 was upregulated in response to many stimuli, and involved in cell stress, such as responding to ischemia in cultured cardiomyocytes[5]. The substantial mechanism may be the protective role of GDF15 in the disease process, including insulin resistance regulation, anti-apoptosis [6], and anti-inflammation [7]. These data provide more insight into the prevention of diabetic complications especially the primary and secondary prevention of cardiovascular death. The predictive power of GDF15 deserves more attention.

References  
[1] Carlsson AC, Nowak C, Lind L, Ostgren CJ, Nystrom FH, Sundstrom J, et al. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach. Ups J Med Sci. 2020;125:37-43. https://doi.org/10.1080/03009734.2019.1696430.[2] Conte M, Sabbatinelli J, Chiariello A, Martucci M, Santoro A, Monti D, et al. Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging. Geroscience. 2021;43:985-1001. https://doi.org/10.1007/s11357-020-00287-w.[3] Niu Y, Zhang W, Shi J, Liu Y, Zhang H, Lin N, et al. The Relationship Between Circulating Growth Differentiation Factor 15 Levels and Diabetic Retinopathy in Patients With Type 2 Diabetes. Front Endocrinol (Lausanne). 2021;12:627395. https://doi.org/10.3389/fendo.2021.627395.[4] Au Yeung SL, Luo S, Schooling CM. The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study. Diabetologia. 2019;62:1638-46. https://doi.org/10.1007/s00125-019-4913-2.[5] Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res. 2006;98:351-60. https://doi.org/10.1161/01.RES.0000202805.73038.48.[6] Heger J, Schiegnitz E, von Waldthausen D, Anwar MM, Piper HM, Euler G. Growth differentiation factor 15 acts anti-apoptotic and pro-hypertrophic in adult cardiomyocytes. J Cell Physiol. 2010;224:120-6. https://doi.org/10.1002/jcp.22102.[7] Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE, Ahasic AM, et al. GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance. Cell. 2019;178:1231-44 e11. https://doi.org/10.1016/j.cell.2019.07.033.



Circulating GDF15 Predicted Mortality in Aging Chinese People with Type 2 Diabetes: Findings from Da Qing Diabetes Study