Differential Association of Inflammatory Markers and Growth Factors with Type 2 Diabetes and Polyneuropathy—A Multimarker Approach

There is emerging evidence supporting a role of inflammation in the development and progression of diabetic sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes. We aimed to characterize inflammatory signatures associated with DSPN and/or type 2 diabetes using a multimarker approach. We measured 92 serum biomarkers including pro- and anti-inflammatory cytokines, chemokines, and growth factors (GF) using the Proseek Multiplex INF I assay (OLINK Proteomics) in 304 individuals with type 2 diabetes and polyneuropathy, defined by the Toronto Consensus Criteria (2011), from the PROPANE study (DSPN) as well as 158 individuals with type 2 diabetes without DSPN (T2D) and 354 individuals with normal glucose tolerance and without DSPN (CON) from the KORA F4 study (DSPN/T2D/CON [mean±SD]: age: 68±9/71±6/69±5 years; male: 76/59/41%; BMI: 30.8±5.3/30.8±4.4/26.9±3.7 kg/m²; diabetes duration: 13.5±9.6/7.6±5.8/- years; HbA1c: 7.4±1.3/6.6+1.0/5.5+0.3%). After adjustment for multiple testing and sex, age, BMI, and smoking, a biphasic pattern of serum levels (normalized protein expression values) with an increase in T2D and decrease in DSPN was observed for four GFs (e.g., transforming GF (TGF)-α: 4.51±0.51 vs. 4.63±0.56 vs. 3.91±0.51; vascular endothelial GF (VEGF): 10.9±0.5 vs. 11.0±0.5 vs. 10.8±0.6), two chemokines (e.g., C-C motif ligand 4 (CCL4): 8.18±0.57 vs. 8.4±0.6 vs. 7.93±0.68) and one cytokine (oncostatin M: 4.83±0.62 vs. 5.06±0.63 vs. 4.35±0.75). Compared to T2D, the levels of another 12 biomarkers were lower in DSPN (e.g., tumor necrosis factor (TNFSF)-14: 5.65±0.55 vs. 4.90±0.77; matrix metalloproteinase (MMP)-1: 14.4±0.7 vs. 14.1±0.9), while five were higher (e.g., CCL20: 5.2±1.1 vs. 5.79±1.23) (all P In conclusion, deficits in growth factors promoting nerve regeneration/angiogenesis and a complex cross-talk between innate and adaptive immunity may contribute to the development of DSPN in type 2 diabetes. Disclosure G.J. Bonhof: None. A. Strom: None. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S. M. Heier: None. C. Meisinger: None. A. Peters: None. M. Roden: Speaker9s Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. B. Thorand: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. D. Ziegler: None.