Markers of chronic low-grade inflammation and serum cytokine levels in patients with type 1 diabetes: associations with time in ranges and glucose variability

Abstract

BACKGROUND: Increased glucose variability is recognized as a risk factor for vascular diabetic complications. It is assumed that deteriorating effect of GV on blood vessels can be realized through the activation of inflammatory signaling pathways.AIM: to determine associations of low-grade inflammation markers and serum cytokines with time in ranges and GV parameters derived from continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D).MATERIALS AND METHODS: In 470 adult patients with T1D, high-sensitivity C-reactive protein (hsCRP) and fibrinogen was measured, neutrophil-lymphocyte ratio (NLR) and the Systemic Immune-inflammation Index (SII) were calculated. In a sample of 130 patients and 20 healthy individuals (control), serum concentrations of interleukins (IL-1β, IL-4, IL-6, sIL-6Rα, IL-19, IL-20, IL-22, IL-26, IL-27, IL-28A, IL-29, IL-32, IL-34, IL-35) were assessed by multiplex analysis. Time in the ranges and GV parameters: Coefficient of Variability (CV), Mean Amplitude of Glycemic Excursions (MAGE), and Mean Absolute Glucose rate of changes (MAG) were derived from CGM data.RESULTS: Patients with Time In Range (TIR) <70% had higher concentrations of hs-CRP and fibrinogen, higher SII values, and demonstrated a trend toward higher TIR compared with those with TIR ≥70% (p=0.018, p=0.026, p=0.037, p=0.101, respectively). Patients with T1D, when compared to control, demonstrated increased concentrations of IL-1β (p<0.0001), IL-6 (p<0.0001), decreased levels of IL-4 (p=0.002), and a tendency to decrease IL-22 and IL-29 (p=0.1). Patients with TIR>70% had higher levels of IL-4 (p=0.02) as well as lower concentrations of IL-1β (p=0.0003) and IL-6 (p=0.007) than patients with TIR≤70%. In a multivariate stepwise regression analysis including clinical data and CGM parameters as independent variables, body mass index was positive predictor of hsCRP and fibrinogen levels, TIR was negatively associated with IL-20 and IL-34, time above range was associated positively with IL-1β, MAGE showed positive association with SII, IL-26 and IL28A, while MAG was positively associated with IL-29.CONCLUSION: T1D patients with non-target TIR (<70%) have higher levels of low-intensity inflammatory markers and serum pro-inflammatory cytokines than patients with TIR>70%. Both hyperglycemia and increased GV are associated with intensity of low-grade inflammation in T1D.