Amaal E Abdulle

Context Systemic inflammation plays a pivotal role in the development of type 2 diabetes (T2D). Objective We hypothesized that circulating levels of calprotectin, a myeloid cell-derived biomarker of inflammation, is associated with the development of new-onset T2D in the general population. Methods A total of 4815 initially nondiabetic participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND), a prospective population-based cohort study, were assessed for plasma levels of calprotectin at baseline. Circulating levels of calprotectin were investigated for potential associations with the risk of new-onset T2D, defined as a fasting plasma glucose level of 7.0 mmol/L or greater, a random plasma glucose level of 11.1 mmol/L or greater, a self-reported physician-based diagnosis of T2D, the use of glucose-lowering drugs, or any combinations thereof. Results Median plasma calprotectin levels were 0.49 (0.35-0.69) mg/L. Plasma calprotectin levels were significantly associated with the risk of new-onset T2D (hazard ratio [HR] per doubling 1.42 [95% CI, 1.22-1.66]; P < .001). The association remained independent of adjustment for age and sex (HR 1.34 [95% CI, 1.14-1.57]; P < .001), but not after further adjustment for potentially confounding factors (HR 1.11 [95% CI, 0.90-1.37]; P = .326), with adjustment for hyperlipidemia and high-sensitivity C-reactive protein explaining the loss of significance. Stratified analyses showed significant effect modification by hypertension, history of cardiovascular disease (CVD), the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (Pinteraction ≤ .001 for each), and the use of lipid-lowering drugs (Pinteraction ≤ .05), with higher HRs in individuals without hypertension, without history of CVD, with below-median HOMA-IR, and in those not using lipid-lowering drugs. Conclusion Elevated plasma levels of calprotectin are associated with a higher risk of developing T2D in the general population and may represent a moveable inflammatory biomarker. This association, however, does not represent a direct effect, and seems dependent on hyperlipidemia and systemic inflammation.

Puffy fingers and Raynaud’s phenomenon (RP) are important clinical predictors of the development of systemic sclerosis (SSc). We aim to assess the prevalence of SSc-related symptoms, explore pulmonary symptoms, and test the usefulness of skin autofluorescence (SAF) as a non-invasive marker for Advanced Glycation Endproducts (AGEs). Subjects from the Lifelines Cohort Study with known connective tissue disease (CTD) were excluded. Patient characteristics, SAF, self-reported pulmonary symptoms, and spirometry were obtained. Subjects (n = 73,948) were categorized into definite RP (5.3%) with and without SSc-related symptoms and non-RP. Prevalence of at least one potential SSc-related symptom (other than RP) was 8.7%; 23.5% in subjects with RP and 7.1% without RP (p < 0.001). Subjects with RP and additional SSc-related symptoms more frequently reported dyspnea at rest, dyspnea after exertion, and self-reported pulmonary fibrosis, and had the lowest mean forced vital capacity compared to the other groups (RP without SSc-related symptoms and no RP, both p < 0.001). In multivariate regression, dyspnea at rest/on exertion remained associated with an increased risk of SSc-related symptoms in subjects with RP (both p < 0.001). SAF was higher in subjects with RP and SSc-related symptoms compared to the other groups (p < 0.001), but this difference was not significant after correction for potential confounders. The prevalence of SSc-related symptoms was approximately three-fold higher in subjects with RP. Pulmonary symptoms are more prevalent in subjects with RP who also reported additional potential SSc-related symptoms. This might suggest that (suspected) early SSc develops more insidiously than acknowledged. According to this study, SAF is no marker for early detection of SSc.

Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) have been associated with acute kidney injury and the severity and progression of chronic kidney disease (CKD). This study investigated its potential utility as a biomarker for the risk of new-onset CKD in a population-based cohort study. Individuals without CKD at baseline (n = 4660) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma NGAL concentrations were investigated for their associations with new-onset CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, urinary albumin excretion (UAE) > 30 mg/24-h, or both. Mean (±SD) plasma NGAL concentrations were 104.0 (±34.7) μg/L and median eGFR was 96 [IQR: 85.3–105.8] mL/min/1.73 m2. After median follow-up of 8.3 [IQR: 7.8–8.9] years, 467 participants developed new-onset CKD. Plasma NGAL concentrations were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.35 [95% CI: 1.11–1.63], p = 0.002), even after adjustment for potentially confounding factors (1.37 [1.09–1.73], p = 0.007) except baseline eGFR (1.09 [0.86–1.37], p = 0.490). In secondary analyses, plasma NGAL concentrations were significantly associated with new-onset CKD as defined by eGFR < 60 mL/min/1.73 m2 alone (adjusted HR per doubling 2.54 [1.69–3.80], p < 0.001), which was abrogated after adjustment for eGFR (1.05 [0.69–1.59], p = 0.828), also when UAE > 30 mg/24-h was set as individual outcome (1.05 [0.82–1.35], p = 0.705). Higher plasma NGAL concentrations are associated with an increased risk of developing CKD in the general population. This association is dependent on renal function, and mainly driven by new-onset CKD as defined by renal function decline.